Until recently, investigations on the fire resistance of steel joints have been neglected by structural engineers under the arguments that the design resistance of connections at room temperature is usually higher than the resistance of the connected members and that the temperature increases more slowly in the joint zone (high concentration of mass, low exposure to radiative fluxes) than in the adjacent beams and columns. However, brittle failures of connection components have been observed especially during the cooling phase of real fires for two main reasons: the high sensitive and nonreversible character of the resistance of bolts and welds at elevated temperatures and the development of high tensile thrusts. The present thesis is a contribution to the understanding of the thermomechanical behaviour of simple connections in steel beam-to-column joints subjected to natural fire conditions, with a special attention to the behaviour of these connections during the cooling phase. The distribution of temperature in joints has been analysed by use of numerical models built in SAFIR software. The simplified methods presently mentioned in the Eurocodes are discussed and new methods, calibrated on the results of numerical simulations, are proposed in the present work to predict the temperature profile in steel beams and joints covered by a flat concrete slab under fire. An existing method aimed at evaluating the distribution of internal forces in restrained steel beams (and by extension, in joints) under natural fire has been analysed in detail. Several modifications have been added in order to improve his method and to extend its field of application. The final version of this analytical method has been implemented and validated against numerical results. An experimental programme aimed at characterising the mechanical behaviour of bolts and welds under heating and subsequent cooling is described in the present thesis. The properties of the tested specimens, the thermal loading applied to these specimens, the test set-ups and the results of the tests are reported in detail. Mechanical models for bolts loaded in tension or in shear have been calibrated on the experimental results. The loss of resistance of bolts and welds due to their non-reversible behaviour under heating and subsequent cooling has been quantified. Finally, a large part of the thesis is dedicated to the development of component-based models representing the action of common simple connections under natural fire conditions and to the analysis of the behaviour of these connections as a part of a sub-structure or large-scale structure. These simple models can be used for parametric analyses because it conciliate a reasonable time of definition of the data, an acceptable time of simulation and a good degree of accuracy of the results. Recommendations for the design of connections have been defined. The ductility of connections has a major influence on the occurrence of connection failures and classes of ductility for connections, dependant of the fire loading, have been defined in this work. / Jusque très récemment, la recherche sur la résistance au feu des assemblages métalliques a été délaissée par les ingénieurs sous le prétexte que la résistance de calcul des assemblages à froid est habituellement supérieure à celle des éléments connectés et que léchauffement est plus lent dans la zone dassemblage que dans les poutres et colonnes adjacentes (grande concentration de matière, exposition réduite aux flux radiatifs). Toutefois, les ruptures fragiles de composants dassemblages sont observées, notamment durant la phase de refroidissement pour deux raisons principales : caractère sensible et non-réversible des boulons et des soudures aux élévations de température et apparition defforts de traction importants. La présente thèse sinscrit comme une contribution à la compréhension des phénomènes gouvernant le comportement des assemblages simples poutre-poteau sous conditions de feu naturel. Une attention spéciale est portée au comportement de ces assemblages durant la phase de refroidissement. La distribution de température dans les assemblages a été analysée grâce à des modèles numériques mis au point dans le programme SAFIR. Les méthodes simplifiées actuellement mentionées dans les Eurocodes actuels sont discutées et de nouvelles méthodes, calibrées sur les résultats numériques, sont proposées dans ce travail pour prédire le profil de température dans les poutres et assemblages métalliques couverts dune dalle en béton sous feu. Une méthode existante destinée à évaluer la distribution des efforts internes dans les poutres en acier restraintes (et par extension, dans les assemblages) sous feu naturel a été analysée en détail. Plusieurs modifications ont été proposées pour améliorer cette méthode et étendre son champ dapplication. La version finale de cette méthode analytique a été implémentée et validée avec des résultats numériques. Une série de tests expérimentaux destinée à caractériser le comportement mécanique des boulons et des soudures sous échauffement et refroidissement est décrite dans cette présente thèse. Les propriétés des spécimens testés, le traitement thermique qui leur est appliqué, le montage des essais et les résultats obtenus sont rapportés en détail. Des modèles mécaniques pour les boulons soumis à traction ou cisaillement sont calibrés sur les mesures expérimentales. La perte de résistance des boulons et des soudures causée par leur comportement non-réversible sous échauffement et refroidissement a été quantifiée. Finalement, une large part de la thèse a été dédiée au développement de modèles basés sur la méthode des Composantes pour représenter laction des assemblages simples courants sous feu naturel et lanalyse de leur comportement dans une sous-structure ou une structure complète. Ces modèles simples permettent de concilier un temps de définition des données raisonnable, un temps de calcul acceptable et un bon niveau de précision des résultats. Des recommandations pour le dimensionnement des assemblages ont été énoncées. Il est démontré que la ductilité des connections a une influence majeure sur lapparition de ruptures dans les assemblages et des classes de ductilité, dépendant du chargement au feu, ont été définies dans ce travail.

Aflatoxins are potent carcinogens produced by the fungus Aspergillus flavus Link:Fr and are a significant preharvest problem in maize production in Texas, the southern US, and subtropical climates. Several sources of maize germplasm are available which reduce preharvest aflatoxin accumulation, but many of these sources lack agronomic performance for direct use as a parent in commercial hybrids. Tropical germplasm is a source of both resistance to aflatoxin accumulation resistance and agronomic performance traits. The goal of this study was to investigate germplasm for traits to reduce preharvest aflatoxin accumulation. The specific objectives of this research were: 1) to validate QTL estimates previously identified in lines per se and estimate new QTL associated with reduced aflatoxin accumulations and agronomic traits; 2) to evaluate agronomic characteristics of selections from a RIL population in testcrosses at multiple locations across Texas; and (3) to release agronomically desirable germplasm sources with reduced risk to preharvest aflatoxin accumulation. A total of 96 QTLs were detected across fourteen measured traits using an RIL population of 130 individuals in testcross hybrids evaluated in five environments. Three QTL detected in per se analyses were also detected in hybrid testcrosses. Previously unreported QTL were detected on chromosomes 3, 4, 8 and 9. Within each of the two years, neither subset of the RIL testcross hybrids produced grain yields equal to commercial hybrid checks in these trials, but one testcross in 2008 produced grain yield within 10 percent of commercial check hybrids and in 2009, five RIL testcrosses produced grain yield within 17 percent of the commercial check hybrids. Although RIL testcrosses did not yield more than the commercial checks, they will be a source of germplasm for reduced aflatoxin. Improved sources of maize germplasm lines Tx736, Tx739, and Tx740 have been selected for adaptation to southern US and Texas growing environments with traits that reduce aflatoxin accumulation. Each of the lines in testcross accumulated significantly fewer aflatoxins than commercial hybrids in the trial.

The main purpose of this study was to explore, analyze and reflect on the meaning, nature, causes and associated dynamics of change in higher education within a Pakistani cultural context. Resistance was a major component of understanding this change. I focused on multiple factors that induced individual/group tendencies to resist or avoid making changes and to devalue change generally. This study employed a multiple case study approach. Semi-structured interviews with designated stakeholders of the planned change initiative were the primary data-collection method. Document analysis, members check and observations were used to triangulate the interview data. The data were analyzed on an ongoing basis. The findings revealed the complex dimensions of participants’ compliance and/or resistance with respect to change at the beginning of the twenty-first century when the Pakistani higher education system was shifting dramatically from a local to global perspective. Despite serious issues and weaknesses, change was gradual over time and the most strongly contested reforms were those that did not align with existing practices. In sum, the findings support the notion that change is complicated, and that the reasons for this complexity stem from factors that are structural, emotional, political and personal. The results of this study will be of interest to administrators and educators as they prepare for future challenges within the Pakistani context. The theoretical and practical implications of these findings are discussed, and directions for future research are identified.

Graduation date: 1993

This cross-sectional study described antimicrobial resistance (AMR) in healthy pigs in 20 Alberta and Saskatchewan herds. All herds used antimicrobials; the daily probability of antimicrobial exposure was 0.8 for nursery pigs and 0.3 for grow-finish pigs. Salmonella spp. (n = 468) were isolated from nursery, grow-finish pigs and sows while <i>Escherichia coli</i> (n = 1439) and <i>Campylobacter</i> spp. (n = 405) were isolated from grow-finish pigs. <p>Fifty-nine percent of the Salmonella were pansusceptible. Isolates from sows were more likely to be pansusceptible than those from other production phases, while Salmonella from nursery pigs were more likely to be multiresistant. All Salmonella and E. coli were susceptible to ceftriaxone and ciprofloxacin, drugs critically important to human medicine, while one E. coli was resistant to ceftiofur. Resistance was most common to tetracycline and sulfamethoxazole (Salmonella, 35% and 27%; E. coli, 68% and 46%). Although often considered an indicator organism, <i>E. coli</i> AMR was a poor sentinel for Salmonella AMR at the herd-level. <p>Antimicrobial resistance genes, described in 151 <i>E. coli</i>, were associated in two sets: aadA1 / sul1 / tetA and blaTEM / strA strB / sul2 / tetB. Associations between genes consistently matched associations between phenotypes suggesting phenotype data may be useful for predicting co-selection. Demonstrating dose-response relationships between various antimicrobial exposures and resistance phenotypes in E. coli reiterated the importance of co-selection. Significant predictors included exposures in other production phases and to unrelated drugs. Four <i>E. coli </i> resistance-phenotypes were associated with macrolide exposure; the most commonly used antimicrobial class in study herds. Additionally, 70% of the Campylobacter were resistant to a macrolide and this resistance was associated with macrolide exposure in nursery pigs. Study herds did not use quinolones. Despite this, 15% of Campylobacter were resistant to a quinolone. Both Campylobacter and <i>E. coli</i> AMR clustered within herds, indicating on-farm interventions could mitigate AMR in pigs.<p>This study described AMR in enteric bacteria from healthy pigs. Identifying dose-response relationships between antimicrobial resistances and exposures to unrelated drugs, and exposures of pigs in different production phases, emphasize the importance of judicious antimicrobial use in pig production.

A fundamental challenge in evolutionary biology and medical genetic research is to connect the phenotype (a disease in humans or an adaptive trait in animals or plants) with the genotype. Using a classical example of an adaptive trait with a strong Mendelian genetic basis - warfarin resistance in the Norway rat (Rattus norvegicus), my dissertation tests the main hypothesis that speculated ‘simple’ adaptive trait has a more complex genetic architecture. Warfarin is an anticoagulant rodenticide used since the 1950s, and also is a widely prescribed blood-thinning drug in human. As a rodenticide, warfarin has initially been very effective. However, resistant rodents have evolved quickly and Vkorc1 (vitamin K epoxide reductase complex subunit 1) is the known resistance gene. As a popular drug, warfarin has a narrow therapeutic window with several genes VKORC1, CYP2C9, CYP4F2 established as biomarkers predicting warfarin dose in humans, suggesting a complex genetic architecture of warfarin resistance in rodents. In my thesis I performed network-guided genomic association studies (NetGWAS) and gene expression analysis to identify candidate genes involved in warfarin resistance based on a sample of ~600 wild rats from 19 populations in Germany. My thesis work revealed that the resistance mutation in Vkorc1 likely is under balancing selection and was recently introduced to the rat population in our study area. A key innovation of my thesis is adopting a NetGWAS approach to prioritize true associations and conducting co-expression network analysis to detect expression changes related to warfarin. My work shows that additional candidate genes are connected to the vitamin K pathway of which Vkorc1 is an essential component. While the validation of identified genes remains a challenge, the value of my thesis for future investigation is shown: one candidate gene Calu (Calumenin) is associated with warfarin resistance in multiple populations and is an essential part of the vitamin K cycle. Finally, my thesis briefly examines the genetics underlying a newly postulated cost of resistance, arterial calcification. This dissertation provides us an innovative framework in which we learned the genetic architecture of an adaptive trait in multiple dimensions: nucleotide or expression variation, genomic distribution and gene-gene interactions.

This cross-sectional study described antimicrobial resistance (AMR) in healthy pigs in 20 Alberta and Saskatchewan herds. All herds used antimicrobials; the daily probability of antimicrobial exposure was 0.8 for nursery pigs and 0.3 for grow-finish pigs. Salmonella spp. (n = 468) were isolated from nursery, grow-finish pigs and sows while <i>Escherichia coli</i> (n = 1439) and <i>Campylobacter</i> spp. (n = 405) were isolated from grow-finish pigs. <p>Fifty-nine percent of the Salmonella were pansusceptible. Isolates from sows were more likely to be pansusceptible than those from other production phases, while Salmonella from nursery pigs were more likely to be multiresistant. All Salmonella and E. coli were susceptible to ceftriaxone and ciprofloxacin, drugs critically important to human medicine, while one E. coli was resistant to ceftiofur. Resistance was most common to tetracycline and sulfamethoxazole (Salmonella, 35% and 27%; E. coli, 68% and 46%). Although often considered an indicator organism, <i>E. coli</i> AMR was a poor sentinel for Salmonella AMR at the herd-level. <p>Antimicrobial resistance genes, described in 151 <i>E. coli</i>, were associated in two sets: aadA1 / sul1 / tetA and blaTEM / strA strB / sul2 / tetB. Associations between genes consistently matched associations between phenotypes suggesting phenotype data may be useful for predicting co-selection. Demonstrating dose-response relationships between various antimicrobial exposures and resistance phenotypes in E. coli reiterated the importance of co-selection. Significant predictors included exposures in other production phases and to unrelated drugs. Four <i>E. coli </i> resistance-phenotypes were associated with macrolide exposure; the most commonly used antimicrobial class in study herds. Additionally, 70% of the Campylobacter were resistant to a macrolide and this resistance was associated with macrolide exposure in nursery pigs. Study herds did not use quinolones. Despite this, 15% of Campylobacter were resistant to a quinolone. Both Campylobacter and <i>E. coli</i> AMR clustered within herds, indicating on-farm interventions could mitigate AMR in pigs.<p>This study described AMR in enteric bacteria from healthy pigs. Identifying dose-response relationships between antimicrobial resistances and exposures to unrelated drugs, and exposures of pigs in different production phases, emphasize the importance of judicious antimicrobial use in pig production.

Many studies have attempted to link antimicrobial use in food animal agriculture with an increased risk of antimicrobial-resistant (AR) bacterial levels in humans. Our data arise from longitudinal aggregated fecal samples in a 3-year cohort study of vertically integrated populations of human workers and consumers, and swine. Human and swine E. coli isolates (N = 2130 and 3485, respectively) were tested for antimicrobial susceptibility using the SensititreTM broth microdilution system. The associations between AR prevalence for each antimicrobial agent, multi-drug resistant E. coli, or multivariate AR E. coli, and the risk factors (host species, production type (swine), vocation (human swine worker versus non-worker), and season) in the study were assessed using generalized estimating equations (GEE), GLM with multinomial distribution, or GEE in a multivariate model using a SAS® macro to adjust for the correlated AR phenotypes. There were significant (p < 0.05) differences in AR isolates: 1) between host-species with swine at higher risk for ceftiofur, chloramphenicol, gentamicin, kanamycin, streptomycin, sulfisoxazole, and tetracycline. The prevalence of ciprofloxacin, nalidixic acid, and trimethoprim/sulfamethoxazole resistance were higher among human isolates, 2) swine production group was significantly associated with AR with purchased boars, nursery piglets, and breeding boars at a higher risk of resistance to streptomycin and tetracycline, and 3) human swine worker cohorts exhibited an elevated tetracycline prevalence, but lowered sulfisoxazole prevalence when compared to nonworkers. High variability among seasonal samples over the 3-year period was observed. There were significant differences in multiple resistance isolates between host species, with swine at higher risk than humans of carrying multi-resistant strains; however, no significant differences in multiple resistance isolates within humans by vocation or within swine by production group. The odds-ratios, adjusted for multivariate dependence of individual AR phenotypes, were increased relative to unadjusted oddsratios among 1) swine as compared to human for tetracycline (OR = 21.8 vs. 19.6), and 2) increased significantly among swine-workers as compared to non-workers only for tetracycline (OR = 1.4 vs. 1.3). Occupational exposure to swine-rearing facilities appears to be associated with an increased relative odds for the prevalence of tetracycline resistance compared to non-workers.

Previous analysis of the bovine SLC11A1 complementary DNA (cDNA) failed to identify any nucleotide variations other than a microsatellite length variation within the 3' untranslated region functionally associated with bovine brucellosis. In this study I set out to identify mutations in the genomic complement of the gene that may be associated with resistance or susceptibility to bovine brucellosis, and to determine if the microsatellite length polymorphism in the 3'UTR of bovine SLC11A1 modulates gene expression and subsequent disease resistance in a phase dependent manner. The results of this study demonstrate that there are seventy-five total single nucleotide polymorphic (SNP) sites (excluding indels) located within the bovine genomic SLC11A1 sequence of a Brucella abortus resistant bull and a susceptible cow. Twenty of these SNPs segregated between resistant and susceptible populations, with 3 non-synonymous SNPs significantly associating with resistance or susceptibility to B. abortus infection. An A695G within exon 2 resulted in a histidine (resistant allele) to arginine (susceptible allele) amino acid substitution and was in significant linkage disequilibrium with the previously described 3' untranslated region (UTR) microsatellite length variation associated with brucellosis resistance. A transcriptional element search in the 3' UTR revealed a ETS-domain PU.1 site, an IFN-γ activation site (GAS), an Interferon Consensus Sequence Binding Protein site (ICSBP) and several Initiation Response sites (Inr), suggesting a possible function for this region in regulation of the expression of SLC11A1. A mobility shift assay confirmed sequence-specific DNA-protein interaction within this region. A luciferase reporter assay indicated that the 3'UTR of SLC11A1 could act as a downstream enhancer for expression. Macrophage killing assays with RAW264.7 cells expressing bovine SLC11A1 demonstrated that the microsatellite repeat is functionally associated with the macrophage killing efficiency, but not in a phase-dependent manner, suggesting that these length polymorphisms do not affect the angular orientation between cooperatively binding transcription factors, and leaves the possibility that the 3'UTR microsatellites regulate SLC11A1 transcription through some alternate mechanism, possibly mRNA stability.

Cancer remains the most cause death disease in Taiwan at least ten years. Liver cancer, which consists predominantly of hepatocellular carcinoma (HCC), is the most common cause of cancer mortality in men and the second most in women. Not only liver section and liver transplantation are used in HCC therapy but also local ablation therapy and transarterial therapy. Transarterial chemoembolization (TACE) is one of the local therapies that inject chemotherapeutic drugs directly into liver tumor. However, drug resistance is the mainly restriction in patient after chemotherapy. Moreover, it is known that drug resistance was associated to over-expression of certain ABC transporter genes, especially ABCB1, ABCG2, and ABCC family in cancer cell and those ABC transporters were also expressed in liver. Base on clinical study, they use 5-fluororuacil, cisplatin and mitomycin-C for liver cancer treatment. In this study, we hypothesized that cancer therapies may be augmented through blocked the drug efflux ABC channels with the ABC transporter inhibitors such as verapamil. The associations among drug treatments, inhibitor incorporation and the expression of ABC transporters were evaluated in HepG2 and Hep3B cells. MTT assay demonstrated that the cell viability was considerable decreased by treating triple drugs with verapamil. RT-PCR data showed that ABC transporters mRNA expression has no significantly change. However, membrane ABCB1 and ABCG2 were induced after drugs and inhibitors treatment either 1 or 24 hours by flow cytometry analysis. P-glycoprotein functional assay also showed p-glycoprotein was inhibited by verapamil, and hence Rhodamine 123 retention was increased. Taken together, there are different response of ABC transporters in HepG2 and Hep3B after drugs and inhibitors treatment. Membrane ABCB1 and ABCG2 were induced by drugs and inhibitors treatment. However, p-glycoprotein¡¦s function was restrained simultaneously by inhibitors treatment. Therefore, verapamil can enhance cell death by inhibiting ABC transporters and its cytotoxic effect rather than the increased expression of ABC transporters. This finding might provide a better way in liver cancer therapy.