In dieser Doktorarbeit wurde untersucht, welche Faktoren Wohlbefinden, wahrgenommene Gesundheit und Mobilitätspraktiken von Radfahrenden und Fußgänger:innen während des Unterwegsseins beeinflussen. Ziel war es, die persönliche Exposition gegenüber Feinstaub und Lärm unterwegs zu messen und diese der individuell wahrgenommenen Belastung gegenüberzustellen. Zudem wurden weitere Faktoren, die das Wohlbefinden beeinflussen, untersucht. Die Arbeit beleuchtet überdies, wie über gesunde und angenehme Mobilität informiert werden könnte. Zuerst wurden mobile qualitative Interviews (Go-/Ride-Alongs) durchgeführt und mit tragbaren Sensoren zur Messung von Feinstaub und Lärm ergänzt. Der situative Kontext, die sensorische Wahrnehmung und soziale Aspekte beeinflussen, ob das Unterwegsseins in der Stadt als gesund und angenehm empfunden wird. Diese Faktoren können in vergleichsweise als hoch belastend gemessenen Situationen ausgleichend wirken. Weiterhin wurden Informationsmöglichkeiten für eine gesunde Mobilität in der Stadt exploriert. Ein Literaturreview hat aufgezeigt, dass Gesundheitsthemen wenig Berücksichtigung in Forschung zu Mobilitäts-Apps finden. Daran anschließend wurden Fokusgruppen durchgeführt. Es wurde ermittelt, wie gesunde und angenehme Routen kommuniziert werden können. Hier könnendas Vorhandensein von Routenalternativen und Bewältigungsstrategien ein Gefühl von Selbstwirksamkeit geben. Es wurde eine „pleasant routing app“ vorgeschlagen, die angenehme und gesunde Routenaspekte integriert. Um die Attraktivität des Fahrradfahrens und zu Fuß Gehens zu steigern, sollten Erfahrungen, Wahrnehmungen und Praktiken von Radfahrenden und Fußgänger:innen berücksichtigt werden. Letztendlich kann somit aktive Mobilität ihr Potenzial entfalten und zu einer lebenswerten, gesunden und umweltfreundlichen Stadt beitragen. / This thesis investigates factors influencing cyclists’ and pedestrians’ health and wellbeing on-the-move. Moreover, the possibilities of smartphone apps for supporting a healthy and pleasant trip are investigated. The scope of this thesis is to combine the topic healthy and pleasant mobility with possibilities of mobility apps. First, the thesis explores how cyclists and pedestrians perceive their personal exposure towards air pollution and noise as well as other factors influencing commuting experience and wellbeing on-the-move. This is contrasted to actual measured particulate matter and noise. Qualitative interviews on-the-move (‘go-/ride-alongs’) are complemented by wearable sensors measuring particulate matter and noise. The results show discrepancies as well as coherences between perceived and measured exposure. The situational context, sensory awareness (e.g. water views) and social cues (e.g. seeing other people) are important for a perceived pleasant commute, even in polluted areas. Second, this thesis identifies how far health impacting factors are considered in research using mobility apps to identify their possibilities for supporting a healthy commute. A literature review reveals that research applying mobility apps is lacking the consideration of health topics and it is proposed to integrate health topics in mobility app development. Following these findings, the thesis investigates communication options to inform about a healthy and pleasant commute. Focus groups were applied showing that information should include feasible coping strategies and increase self-efficacy. Pleasant trip characteristics could be included in a healthy mobility app. If active mode users’ experiences, perceptions and practices are considered, cycling and walking can become more attractive and more people are encouraged to cycle or walk. Hence, active modes can unfold their potential for supporting the transformation towards liveable, healthy and environmentally friendly cities.

Die Unsicherheiten bei der Beobachtung und Modellierung der Nährstoffverfügbarkeit und des Nährstoffflusses erschweren das Verständnis von Nährstoffkreislauf und Nährstofftransportprozessen und die Vorhersage des Verhaltens von Nährstoffen. Diese Arbeit beginnt mit einer Literaturüberblick über Arten und Quellen von Unsicherheiten bei der Beobachtung und Modellierung von Nährstoffen in Gewässern. Basierend auf dieser Überblick werden drei Fallstudien zur Beobachtung und Modellierung von Nährstoffen unter Berücksichtigung von Unsicherheiten vorgestellt. In der ersten Studie wurden die Unsicherheiten verschiedener Inferenzmethoden zur Klassifizierung des Gewässergüte in Bezug auf den gesamten reaktiven Phosphor (TRP) mit hochaufgelösten Daten aus landwirtschaftlichen Einzugsgebieten bewertet. In der zweiten Studie wurden die in den hochauflösenden Daten beobachteten Konzentrations-Abfluss (C-Q) Hysteresen mit einem empirischen Modell formuliert, um TRP-Transferereignisse zu charakterisieren. Die Quelle und Pfade von Nährstoffübertragungen wurden aus den Ergebnissen abgeleitet, um Entscheidungen im Wassermanagement zu unterstützen. Die Konzentration-Abfluss-Temperatur (C-Q-T) Beziehung wurde für Nitrat (NO3) in einem von Borkenkäferbefall betroffenen Waldeinzugsgebiet untersucht. Die zeitlichen Variationen der Parameter eines einfachen mechanistischen Modells informierten über die Entwicklung der hydrobiochemischen Prozesse als Reaktion auf die natürliche Störung. In einem interdisziplinären Essay, der diesen Fallstudien folgt, wurde eine buddhistische Perspektive eingenommen und diskutiert, worin die grundsätzlichen Ursachen für das Leiden unter Unsicherheit in der Wissenschaft liegen, sowie Möglichkeiten, Wissenschaft mit Selbstreflexion, Mitgefühl und Frieden zu betreiben. In den Schlussfolgerungen wird eine Kontemplation über die Erfahrung, mit der Unsicherheit in der hydrologischen Wissenschaft in dieser Dissertation präsentiert. / Uncertainty in monitoring and modelling availability and flux of nutrient pollutants obscures understanding of nutrient cycle and transport processes and prediction of nutrient behaviours. This thesis starts with a literature review of types and sources of uncertainty in monitoring and modelling of the nutrients in waters. Based on this review, three study cases of monitoring quantities and modelling behaviours of the nutrients with the considerations of uncertainty are presented. In the first study, the uncertainties of different inference methods for classifying physico-chemical status in terms of total reactive phosphorus (TRP) were assessed based on high-resolution data from agricultural catchments. In the second study, concentration-discharge (C-Q) hystereses observed in the high-resolution data were formularised with an empirical model and to characterise TRP transfer events at the sub-hourly scale. The sources and pathways of nutrient transfers were inferred from the transfer event characteristics to inform major targets for water management measures. In the third study, the C-Q relationship was further researched for nitrate (NO3) at a bi-weekly to monthly frequency in a forest catchment affected by bark beetle infestation. The temporal variations of the parameters of a simple mechanistic model describing the concentration-discharge-temperature (C-Q-T) relationship informed the evolution of catchment-scale hydrological and biogeochemical processes in response to the natural disturbance. In an interdisciplinary essay following the case studies, a Buddhist perspective on fundamental causes of the suffering around uncertainty in science and ways to pursue science with self-reflection, compassion and peacefulness were discussed. Contemplations on the experience of confronting the uncertainty in the hydrological science of this thesis are also presented in the conclusions.

International Telemetering Conference Proceedings / October 27-30, 1997 / Riviera Hotel and Convention Center, Las Vegas, Nevada / The most bandwidth-efficient communication methods are imperative to cope with the congested frequency bands. Pulse Shaping methods have excellent effects on narrowing bandwidth and increasing band utilization. The position of the baseband filters for the pulse shaping is crucial. Filters after the modulator will have non-constant envelope and before the modulator will have constant envelope. These two types have different effects on narrowing the bandwidth and producing bit errors. The constant envelope 8 PSK is used throughout the simulations and is compared with the non-constant envelope results. This work provides simulation results of spectrum analysis and measure of bit errors produced by pulse shaping in an AWGN channel.

With the current crisis of organ shortage and an increasing number of dialysis patients,studies directed at ameliorating such a substantial organ discrepancy are of considerable importance to the transplant community. The use of extended criteria donation has helped to compensate the disparity of organs however, we are still a long way from achieving satisfactory targets. Still there are many organs from older donors that are discarded primarily on the basis of chronological age. It is here that biological age may display a crucial role in allowing the transplant team to characterize donor organs with greater accuracy. Indeed both biological and chronological age are very closely related and ECD criteria are based very much on the latter, albeit with other clinical variables. However the biomarker of ageing CDKN2A which is suitably represented by Baker and Sprott’s criteria, displays closer variabilities with post-operative transplant function, at least up to one year. Telomere length known as the “Gold standard” biomarker of ageing does not display as robust a role in predicting organ function as CDKN2A. The classification of organs represented in this text from category I-IV serves merely as a guide to future studies and is yet to be validated in larger clinical trials. It is however a simple and rapid assessment tool (Gingell-Littlejohn et al PLOS One 2013). Relatively advanced cellular senescence was displayed in the mutant AS/AGU rat kidney when compared to the parent AS strain. This was exploited in a unique animal model to study the effects of ischaemia reperfusion injury on the mutant kidney, hence mimicking to a certain degree the transplant related injuries in ECD kidneys. Although ischaemic times in the model were moderate in nature, there was nonetheless a difference in the tolerance to IR injury between parent and mutant strain as evidenced by increased p16 and p21 staining in AS/AGU rats. Such a model therefore is exclusive in that interventions to improve ECD renal function post-transplantation can accurately and conveniently be represented and studied at a pre-clinical level. Anti-ischaemic compounds have been the subject of much debate over the years, however a single “Holy Grail” compound able to completely abolish the injurious effects of IR injury has never been elicited. mTOR inhibitors however, display several cellular effects and act as potent immunosuppressants. They (AZ-6) have also been shown to partially mediate the detrimental effects of IR injury on the native kidneys of AS rats in a specifically designed animal model as shown. Further studies encompassing transplanted kidneys from mutant AS/AGU rats exposed to such a promising agent would be of undoubted importance to the clinical field of transplantation, potentially leading to immeasurable economic and patient benefits.

Feline Osteoarthritis (OA) is a pathological change of a diarthrodial articulation which primarily occurs in older cats. The aims of this study were:- 1) to define the radiographic features of OA in the cat for each individual appendicular joint; 2) to relate the radiographic features to the gross pathologic and histopathologic features; 3) to explore underlying causes of OA in cats, 4) to identify the presence of Protease Activated Receptor-2 (PAR-2) and matriptase in feline articular cartilage and synovial membrane and to determine their role in OA pathogenesis. The present study has defined five radiographic features of OA for each appendicular joint:- presence of osteophytes, enthesiophytes, areas of abnormal mineralisation,synovial effusion and joint remodelling. The study furthermore suggested that increases in radio-opacity beneath the semilunar notch, along the femoral trochlea, beneath the tibial plateau and on the femoral head/neck are also important radiographic features. The radiographic prevalence was highest in the elbow (23.9%, 93/389) and stifle (23.9%,93/389) joints, followed by the hip (21.1%, 82/389), tarsal (17.7%, 69/389), shoulder(6.7%, 27/389) and carpal (6.4%, 25/389) joints. The results from this study demonstrate that the presence of a radiographically apparent supinator sesamoid bone(SSB), meniscal mineralisation (MM) and two fabellae are related to cartilage pathology and can be indicators of OA. Prevalence rates for gross pathology changes were highest in the elbow (20.2%,102/506) joint, followed by the stifle (19.6%, 99/506), hip (18.4%, 93/506), shoulder (17.8%, 90/506), tarsal (15.0%, 76/506), and carpal (9.1%, 46/506) joints. Eight key gross pathologic features were identified- cartilage discolouration, cartilage fibrillation,cartilage ulceration, cartilage erosion, osteophytes, thickening of joint capsule, synovium discolouration and joint remodelling. The radiographic and gross pathologic total scores were positively correlated in each appendicular joint and the joint most likely to have cartilage damage without radiographic evidence of OA is the shoulder (71.1%, 64/90) followed by the elbow (39.1%, 9/23), hip (32.4%, 11/34), stifle (26.1%,6/23), carpal (23.1%, 21/91) and tarsal (14.9%, 7/47) joints. Four possible underlying conditions that lead to secondary OA were identified:- radioulnar incongruity, hip dysplasia (HD), cranial cruciate ligament (CCL) disease and primary meniscal mineralisation. The identification of PAR-2 and matriptase proteins and gene expression in feline articular tissues is a novel and important finding supporting the hypothesis that serine proteases are involved in the articular cartilage degradation seen in feline OA.

Previous studies have identified stem cell populations in articular cartilage using colony forming assays and mesenchymal stem cell (MSC) marker expression. The specificity of classical MSC markers for isolation of stem cells within articular cartilage is insufficient, with large and highly variable quantities being reported in the literature. This study has demonstrated, for the first time, a panel of stem cell markers specific for articular cartilage-derived stem cells (ACSC). ACSCs were isolated, quantified and cultured from healthy and OA joints. Stem cells were clonally-derived cell lines that proliferated beyond 50 population doublings whilst maintaining a phenotype, and demonstrated tri-lineage potential. We discovered that OA cartilage had a two-fold increase in stem cell number, consisting of two divergent stem cell sub-populations. These divergent populations varied in proliferative capacity with only 50% of stem cells from the OA joint capable of extended proliferation in vitro. Using transcriptomic next generation sequencing of culture-expanded chondrocytes and ACSCs we successfully identified differentially expressed genes and a panel of novel markers of cartilage-specific stem cells. Novel markers were validated using qPCR and protein labelling and, were specifically expressed in ACSCs, with no expression in the culture-expanded full-depth chondrocytes. Using immunofluorescence for novel stem cell markers we found articular cartilage-derived stem cells are localised within the transitional zone in normal cartilage and the superficial zone in OA cartilage. OA cartilage was found to contain a 2-fold increase in stem cells using immunofluorescence. Subsequently, we used the panel of novel markers and fluorescent active cell sorting to isolate a sub-population from full-depth cartilage with stem cell characteristics. These cells were plastic adherent, clonogenic, with proliferative capacity greater than 50PD and displayed tri-lineage potential, therefore meeting all criteria for classification as a MSC population. The use of specific markers to isolate ACSCs will allow for further characterisation of stem cells, including a more in-depth understanding of the mechanisms of proliferation, differentiation and degeneration within articular cartilage.

Duplication of the proteolipid protein (PLP1) gene, which encodes the most abundant protein of central nervous system (CNS) myelin, is the most common cause of Pelizaeus Merzbacher disease (PMD). Various animal models have been generated to study the effect of Plp1 gene overexpression on oligodendrocyte and myelin sheath integrity. The #72 line harbours 3 additional copies of the murine Plp1 gene per haploidic chromosomal set. Homozygous #72 mice appear phenotypically normal until three months of age, after which they develop seizures leading to premature death at around 4 months of age. An earlier study examining the optic nerve showed a progressive demyelination accompanied by marked microglial and astrocytic responses. Using electron microscopy and immunohistochemistry, I demonstrated that initial myelination of the #72 corpus callosum was followed by a progressive demyelination, probably mediated by a distal “dying back” phenomenon of the myelin sheath. No evidence of effective remyelination was observed despite the presence and proliferation of oligodendrocyte progenitor cells (OPCs). A marked increase in density and reactivity of microglia/macrophages and astrocytes, and the occurrence of axonal swellings, accompanied the demyelination. In situ and in vitro evaluation of adult #72 OPCs provided evidence of impaired OPC differentiation. Transplantation of neurospheres (NS) into adult #72 mouse corpus callosum confirmed that axons were capable of undergoing remyelination. Furthermore, NS transplanted into neonatal CNS integrated into the parenchyma and survived up to 120 days, demonstrating the potential of early cell replacement therapy. Taking advantage of the spatially distinct pathologies between the retinal and chiasmal region of the #72 optic nerve, I evaluated the capability of diffusion weighted MRI to identify lesion type. I found significant differences between #72 and wild type optic nerves, as well as between the two distinct pathological regions within the #72 optic nerve. These results confirm the potential of the #72 mouse to serve as a model to study chronic demyelination. The study also demonstrates the utility of the #72 mouse to evaluate cell transplant strategies for the treatment of chronic CNS white matter lesions and PMD. Additionally, DW MRI has potential as a modality capable of diagnosing myelin-related white matter changes, and may be applicable to the clinical setting.

EHMT1 is a gene that encodes an epigenetic regulator important for normal brain development. Disruption in EHMT1 is associated with a number of neurodevelopment and psychiatric conditions, like schizophrenia, Autism Spectrum Disorders, developmental delays and intellectual disabilities. In order to help elucidate the role of Ehmt1 in cortical development two models are examined: the differentiation of mouse pyramidal neurons lacking one copy of the gene and a forebrain-specific Ehmt1-haploinsufficient mouse model. Ehmt1+/- cells demonstrated changes in cell cycle, with significant differences in proliferation rates at embryonic stem cell and neural progenitor stages. Ehmt1+/- cells demonstrated significantly different transcriptional profiles in early and late stages of progenitor development, which suggested these cells, underwent precocious differentiation. In addition, the dysregulation of mRNA expression in a number of the Nrsf/Rest repressor complex members and Rest target genes was found; and Ehmt1+/- cells did not survive as post-mitotic neurons. The forebrain-specific Ehmt1-haploinsufficient mouse model, Ehmt1D6Cre/+, importantly showed normal Mendelian birth ratios, survival, motor coordination and function and no gross morphological changes in brain structure. However, these mice demonstrated differences in activity levels and anxiety-related measurements; deficits in sensorimotor gating and object recognition; and significant differences in a number of electrophysiological measurements, including abnormal event-related neural responses in the cortex and high frequency oscillatory patterns. Taken together, these data suggest that Ehmt1 expression is important for normal pyramidal development and Ehmt1 haploinsufficiency throughout development manifests cortical dysfunction, which leads to marked behavioural and electrophysiological abnormalities.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Chronic lymphocytic leukaemia (CLL) is a lymphoid malignancy which despite advances in the treatment options available is still incurable. Characterised by the gradual accumulation of CD5+ B cells, the paradigm that this is due to failed apoptosis has been challenged and a significant proliferative component has been identified. However, despite the crosstalk between pathways which regulate metabolism and proliferation the metabolic characteristics of these cells are not fully understood. Furthermore, there is a renewed interest in the field of cancer cell metabolism because of the Warburg effect, a hallmark of malignancy whereby cells preferentially switch to aerobic glycolysis and rapidly consume glucose. This has led to the development of new drugs such as AZD3965 an inhibitor of monocarboxylate transporter 1 (MCT1), which along with MCT4 mediates the export of lactate, a toxic bi-product of glycolysis, out of the cell. The aim of this project was to assess whether therapeutically targeting MCT -1 and -4 would be a viable approach for CLL. Chapter 2 of this thesis examines expression of MCT -1 and -4 as well as a specific chaperone protein needed for the surface expression of these proteins, CD147. This chapter confirms the presence of both MCT -1 and -4 and CD147 in normal B cells as well as demonstrating for the first time that these transporters are expressed in CLL cells using Western blotting and qRT-PCR to assess the MCTs and flow cytometry to measure CD147. The levels of both MCTs and CD147 are demonstrated to be significantly reduced in CLL cells in comparison normal B cells likely due to the adoption of a quiescent phenotype to aid cell survival. The following chapter investigates this further by assessing whether there are any changes in expression under the influence of microenvironmental stimuli, specifically CD40 ligand (CD40L). In this chapter it is demonstrated for the first time that MCT4 is upregulated in CLL cells in response to CD40L. Analysis of gene expression using a Fluidigm Biomark™ array suggests this is due to the induction of glycolysis and that CLL cells may promote fatty acid synthesis as well as instigating changes in the metabolism of the tumour stroma possibly to provide substrates. Finally, chapter 4 evaluates the sensitivity of CLL cell lines to AZD3965 using cell death and cell viability assays. Both MEC-1 and HG3 CLL cell lines are shown to be resistant to MCT1 inhibition using AZD3965 and silencing of MCT4 using siRNA cells also has no effect on the viability of MEC-1 cells. That MCT4 can compensate for MCT1 inhibition is shown by the transient expression of MCT4 in a Raji cell line where only MCT1 is expressed. Taken together, the data presented in this study indicates that while the inhibition of MCT1 is likely to be ineffective dual inhibition of both MCT -1 and -4 may be a viable strategy for the localised inhibition of CLL in the secondary tissues. Furthermore, MCT inhibition in this disease may have the potential to negate mechanisms of resistance and protection from oxidative stress mediated by CD40L.