A recent clinical trial for locally advanced breast cancer patients treated with epirubicin and docetaxel prior to surgery reported significant dose-dependent reductions in tumour RNA integrity values which correlated with pathological complete response. The purpose of the present study was to assess whether similar chemotherapy-dependent alterations in RNA integrity could occur in vitro and to assess its relationship, if any, to apoptosis. Treatment of wildtype A2780 ovarian carcinoma cells with taxanes resulted in dose- and time-dependent RNA degradation, identified as several unique bands on electropherograms having mobilities lower than the 28S and 18S rRNAs. We refer to this chemotherapy-dependent generation of aberrant RNA bands on electropherograms as “RNA disruption”. RNA disruption was found to be temporally associated with the induction of apoptosis, as determined by the appearance of a sub G1 peak of DNA content, positive annexin-V staining, and both PARP-1 and caspase-3 cleavage. Treatment of cells with a caspase-3 inhibitor resulted in a significant reduction in rRNA disruption, suggesting the involvement of caspase-3 or related caspases in RNA disruption. In contrast, docetaxel-dependent rRNA disruption was absent when docetaxel was administered to docetaxel-resistant A2780DXL cells, indicating that changes in RNA integrity may possibly differentiate between responsive and non-responsive tumours in cancer patients.

Previous research has demonstrated that exposure to family disruption/father absence (due to parental relationship dissolution) is a significant risk factor for early pubertal development in daughters. Moreover, the earlier in life that this exposure occurs, the greater the risk of these outcomes for girls. Two opposing classes of explanation have been proposed for this reliable finding. First, evolutionary-based developmental experience models have proposed that father absence may actually cause early pubertal development in daughters through mechanisms that remain to be elucidated. Second, this association may arise from either a genetic or a family-wide environmental confound. To discriminate between these two competing classes of explanation (i.e., causal vs. noncausal), a retrospective study employing a community sample of full biological sister pairs was conducted in New Zealand. This study examined menarchael age in (a) a primary group comprising age-discrepant biologically disrupted/father absent sister pairs (n = 68), and (b) a matched control group comprising age-discrepant biologically intact/father present sister pairs (n = 93). According to the causation model, if greater exposure to family disruption/father absence causes earlier pubertal development in girls, then in families in which (a) full biological sisters are discrepant in age, and (b) the younger sister has experienced more prolonged father absence than has her older sister, younger sisters should be at greater risk for earlier pubertal development. By contrast, if a genetic or family-wide environmental confound explains this association, full biological sisters should not systematically differ in pubertal timing as a function of birth order, even if they have experienced different amounts of father absence. The unique contribution of the current study to this area of inquiry is its employment of a differential sibling exposure design to test the explanatory value of the two opposing classes of explanation (i.e., causal versus noncausal). This genetically and environmentally controlled sibling design was utilised (a) to test the central hypothesis that the birth order/age discrepancy (older versus younger) between sisters would interact with family type (biologically disrupted vs. biologically intact) to predict the size of sibling differences in menarcheal age, and (b) to test for potential moderating effects of paternal dysfunction. Consistent with evolutionary causal models, the current sibling comparison study revealed that within biologically disrupted/father-absent families, younger sisters (who had more prolonged exposure to father absence) had earlier menarcheal ages than did their older sisters. The current study was therefore not only able to distinguish between the two competing classes of explanations, but its findings plausibly supported a causal rather than a noncausal explanation for the association between father absence and earlier pubertal timing in girls. Moreover, it revealed that this association is more nuanced than previously thought, because the accelerating effect of family disruption/father absence on daughters’ menarcheal timing was moderated by fathers’ functioning in the family. The current study has eight important limitations that can be used to direct future research. These limitations are detailed along with proffered suggestions (where applicable) for addressing them in future studies. Possible mediating mechanisms for the earlier menarcheal timing found in daughters from biologically disrupted/father absent families are also proposed. Finally, the implications of the current study’s findings for both parents and daughters in biologically disrupted/father absent families are discussed.

Traumatic brain injury (TBI) is a major cause of death and disability throughout the world with few pharmacological treatments available for individuals who suffer from neurological morbidities associated with TBI. Cellular and molecular pathological processes initiated at the time of injury develop into neurological impairments, with chronic sleep disorders (insomnia, hypersomnolence) being among the somatic, cognitive and emotional neurological impairments. Immediately post-injury, TBI patients report excessive daytime sleepiness, however, discordant opinions suggest that individuals should not be allowed to sleep or should be frequently awoken following brain injury. To provide adequate medical care, it is imperative to understand the role of acute post-traumatic sleep on the recovery of neurological function after TBI. The aim of this thesis was to examine post-traumatic sleep after experimental TBI, defined as an increase in sleep during the first hours post-injury. In these studies, we non-invasively measured sleep activity following diffuse brain injury induced by midline fluid percussion injury to examine the architecture of post-traumatic sleep in mice. We detected significant injury-induced increases in acute sleep for six hours regardless of injury severity or time of day injury occurred. We found concurrent increases in cortical levels of the sleep promoting inflammatory cytokine interleukin 1-beta. We extended the timeline of post-injury sleep recording and found increases in post-traumatic sleep are distinctly acute with no changes in chronic sleep following diffuse TBI. Further, we investigated if post-traumatic sleep was beneficial to neurological outcome after brain-injury by disrupting post-traumatic sleep. Disruption of post-traumatic sleep did not worsen functional outcome (neuromotor, sensorimotor, cognition) at one week after diffuse TBI. With sufferers of TBI not always seeking medical attention, our final studies investigated over-the-counter analgesics and their effect on post-traumatic sleep and functional outcome. Acute administration of analgesics with varying anti-inflammatory properties had little effect on post-traumatic sleep and functional outcome. Overall, these studies demonstrated translational potential and suggest sleep after a concussion is part of the natural recovery from injury. While disrupting sleep does not worsen outcome, it is in no way beneficial to recovery. Additionally, a single analgesic dose for pain management following concussion plays little role in short term outcome.

Current municipal wastewater treatment plants (MWWTP) technologies are insufficiently removing emerging contaminants of concern. These emerging contaminants are an issue as many are known endocrine disrupting compounds (EDCs). EDCs are contaminants that can have severe and irreversible impacts on highly conserved endocrine systems that are critical during developmental periods in vertebrates as well as during adult life. Many EDCs have non-monotonic dose-response curves yet they are not often tested at low, environmentally relevant concentrations. EDC research to date has focused heavily on xenoestrogenic compounds whereas thyroid hormone (TH) disruption has been largely overlooked. TH is conserved in all vertebrates and plays crucial roles in neural development, basal metabolism, and thermoregulation. TH is comprised of thyroxine (T4), often known as the transport form of TH, and triiodothyronine (T3), the more bioactive form of TH. A TH spike occurs in the perinatal period of humans, and when disrupted, this spike can cause severe developmental defects. An analogous, but perhaps more overt, TH spike occurs in amphibians. TH is the sole hormone that drives amphibian metamorphosis, thus providing an excellent model for TH action. Our lab has previously developed the cultured tailfin (C-fin) assay, which uses biopsies from premetamorphic Rana catesbeiana tadpole tailfins cultured in the presence of an exogenous chemical of concern to assess perturbations to TH- and stress-responsive gene transcript levels by QPCR. This thesis uses the C-fin assay to assess the efficacy of removal of biological TH- and stress-altering activity in conventional municipal wastewater treatment systems. We first assess the successive levels of a full-scale conventional activated sludge (CAS) MWWTP in its ability to reduce perturbations of mRNA transcript levels of the critical TH receptors alpha (thra) and beta (thrb), and stress responsive gene transcripts superoxide dismutase (sod), catalase (cat) and heat shock protein 30 (hsp30). Secondary treatment of wastewater effluents removes cellular stress perturbations when compared to influents, but thr disruptions remain after conventional secondary wastewater treatment. We then assess three pilot-sized conventional secondary MWWTP configurations run at two operational conditions. The C-fin assay results suggest that the current understanding of operational conditions and the efficiency of complex MWWTP configurations is not clear-cut when assessed by biological endpoints such as the transcript abundance perturbations in the C-fin assay. Finally, the C-fin assay is used to investigate transcript profiles of genes of interest when the tissues are treated with the endogenous hormones T3, T4, and estradiol (E2). Our results indicate that T4 acts as more than solely a T3-prohormone and that gene expression levels in response to the two different forms of TH can be T3 or T4 specific. E2 effects, although implicated in altering TH-mediated responses in other contexts, do not affect TH-responsive gene transcripts in the C-fin. The data presented use the novel C-fin assay to challenge and advance the currently accepted views of TH-action, as well as develop necessary yet practical biological knowledge for management of emerging contaminant release from MWWTPs. / Graduate / 0383 / 0768 / 0307 / polaw@uvic.ca

Deploying networks onboard mass transit vehicles, e.g., trains and buses, and connecting these moving networks to the Internet using cellular or satellite services is seen as a promising technology to meet the broadband demand in the transport sector. This thesis examines the problem of service disruptions in such moving networks and proposes original solutions to manage these disruptions. Service disruption is caused by two main reasons. First, unavailability of wireless resources in the back-haul (e.g., cellular) network may prevent successful handoff of all passenger calls when the moving vehicle leaves the coverage of one radio tower and enters another. Second, the moving network may face frequent network disconnections when the vehicle travels through environments with severe radio coverage, e.g., tunnels. To address service disruption due to back-haul resource unavailability, an advance resource reservation frame work is proposed whereby the deterministic mobility of public transport is exploited to reserve bandwidth at target radio base-stations along the route of the vehicle. The viability of the proposed advance reservation framework is validated by (i) a predictability analysis of resource demand of moving networks using real passenger data, which show that it is possible to predict the demand at an upcoming location based on past data and the passenger count at the current location, and (ii) design of cellular extensions which show that advance reservation not only can be accommodated in existing cellular architectures with minimal modifications, it can also guarantee fast and scalable access to massive reservation data. To quantify the effect of temporary network disconnections on the probability of service disruption, new mathematical models have been developed and validated by computer simulation. Finally, a novel proactive admission control (PAC) approach is proposed to reduce service disruption by rejecting new call requests when the moving network is predicted to experience an imminent network disconnection. Using mathematical modelling, it has been demonstrated that PAC reduces service disruption probability exponentially as a function of the proactive decision time with only a linear increase in the new call blocking probability. Practicality of the PAC approach has been confirmed using empirical data from actual vehicular trips.

Estrogenic contamination of waterways is of world-wide concern due to the adverse effects observed in aquatic biota. Recently, wastes from agricultural activities have been identified as likely sources of steroid estrogens released into the environment. Wastes from dairying activities are of particular concern in New Zealand. This project included development of analytical methods to measure free and conjugated estrogens, measurement of estrogens from the source to receiving environments and an investigation of effluent treatment technologies. The analytical method developed in this study was based on GC-MS measurement of free estrogens (17α-estradiol (17α-E2), 17β-estradiol (17β-E2) and estrone (E1)) and LC-IT-MS measurement of their sulfate-conjugates (17α-E2-3S, 17β-3S, E1-3S) in raw and treated farm dairy shed effluents (DSE). Effluents from farms in the Canterbury and Waikato Regions, two regions where dairy farming is the dominant land-use, were collected and analysed. All effluents demonstrated high concentrations of steroid estrogens, particularly 17α-E2 (median 760 ng/L). Estrogenic activity was also elevated, at up to 500 ng/L 17β-E2 equivalents using the E-Screen, an in vitro cell proliferation bioassay. Comparison to the chemical data indicated that for most samples, the highest proportion of estrogenic activity was derived from steroid estrogens naturally excreted by dairy cows. Conjugated estrogens were measured in several raw effluent samples, at similar concentrations to those of free estrogens, particularly E1. Dairy effluent treatment systems reduced free estrogen concentrations by 63-99% and reduced estrogenic activity by up to 89%. In spite of high removal efficiencies, estrogens remained elevated in the treated effluents that are discharged into waterways. Steroid estrogens and estrogenic activity were detected in streams and groundwater in areas impacted by dairy farming. Although concentrations were generally low, in two streams the concentrations were above levels regarded as safe for aquatic biota (<1 ng/L). The results demonstrate that dairy effluents are indeed a major source of estrogens to the environment and to waterways.

Licentiatavhandling (sammanfattning) Alnarp : Sveriges lantbruksuniversitet. / Härtill 2 uppsatser.

Disruptions can cause projects to fail. Within the project management literature, approaches to managing disruptions consist of uncertainty, risk, opportunity, change, and crisis management. These approaches focus on developing strategies to manage perceived threats and also work towards predicting risk, therefore, reducing vulnerability. This vulnerability-reduction only focus is limiting because it takes the focus away from the development of a general capacity for readiness and for responding to uncertain situations. A resiliency approach enables a simultaneous focus on vulnerability reduction, readiness and response and thus ensures recovery. Given the context and discipline specific nature of the resilience concept, and the little or no attention in projects, this thesis conceptualises resilience in projects. This conceptualisation is to enable the identification of factors to consider and indicators to ensure overall project recovery, through the identification of dimensions and antecedents of resilience respectively. The aim of this study therefore, is to develop a framework to conceptualise resilience in projects. To achieve this aim, three case studies, namely; building, civil engineering and engineering construction projects were investigated. Within each case study, the critical incident technique was employed to identify disruptions and their management through direct observations of human activities, narration of critical incidents and review of documents on disruption. Following this, a comparative analysis and synthesis of the case studies was carried out and findings revealed definition, dimensions, antecedents and consequences of resilience in projects. Specifically, resilience in projects is defined as; the capability of a project to respond to, prepare for and reduce the impact of disruption caused by the drifting environment and project complexity. The dimensions of resilience are; proactivity, coping ability, flexibility and persistence. Proactivity can be defined as an anticipatory capability that the project takes to influence their endeavours whilst coping ability can be defined as the capability to manage and deal with stress caused by disruptions within the projects. Furthermore, flexibility can be defined as the capability of a project to manage disruption by allowing change but ultimately making sure that the aim is maintained and persistence is the capability to continue despite difficult situations. Several antecedents of these dimensions of resilience are identified. For proactivity these include contract, training, monitoring, contingency and experience. For coping ability these include the contract, training, contingency and experience. For flexibility these include open-mindedness, planning, continual monitoring and continual identification of ideas and for persistence these include continual monitoring, planning and negotiation. Also, the consequence of resilience in projects is recovery through response, readiness and vulnerability reduction. This conceptualisation of resilience is then synthesised into a validated framework for resilience in projects. Theoretically, this research provides definition, dimensions, antecedents and consequence for resilience in projects and a theoretical starting point for the concept of resilience in projects. The significance of this research to practice is the identification and development of a more holistic perspective of managing disruptions in projects through the identified dimensions, antecedents and consequences. These dimensions, antecedents and consequences provide clarity for the roles of project managers and team members in managing disruptions and thus, expand the eleventh knowledge area; project risk management, of the Project Management Book of Knowledge (PMBOK). In addition, the dimensions, antecedents and consequences of resilience in projects contribute to the curriculum development in project management and thus, provide factors and indicators that project managers require in managing disruptions.

Most firms are still failing to think strategically and systematically about managing supply disruption risk and most of the supply chain management efforts are focused on reducing supply chain operation costs rather than managing disruption. Some innovative firms have taken steps to implement supply chain risk management (SCRM). Inventory management is part of SCRM because supply disruptions negatively affect the reliability of deliveries from suppliers and the costs associated with the ordering process. The complexity of existing inventory models makes it challenging to combine the management of the supply process and inventory in a single model due, for example, to the difficulty of including the characteristics of the disruption process in the supply chain network structure. Therefore, there is a need for a simple flexible model that can incorporate the key elements of supply disruption in an inventory model. This thesis presents a series of models that investigate the importance of information on disruption discovery and recovery for a firm’s supply and inventory management. A simple two-echelon supply chain with one firm and two suppliers (i.e., referred to as the onshore and offshore suppliers) in a single product/component setting has been considered in this thesis for the purpose of experimental analyses. The sourcing decisions that the firm faces during periods of supply disruption are examined leading to an assessment of how information about the risk and length of disruption and recovery can be used to facilitate the firm’s sourcing decisions and monitor the performance of stock control during the disruption. The first part of this thesis analyses basic ordering models (Model 1 and Model 2 respectively) without the risk of supply disruption and with the risk of supply disruption. The second part analyses the value of supply disruption information, using a model with advance information on the length of disruption (Model 3) and a model with learning about the length of disruption (Model 4). The third part explores a quantitative recovery model and the analyses in this part consider of three models. Model 5 assumes a basic phased recovery model, Model 6 assumes advance information about the phased recovery process and Model 7 assumes learning about the phased recovery process. The last part of this thesis investigates the order pressure scenario that exists in the firm’s supply chain. Under this scenario, disruption to one part of the supply chain network increases demand on the remainder resulting in a lower service levels than normal. This scenario is applied to all the previous models apart from Model 1. The models in this thesis are examined under finite and infinite planning horizons and with constant and stochastic demand. The objective of the models is to minimise the expected inventory cost and optimise the order quantity from the suppliers given the different assumptions with respect to the length of supply disruption and information about the recovery process. The models have been developed using the discrete time Markov decision process (DTMDP) technique and implemented using the Java programming language. The findings of this thesis could be used to help a firm that is facing the risk supply disruption to develop its SCRM program. The findings highlight the importance of considering quantitative measures of the disruption and recovery processes, something which is still not popular within SCRM in some organisations.

Endocrine disrupting chemicals in wild animals, including fish, can disrupt reproduction by causing intersexuality. Organic pollutants, specifically polychlorinated biphenyls (PCBs), have been shown to be estrogenic or anti-androgenic likely contributing to intersexuality in males. Organic pollutants persist in the environment despite being restricted for use in the United States. Bluegills, Lepomis macrochirus, play a crucial role in lake food webs as forage and sport fish and may be affected by PCBs. In the current study, male bluegills collected in 2010 from selected Illinois lakes were analyzed to quantify PCB body residues and the incidence of intersexuality (n=200). Experiments were then conducted in 2011 and 2012 to assess the reproductive output of mature males with varying PCB body residues paired with mature females containing no detectable PCB body residues held in uncontaminated 0.05-hectare research ponds (Southern Illinois University Touch of Nature Pond Facility). Lake-specific male bluegill whole-body tissue PCB body residues ranged from below reporting limit to 2 mg/kg dry weight (non-lipid normalized basis) and varied significantly among lakes (F7,32= 9.59, p<0.0001). No male intersex bluegills were found. In both reproductive experiments, abundance of young declined as male PCB body residues increased (F 4,18 = 13.28; P=0.002). Adult survival was unrelated to reproductive output. Taken together, these results suggest PCBs, which are ubiquitous in aquatic and terrestrial habitats, have the ability to alter male reproductive performance, and possibly population dynamics and community structure through reduced recruitment, in the absence of overt intersexuality.