Beyond the NFAT Horizon: From Cyclosporine A-Induced Adverse Skin Effects to Novel Therapeutics

The immunophilin ligand, cyclosporine A (CsA), which inhibits nuclear factor of activated T cells (NFAT) activity, is a cornerstone of immunosuppressive therapy. Yet, the molecular basis of its prominent, nonimmunosuppression-related adverse skin effects, namely drug-induced excessive hair growth (hypertrichosis), is insufficiently understood. Here, we argue that analysis of these adverse effects can uncover clinically important, previously unknown mechanisms of CsA and identify new molecular targets and lead compounds for therapeutic intervention. We exemplify this through our recent discovery that CsA suppresses the potent Wnt inhibitor, secreted frizzled related protein (SFRP)1, in human hair follicles, thereby promoting hair growth and causing hypertrichosis. On this basis, we advocate a new focus on deciphering the molecular basis of the adverse effects of CsA in suitable human model systems as a lead to developing novel therapeutics. Cyclosporine A (CsA) is a potent immunosuppressant that is required to prevent transplant rejection.CsA treatment leads to a wide range of adverse effects such as hypertrichosis. This adverse effect has served as a blueprint to identify novel strategies to enhance human hair growth.The molecular basis of CsA is thought to occur via canonical nuclear factor of activated T cells (NFAT) inhibition in murine models. However, recent mechanistic work in human tissue reveals nonimmunosuppressive NFAT-independent mechanisms through enhancing Wnt activity.Therefore, it is time to look beyond the NFAT horizon and explore the molecular basis of the complex adverse effects of CsA as a research strategy for identifying novel and well-tolerated therapeutics

Covariates of Intraspecific Variation in Hibernation Expression in the Northernmost Population of Black-tailed Prairie Dogs

Hibernation is an energy-saving strategy employed by species to survive periods of low resource abundance and inclement weather. Due to the costs and benefits associated with the use of torpor and arousal during hibernation, individuals are predicted to hibernate according to their energetic state entering hibernation and their requirements following hibernation. The timing and quantity of energetic requirements following hibernation can vary between the sexes due to differences in selective pressures. Thus, there is potential for sexual variation in hibernation expression to exist. Species and/or populations that exhibit individual variation in hibernation expression lend themselves as an ideal species to test such predictions. Black-tailed prairie dogs (Cynomys ludovicianus) are a species that demonstrates tremendous variation in over-winter thermoregulatory strategies across their range. Prairie dogs within Canada comprise the northernmost population of this species and are the only population of black-tailed prairie dogs known to consistently hibernate over winter. Previous studies reveal variation in hibernation expression within this population. Yet, it is currently unknown what influences this variation, and in general, this unique aspect of their biology remains understudied. However, recent study indicates that males and females differ in their overwinter winter mass loss which may result from differences in hibernation expression. In this thesis, I investigated the role of sex and pre-hibernation body condition on hibernation expression and over-winter energy expenditure in a single colony of prairie dogs located in Grasslands National Park, SK, CA. First, I investigated whether males and females differed in their hibernation expression and energy expenditure by assessing the use of various hibernation traits and quantifying over-winter change in body condition. I found that females had longer hibernation periods, used more bouts of torpor, and overall spent a greater amount of time in torpor compared to males. However, males spent a greater proportion of their shorter hibernation period in torpor and used longer, colder bouts of torpor. Despite differences in hibernation expression, I did not find any evidence that males and females lost similar amounts of condition over winter, though males appeared to lose condition at a faster rate. However, results regarding over-winter changes in body condition should be interpreted with caution due to discrepancies between when male and female prairie dogs hibernated relative to when I recorded body condition measurements. I also conducted a supplemental feeding trial during a portion of the pre-hibernation fattening period of prairie dogs to expand variation in pre-hibernation body condition and combined this data with previously existing data to investigate the influence of pre-hibernation body condition on hibernation expression and over-winter change in body condition. I found that, relative to individuals in poor condition, individuals in better pre-hibernation body condition did not shorten the duration of the hibernation period but did reduce the proportion of the hibernation period spent torpid and increased the length of arousal bouts. Prairie dogs in good pre-hibernation body condition did experience a greater decrease in body condition over winter but still emerged from hibernation in better condition compared to individuals of a poorer condition. The work presented in this thesis increases our understanding of a relatively unknown aspect of black-tailed prairie dog biology - hibernation. Additionally, this thesis improves our understanding of the factors that influence hibernation expression and how individuals alter their use of hibernation with respect to their energetic condition. Future research investigating prairie dog body mass dynamics immediately after hibernation and the effects of sociality and predation on hibernation could be explored to further our understanding of hibernation use. Increasing our understanding of the factors that influence intraspecific variation in hibernation expression can lead to advances in understanding how hibernation evolved as well as aid us in our predictions of if and how populations will respond to changing environments

Science Applications Forum Enhancing fisheries education through the Canadian Fisheries Research Network: a student perspective on interdisciplinarity, collaboration and 4 inclusivity 5 6

Abstract 31 Fisheries sciences and management involve complex problems not easily addressed by a single 32 set of stakeholders or methodologies from one discipline; accordingly, the Canadian Fisheries 33 Research Network (CFRN) was initiated to increase fisheries research capacity in Canada 34 through interdisciplinary and inclusive research collaborations. We compared the value of the 35 CFRN students' learning experience to that offered in traditional fisheries programs at Canadian 36 universities in training post-graduate students to tackle complex fisheries problems. This paper 37 presents 1) a review of the current state of fisheries education across Canada and 2) reflections 38 on our training within the CFRN, and challenges to implementing its innovative approach to 39 fisheries education. We found few dedicated fisheries programs in Canada and concluded that 40 fisheries research typically relies on securing a supervisor with an interest in fisheries. In 41 contrast, the CFRN enhanced our university training through interdisciplinary and inclusive 42 research collaborations, and by exposure to the realities of industry, government and academics 43 collaborating for sustainable fisheries. We propose a new approach to post-graduate level 44 fisheries education, one that combines interdisciplinarity, collaboration, and inclusivity to 45 produce more capable fisheries scientists and managers. Furthermore, we made 46 recommendations on how universities, researchers, and funding agencies can successfully 47 incorporate these themes into fisheries education. 4

Effects of reflux laryngitis on non-nutritive swallowing in newborn lambs

Reflux laryngitis in infants may be involved not only in laryngeal disorders, but also in disorders of cardiorespiratory control through its impact on laryngeal function. Our objective was to study the effect of reflux laryngitis on non-nutritive swallowing (NNS) and NNS-breathing coordination. Two groups of six newborn lambs, randomized into laryngitis and control groups, were surgically instrumented for recording states of alertness, swallowing and cardiorespiratory variables without sedation. A mild to moderate reflux laryngitis was induced in lambs from the experimental group. A significant decrease in the number of NNS bursts and apneas was observed in the laryngitis group in active sleep (p=0.03). In addition, lower heart and respiratory rates, as well as prolonged apnea duration (p<0.0001) were observed. No physiologically significant alterations in NNS-breathing coordination were observed in the laryngitis group. We conclude that a mild to moderate reflux laryngitis alters NNS burst frequency and autonomous control of cardiac activity and respiration in lambs

The coloniality of infrastructure: Engineering, landscape and modernity in Recife

Geographical scholarship has, since the late 1990s, shown how infrastructure was central to the making of urban modernity and the metabolic transformation of socio-natures. Meanwhile, the work of Latin American scholars including Aníbal Quijano and Maria Lugones has focussed attention on the imbrications between modernity and coloniality, in particular through the international racial division of labour. Moving between these ideas, I argue that there is intellectual and political ground to be gained by specifically accounting for the coloniality of infrastructure, in both its material and epistemic dimensions. I ground the analysis in the history of Recife, Northeast of Brazil, analyzing the role of British engineering in the production of the city's landscape and infrastructure, and address the epistemic dimensions of the coloniality of infrastructural by exploring infrastructural spectacle in 1920s Recife. Finally, I explore how the coloniality of infrastructure directs our attention to race, labour and finance

The Channel Tunnel and its Early History—I

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Charing Cross Station and Hotel

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