Purpose: To explore the difference between continuous and pulsed photobiomodulation (PBMT) versus a placebo treatment when using a red-blue light combination over multiple treatment sessions to decrease the symptoms of muscle damage in the quadriceps muscle after a bout of muscle damaging exercise. Methods: Thirty-six healthy, nonactive male and female participants were randomly assigned to one of three groups: continuous PBMT, pulsed PBMT, and placebo treatment. Participants were assessed for muscle damage with knee extension maximal isometric and isokinetic contractions, as well as Visual Analog Scale (VAS) and Lower Extremity Functional Scale (LEFS) scores. Blood creatine kinase (CK) was also analyzed. Participants were given treatment immediately prior to undergoing a bout of damaging eccentric exercise. Participants were treated with PBMT for the next 4 consecutive days for a total of 5 treatments. Results: The continuous treatment group lost significantly less isokinetic average peak torque than the placebo treatment when averaged across all time points postexercise. However, for isometric testing, the continuous group had more reduction in force compared to the placebo group. Between the treatment groups, the continuous treatment group had significantly more muscle soreness measured by the VAS and had significantly less function in daily tasks reported on the LEFS patient-oriented outcome scale. There was no significant difference in level of creatine kinase between the treatment groups. Conclusion: Pulsed photobiomodulation treatments had no significant effect when compared to the placebo group. Continuous photobiomodulation helped to reduce isokinetic force loss, yet exacerbated all other muscle damage markers following exercise relative to the placebo condition.

Context: Knee injury is a common problem for runners. Knee pain is a common symptom in knee injury and is associated with alterations in knee and hip muscle activation and hip joint angles. Relieving pain through intervention may help to restore neuromuscular function. Objective: To examine the effects of ice and transcutaneous electrical nerve stimulation (TENS) combination treatment on perceived knee pain, hip frontal plane angle, and muscle activation during running in individuals with experimental knee pain (EKP). Design: Crossover. Setting: Laboratory. Subjects: 19 participants (11 males and 8 females, 23.2 ± 1.9 y, 176 ± 11.6 cm, 71.5 ± 16.9 kg; right leg dominant). Interventions: Hypertonic saline was infused into the infrapatellar fat pad for 74 minutes (total 11.1 mL). Subjects underwent 2 treatment conditions (sham; ice/TENS combination). Measurements were recorded during running at 4 time points (preinfusion, postinfusion, posttreatment, and postinterval). Main Outcome Measures: Perceived knee pain on a 100-mm visual analog scale (VAS), knee and hip muscle peak electromyography (EMG) amplitude, and hip adduction angles. Results: Hypertonic saline infusion increased perceived anterior knee pain in all participants. The average of peak perceived knee pain was 28 mm on a 100-mm VAS in EKP application. While the increased perceived knee pain level stayed consistent across time in the sham session, ice/TENS combination treatment significantly reduced perceived knee pain by 35% at 6 minutes after the treatment start (p = 0.049), and the reduced knee pain lasted for 22 minutes (p > 0.05). Peak EMG amplitude of the gluteus medius was decreased by 13.5% and 14.3% (p = 0.023; p = 0.013) during running after EKP in sham and treatment sessions, respectively. However, the peak EMG amplitude was not restored to pain-free level during running after the treatment (p = 0.026). No other muscles changed their peak EMG amplitude due to EKP or treatment. Hip adduction angles during running were also not altered by EKP or treatment (p > 0.3) in both sham and treatment sessions. Conclusions: EKP increased perceived knee pain and decreased peak muscle activation of the gluteus medius during running. Ice/TENS combination treatment reduced perceived knee pain quickly, but did not restore neuromechanics during running.

Les gamètes femelles appelés ovocytes sont produits par un type spécifique de division cellulaire appelée méiose. Afin de produire des gamètes haploïdes, et contrairement aux divisions mitotiques des cellules somatiques, la méiose implique une seule étape de réplication du génome suivie de deux étapes de ségrégation des chromosomes. La fidélité de la ségrégation des chromosomes pendant la méiose est cruciale pour éviter l’aneuploïdie embryonnaire qui entraînerait des défauts de développement ou un avortement spontané. Dans la plupart des types cellulaires, la ségrégation des chromosomes repose sur un fuseau composé de microtubules. En parallèle à l'assemblage du fuseau, des complexes multi-protéiques appelés kinétochores s’assemblent sur le côté des chromosomes et leur permettent d’interagir avec les microtubules dynamiques du fuseau. Étonnamment, la ségrégation des chromosomes dans l'ovocyte de C. elegans se déroule d'une manière atypique indépendante des kinétochores. Le mécanisme alternatif utilisé dans ces oocytes pour la ségrégation des chromosomes est cependant inconnu. Au cours de mon doctorat, j'ai utilisé une combinaison d'imagerie photonique à haute résolution temporelle, corrélée à de la microscopie électronique à haute résolution spatiale. J’ai également utilisé de la photoablation par laser des microtubules et réalisé l'inhibition ciblée de protéines clés pour disséquer le mécanisme atypique de ségrégation des chromosomes dans l'ovocyte de C. elegans. Mes résultats montrent que la ségrégation des chromosomes est produite par une force dépendante des microtubules qui pousse les chromosomes. Par une analyse détaillée de l’organisation des microtubules dans des fuseaux en anaphase partiellement reconstruits par microscopie électronique en tomographie, je propose un modèle impliquant la génération de force par l'allongement d’un réseau de courts microtubules formant le fuseau central. De plus, je démontre que l'activité de l'orthologue de CLASP chez C. elegans (CLS-2) est essentielle pour l'assemblage du fuseau en anaphase. Ce travail est actuellement sous presse dans le journal Nature Communications. Parallèlement, j'ai disséqué le rôle de CLS-2 dans l'assemblage du fuseau d'ovocytes et la ségrégation chromosomique. J'ai perturbé de manière systématique les domaines individuels et les résidus conservés de manière évolutive dans CLS-2 pour déterminer leur contribution à la fonction et à la localisation de cette protéine pendant la première méiose femelle. Dans l'ensemble, mes résultats montrent que la ségrégation chromosomique dans l'ovocyte de C. elegans consiste en un mécanisme de poussée chromosomique atypique et dépendant de CLS-2. / Female gametes called oocytes are produced through a specific type of celldivision termed meiosis. In order to produce haploid gametes, and unlike mitoticdivisions of somatic cells, meiosis involves a single round of genome replication followed by two rounds of chromosome segregation. Accuracy of chromosome segregation during meiosis is crucial to avoiding embryonic aneuploidy that wouldlead to developmental defects or spontaneous abortion. In most cell types,chromosome segregation relies on a microtubule-based spindle. Concomitant tospindle assembly, multi-protein complexes termed kinetochores assemble on the side of chromosomes and couple microtubule dynamics to chromosomal movements. Strikingly, in the C. elegans oocyte chromosome segregation occurs in an atypical kinetochore-independent manner. The alternative mechanism used in these oocytes for chromosome segregation is however unknown. During my PhD, I used a combination of high spatial and temporal resolution live imaging, correlated light and electron tomography, laser-mediated photoablation of microtubules, and targeted inhibition of key proteins to dissect this a typical mechanism of chromosome segregation in the C. elegans oocyte. Myresults show that chromosome segregation is driven by a microtubule-dependent force that pushes the segregating chromosomes apart during anaphase. Aftercareful analysis of partially reconstructed anaphase spindles by electrontomography for microtubule quantity, length, orientation, and overlaps, I proposea model involving the elongation and/or sliding of tiled microtubules in the central spindle as the candidate structure responsible for this force generation. Additionally, I demonstrate that the activity of the C. elegans CLASP ortholog CLS-2 is essential for proper anaphase spindle assembly. This work is currently in press at Nature Communications.In parallel, I have more closely examined the role of the C. elegans CLS-2 in oocyte spindle assembly and chromosome segregation. I have thoroughly and systematically perturbed the individual domains and evolutionarily conserved residues in CLS-2 to determine their contribution to the function and localization ofthis protein during the first female meiosis. Overall my results show that chromosome segregation in the C. elegans

Parmi les stratégies d'amélioration des traitements des infections bactériennes chroniques, visant à accroître l'activité bactéricide ou à limiter la sélection de résistances, le développement de combinaisons d'antibiotiques existants constitue une stratégie prometteuse. L'objectif de cette thèse était d'évaluer l'efficacité d'une combinaison d'antibiotiques sur un biofilm bactérien dans un système in vitro dynamique qui permet de simuler les concentrations d'antibiotiques observées chez les patients traités. Nous avons montré que pour des infections complexes dues à de fortes charges bactériennes ou à la présence d'un biofilm, les études dans le système in vitro dynamique menées sur plusieurs jours apportaient plus d'informations sur l'efficacité d'une combinaison d'antibiotiques que des techniques standardisées menées avec des concentrations d'antibiotiques stables au cours du temps. Nous avons aussi montré que sur un biofilm, même si certaines associations n'ont pas d'impact sur la biomasse du biofilm elles permettent en revanche de maintenir des populations moins sensibles aux antibiotiques à des seuils relativement bas, alors que les mêmes antibiotiques utilisés seuls favorisent l'émergence de résistances au cours du traitement. Enfin, des essais préliminaires pour mimer des infections comme les mammites bovines ou les cystites ont montré que ce système pouvait être plus largement utilisé pour l'optimisation des schémas thérapeutiques en médecine humaine et en médecine vétérinaire. / Among strategies to improve the treatment of chronic bacterial infections by increasing the bactericidal activity or by limiting the selection of resistance, the development of combinations of existing drugs is a promising strategy. The aim of this thesis was to evaluate the efficacy of a combination of antibiotics on a bacterial biofilm in a dynamic in vitro system which allows to simulate the concentrations observed in patients. We have shown that for complicated infections due to large bacterial loads or to biofilms, in vitro dynamic studies over several days provided more information on the efficacy of a combination of antibiotics than classical methods conducted with constant antibiotic concentrations over time. We have also shown that on a biofilm, even if associations do not have an impact on the overall size of the biofilm, they maintain less-susceptible populations at relatively low levels, whereas the same antibiotics promote the emergence of resistance during treatment when used alone. Finally, preliminary trials to mimic infections such as bovine mastitis or cystitis have shown that this system could be more widely used for the optimization of dosage regimens in human medicine and veterinary medicine.

Anthelmintic resistance of parasites infecting livestock animals is a global problem resulting in decreased animal welfare and production losses. Horses are not exempt from this issue as wide-spread anthelmintic resistance exists among the equine cyathostomins and Parascaris spp. Of the three drug classes available for treating equine intestinal helminths anthelmintic resistance, defined as less than 90-95% drug efficacy, exist to all three. New pharmaceutical control regimens and the elucidation of parasite drug response mechanisms are needed. Two studies were carried out evaluating combination deworming regimens. A population of cyathostomins with known resistance to the benzimidazole (BZ) and pyrimidine drug classes maintained in a herd of Shetland ponies was used. Fecal egg counts were performed every two weeks and used to evaluate drug efficacy. The first study evaluated the combination of a BZ and pyrimidine drug for four consecutive treatments, and compared the individual drug efficacies before and after combination use. The first combination treatment exhibited an additive effect at 76.6%, but the subsequent three combination treatments decreased to approximately 40%. There was no significant difference between the initial and final efficacies of individual drugs (BZ, p=0.4421; pyrimidine, p=0.8361). It appears the combination treatment selected for double-drug resistant adult parasites. The timeframe of this study (1 year) and the one year lifespan of adult cyathostomins prevented observations of combination treatment on subsequent generations, however given the sustainability of resistance in this cyathostomin population, it seems unlikely efficacy would improve over time. The second study examined the combination of a BZ drug with a macrocyclic lactone (ML) drug. This parasite population was 100% naïve to the ML drug class. This study was carried out in a similar manner to the first, except only two combination treatments were given. ML exhibited 100% efficacy when it was used alone, or in combination. The initial and final BZ efficacy did not significantly differ (p=0.9890). In summary, the results described herein do not support the use of combination treatments where resistance is prevalent, but more long term studies are needed to fully understand the long-term effects on subsequent generations. The in vitro maintenance of Parascaris spp. provides opportunity for various molecular analyses. An objective motility scoring assessment allowed for continuous monitoring of worm viability. In this study, several saline solutions, nutrient supplements, environmental conditions, and Roswell-Park Memorial Institute medium 1640 (RPMI-1640) were evaluated for the longevity and viability of adult Parascaris spp. Overall, RPMI-1640 resulted in better longevity (168 hours) and significantly better viability (pParascaris spp. to in vitro drug exposure. Oxibendazole at 10 µg/mL for 24 hours and ivermectin at 1 µg/mL for three hours were employed, and worms were used for transcriptomic analyses to identify drug response mechanisms. The top four genes which were significantly different between drug treated and control groups were: cyp4504C1, sup-9, frmd4a, and klhdc10. It is hypothesized that cyp4504C1 and klhdc10 are drug detox mechanisms, while sup-9 and frmd4a may be indirect response related to the drug effects. Their expression was further evaluated using quantitative RT-PCR, however there was no significant difference in any gene expression between groups. It should be noted that there are several limitations associated with the qPCR method, and the lack of significance should not rule out the possible involvement of these genes and more research on drug response mechanisms is needed. In summary, there is very little research regarding combination deworming in horses, and their current use is largely due to some success for ruminant parasites, but the current work summarized herein does not support their use. Finally, until now the lack of in vitro methods for equine helminths has significantly delayed the elucidation of drug response mechanisms. This was the first whole-transcriptome approach for any ascarid parasite and uncovered proteins with possible involvement in drug metabolism or compensate for the toxic effects Overall, the research surrounding anthelmintic resistance in livestock helminths, particularly in horses, is lacking and the resistance crisis demands further investigation.

Combining multiple forecasts in order to generate a single, more accurate one is a well-known approach. A simple average of forecasts has been found to be robust despite theoretically better approaches, increasing availability in the number of expert forecasts, and improved computational capabilities. The dominance of a simple average is related to the small sample sizes and to the estimation errors associated with more complex methods. We study the role that expert correlation, multiple experts, and their relative forecasting accuracy have on the weight estimation error distribution. The distributions we find are used to identify the conditions when a decision maker can confidently estimate weights versus using a simple average. We also propose an improved expert weighting approach that is less sensitive to covariance estimation error while providing much of the benefit from a covariance optimal weight. These two improvements create a new heuristic for better forecast aggregation that is simple to use. This heuristic appears new to the literature and is shown to perform better than a simple average in a simulation study and by application to economic forecast data.

Lung cancer is the second most common cancer type and is associated with high mortality rates. The survival rate for lung cancer patients has increased slowly in the last decade mainly as the result of the development of novel targeted and immune therapies. However, non-small cell lung cancer patients lacking known or actionable driver mutations and small cell lung cancer patients with recurrent disease are still in urgent need of new therapies. Drug repurposing is an efficient way to identify new therapies since it uses clinically relevant small molecule drugs. Determination of off-targets of small molecules is a novel approach towards drug repurposing as unintended targets can play important roles for a new clinical application. Here we apply functional proteomics and systems pharmacology approaches to determine target profiles and differential mechanisms of action, independent of the intended targets, of small molecules with similar chemical structures. Using chemical proteomics, we elucidated the differential target profiles of two clinical CDK4/6 inhibitors: palbociclib and ribociclib. We observed that palbociclib, but not ribociclib, is a dual protein and lipid kinase inhibitor that in addition to the intended cell cycle pathway modulates the PI3K/AKT and autophagy pathways. Furthermore, we investigated the off-targets of two MET/VEGFR inhibitors, foretinib and cabozantinib. Foretinib, but not cabozantinib, was found to reduce cell viability and induce cell cycle arrest and apoptosis in lung cancer cell lines. Using a systems pharmacology approach, which included chemical proteomics, phosphoproteomics and RNA-Seq, integrated data analysis and subsequent functional validation revealed a complex polypharmacology mechanism of action of foretinib, which involves the simultaneous inhibition of MEK, AURKB and FER protein kinases. Because AURKB is an important protein kinase for the proliferation of MYC-amplified small cell lung cancer cells, we were able to design a drug combination of foretinib with barasertib, a much more potent AURKB inhibitor, that enhanced specifically the cell death of MYC-amplified small cell lung cancer cells. In summary, we show that small structural changes of closely related clinical drugs can result in pronounced differences in their target profiles and anticancer activities through differential polypharmacology mechanisms and that an integrated systems pharmacology approach can identify new repurposing opportunities for these drugs in cancers with high unmet medical need.

Hydrologic and climate models predict variables through a simplification of the underlying complex natural processes. Model development involves minimising predictive uncertainty. Predictive uncertainty arises from three broad sources which are measurement error in observed responses, uncertainty of input variables and model structural error. This thesis introduces ways to improve predictive accuracy of hydroclimatic models by considering input and structural uncertainties. The specific methods developed to reduce the uncertainty because of erroneous inputs and model structural errors are outlined below. The uncertainty in hydrological model inputs, if ignored, introduces systematic biases in the parameters estimated. This thesis presents a method, known as simulation extrapolation (SIMEX), to ascertain the extent of parameter bias. SIMEX starts by generating a series of alternate inputs by artificially adding white noise in increasing multiples of the known input error variance. The resulting alternate parameter sets allow formulation of an empirical relationship between their values and the level of noise present. SIMEX is based on the theory that the trend in alternate parameters can be extrapolated back to the notional error free zone. The case study relates to erroneous sea surface temperature anomaly (SSTA) records used as input variables of a linear model to predict the Southern Oscillation Index (SOI). SIMEX achieves a reduction in residual errors from the SOI prediction. Besides, a hydrologic application of SIMEX is demonstrated by a synthetic simulation within a three-parameter conceptual rainfall runoff model. This thesis next advocates reductions of structural uncertainty of any single model by combining multiple alternative model responses. Current approaches for combining hydroclimatic forecasts are generally limited to using combination weights that remain static over time. This research develops a methodology for combining forecasts from multiple models in a dynamic setting as an improvement of over static weight combination. The model responses are mixed on a pair wise basis using mixing weights that vary in time reflecting the persistence of individual model skills. The concept is referred here as the pair wise dynamic weight combination. Two approaches for forecasting the dynamic weights are developed. The first of the two approaches uses a mixture of two basis distributions which are three category ordered logistic regression model and a generalised linear autoregressive model. The second approach uses a modified nearest neighbour approach to forecast the future weights. These alternatives are used to first combine a univariate response forecast, the NINO3.4 SSTA index. This is followed by a similar combination, but for the entire global gridded SSTA forecast field. Results from these applications show significant improvements being achieved due to the dynamic model combination approach. The last application demonstrating the dynamic combination logic, uses the dynamically combined multivariate SSTA forecast field as the basis of developing multi-site flow forecasts in the Namoi River catchment in eastern Australia. To further reduce structural uncertainty in the flow forecasts, three forecast models are formulated and the dynamic combination approach applied again. The study demonstrates that improved SSTA forecast (due to dynamic combination) in turn improves all three flow forecasts, while the dynamic combination of the three flow forecasts results in further improvements.

Knowledge is recognised as being an important asset in organisations these days. Despite this, many organisations are not doing enough to effectively manage this important asset for its competitive advantage. In response to this, knowledge management which is defined as a process that effectively creates, captures, shares and uses organisation-wide knowledge to improve the organisation's performance was conceived and has since gained widespread acceptance the world over. Despite its widespread acceptance, little is known about the current levels of knowledge management practice within the Malaysian context, in particular amongst the Multimedia Super Corridor status companies in Malaysia. In view of this, the research problem formulated for this study is: 'How and why do Multimedia Super Corridor status companies in Malaysia practise knowledge management?' Based on this research problem, three research questions that look specifically at the knowledge management enablers, knowledge management processes and knowledge management outcomes were identified based on the literature review. The literature review provides an overview of knowledge and the different types of knowledge. It then chronicles the developments of knowledge management and canvasses extant literature on knowledge management within the Malaysian context. It found that there are various enablers of knowledge management that may impact on the level of knowledge management practice in Malaysia. These enablers can be broadly categorised as culture, structure, people and information technology infrastructure. To further comprehend the knowledge creation process, this study utilised Nonaka and Takeuchi's (1995) socialisation, externalisation, combination and internalisation (SECI) model for knowledge creation. In addition to this, organisational efficiency, competitive advantage, maximisation of organisational potential, and better management of knowledge assets were identified as key knowledge management outcomes in organisations. These knowledge management enablers, processes and outcomes were used to develop a preliminary theoretical framework upon which this research was based upon. This exploratory research employs the use of qualitative multiple case studies operating within a critical realism research paradigm. This research uses a total of four cases with three interviews each giving a total of twelve interviews. The literature review and two in-depth convergent interviews were the basis upon which the interview protocol was formulated. This interview protocol was then administered to a pilot case involving three interviews. This process was repeated in the main data collection stage on three different cases with three interviews per case. The main findings of this research are the ten different enablers of knowledge management that either take on the roles of inhibitor or facilitator. The facilitators of knowledge management are collaboration, mutual trust, learning, leadership, incentives and rewards, IT infrastructure and T-shaped skills. The inhibitors of knowledge management are centralisation and kiasu-ism. Another variable - formalisation has both positive and negative effects on knowledge management as it acts as an inhibitor to the socialisation knowledge creation process but acts as a facilitator to the other three knowledge processes. This research also found that all four knowledge processes - socialisation, externalisation, combination and internalisation are being used by all cases to create knowledge with preference given to socialisation and combination. In addition, knowledge management is found to positively affect the organisations’ competitive advantage, organisational efficiency, maximising organisational potential and effective management of knowledge assets. Further research utilising a quantitative approach to test the theory developed from this study apart from analysing the new variable kiasu-ism and the concept of ba were suggested to better comprehend the practise of knowledge management in Malaysia.

This thesis investigates the major errors and processes affecting the performance of a viable, standalone point positioning technique known as single frequency Precise Point Positioning (PPP). The PPP processing utilises both single frequency code and carrier phase GPS observables. The mathematical model implemented is known as the code and quasi-phase combination. Effective measures to improve the quality of the positioning solutions are assessed and proposed. The a priori observations sigma (or standard deviation) ratio in the sequential least squares adjustment model plays a significant role in determining the accuracy and precision of the estimated solutions, as well as the solutions convergence time. An