Objectif - Réaliser une étude en morphométrie géométrique pour définir la variabilité des sinus frontaux et maxillaires au sein d’une population adulte et pour l’établissement du profil biologique des individus à partir de la géométrie des sinus frontaux et maxillaires.- Valider un modèle de simulation numérique des écoulements pour l’étude de la ventilation nasosinusienne chez l’adulte et observer l’influence de la conformation sinusienne sur la ventilation nasosinusienne.Nous avons défini 20 landmarks fiables et reproductibles pour les sinus frontaux et maxillaires. Nous avons décrit la variabilité des sinus frontaux et maxillaires au sein d’un échantillon de population adulte. Enfin, nous avons mis en évidence l’existence d’allométries pour les sinus frontaux et maxillaires mais aussi l’existence d’un dimorphisme sexuel pour la conformation des sinus maxillairesNous proposons un modèle fiable de simulation numérique des écoulements à partir d’examen tomodensitométriques. Sur la base de ce modèle, nous n’avons pas mis en évidence d’influence de la conformation sinusienne sur la ventilation nasale et le conditionnement thermique de l’air inspiré et expiré. / Objectives - to conduct a morphometric geometric study in order to define the variability of the frontal and maxillary sinuses in an adult population and to determinate the sex of individuals - to validate a Computational fluid dynamic model of the nasal airflow and to describe the influence of the sinus conformation on the nasal airflow.We defined twenty reliable and reproducible landmarks for frontal and maxillary sinuses. We described the variability of the frontal and maxillary sinuses in an adult population sample. Finally, we highlighted the existence of allometries for frontal and maxillary sinuses but also the existence of a sexual dimorphism in the conformation of the maxillary sinusesComputational fluid dynamics:We offer a reliable model for numerical simulation of flows from CT examination. Based on this model, we have not shown any influence of the conformation on the nasal sinus ventilation and thermal conditioning of the inhaled and exhaled air. We showed no ventilation in the sinuses in the nasal respiratory cycle. Future studies will endeavor to define a humidity conditioning air model and a simulation model of production of NO and gas exchange between sinuses and nasal cavities.

The objective of this study was to investigate the role of organic cation transporters (OCTs) in the uptake of hydrophilic drugs into the olfactory bulb and subsequently to the brain. Two OCT2 substrates, amantadine and cimetidine were used as model drugs for this purpose. Bovine nasal explants (olfactory and respiratory tissue) were used as an in vitro model for preliminary screening to identify the role of transporters involved in the uptake of drug across these tissues. It was observed from both PCR and immunohistochemistry that OCTs, OCT2, OCTN1 and OCTN2 were present in the bovine respiratory and olfactory mucosa. Transport studies of amantadine in the presence and absence of OCT2 and OCTN2 inhibitors indicated that both these transporters play a role in the transport of amantadine across the bovine respiratory mucosa, whereas transport across the olfactory mucosa was predominantly via OCT2. This was followed by in vivo studies in rats where the blood, striatum and olfactory bulb concentrations of amantadine were determined following intranasal and intra-arterial administration. Shortly after nasal administration, the olfactory bulb concentrations exceeded the concentrations in the striatum suggesting the olfactory pathway to be the major route of uptake. Co-administration of the drug with an OCT2 inhibitor intranasally showed statistically significant reductions in the brain uptake of amantadine. A synergistic inhibitory effect on amantadine uptake was observed with the combined inhibition OCT2 and OCTN2. Additionally, the CNS exposure of these drugs following intranasal administration in the presence and absence of the OCT inhibitors was evaluated using the ratio of the free drug concentrations in the brain compared to plasma. While the plasma concentration profiles were similar both in the presence and absence of inhibition, the free drug ratios were highest when no inhibitor was included. Additionally similiar in vivo studies were also carried out for a second model drug, cimetidine, where cimetidine uptake into the rat brain was found to be significantly reduced in the presence of the OCT2 inhibitor, pentamidine. This demonstrates that there was a greater CNS exposure to each drug when OCT transporters were active, confirming their role in their direct CNS distribution from the nasal cavity to the brain. The results of this study suggest that OCT substrates might be good candidates for the delivery to the brain via the olfactory route.

Critical velocity is defined as projectile striking velocity that causes instantaneous rupture of the specimen under transverse impact. The main goal of this dissertation was to determine the critical velocities of a Twaron^® 2040 warp yarn impacted by different round indenters. Special attention was placed to develop models to predict the critical velocities when transversely impacted by the indenters. An MTS 810 load frame was utilized to perform quasi-static transverse and uniaxial tension experiments to examine the stress concentration and the constitutive mechanical properties of the yarn which were used as an input to the models. A gas/powder gun was utilized to perform ballistic experiments to evaluate the critical velocities of a Twaron^® 2040 warp yarn impacted by four different type of round projectiles. These projectiles possessed a radius of curvature of 2 μm, 20 μm, 200 μm and 2 mm. The results showed that as the projectile radius of curvature increased, the critical velocity also increased. However, these experimental critical velocities showed a demonstrated reduction as compared to the classical theory. Post-mortem analysis via scanning electron microscopy on the recovered specimens revealed that the fibers failure surfaces changed from shear to fibrillation as the radius of curvature of the projectile increased. To improve the prediction capability, two additional models, Euler-Bernoulli beam and Hertzian contact, were developed to predict the critical velocity. For the Euler–Bernoulli beam model, the critical velocity was obtained by assuming the specimen ruptured instantaneously when the maximum flexural strain reached the ultimate tensile strain of the yarn upon impact. On the other hand, for the Hertzian contact model, the yarn was assumed to fail when the indentation depth was equivalent to the diameter of the yarn. Unlike Smith theory, the Euler-Bernoulli beam model underestimated the critical velocity for all cases. The Hertzian model was capable of predicting the critical velocities of a Twaron^® 2040 yarn transversely impacted by 2 μm and 20 μm round projectiles.

abstract: Desert ecosystems of the southwest United States are characterized by hot and arid climates, but hibernating bats can be found at high altitudes. The emerging fungal infection, white-nose syndrome, causes mortality in hibernating bat populations across eastern North America and the pathogen is increasingly observed in western regions. However, little is known about the ecology of hibernating bats in the southwest, which can help predict how these populations may respond to the fungus. My study investigated hibernating bats during two winters (2018-2019/2019-2020) at three caves in northern Arizona to: (1) describe diversity and abundance of hibernating bats using visual internal surveys and photographic documentation, (2) determine the duration of hibernation by recording bat echolocation call sequences outside caves and recording bat activity in caves using visual inspection, and (3) describe environmental conditions where hibernating bats are roosting. Adjacent to bats, I collected temperature and relative humidity, which I converted into absolute humidity. I documented hibernation status (i.e. active vs. not active) and roosting body position (i.e. open, partially hidden, and hidden). Between September 2018 and April 2019, 246 bat observations were recorded across the three caves. The majority of bats were identified as Myotis spp. (45.9\%, n=113), followed by Corynorhinus townsendii (45.5\%, n=112), Parastrellus hesperus (4.8\%, n=12), Eptesicus fuscus (3.6\%, n=9). Between September 2019 and April 2020, I documented a total of 361 bat observations across the three caves. C. townsendii was most prevalent (52.9\%, n=191), followed by the category P. hesperus/Myotis spp. (25.7\%, n=93), Myotis spp. (12.4\%, n=45), P. Hesperus (4.4\%, n=16), E. fuscus (3.6\%, n=13) and Unknown (0.8\%, n=3). Average conditions adjacent to bats were, temperature=12.5ºC, relative humidity=53\%, and absolute humidity=4.9 g/kg. Hibernating bats were never observed in large clusters and the maximum hibernating population size was 24, suggesting low risk for pathogen transmission among bats. Hibernation lasted approximately 120 days, with minimal activity documented inside and outside caves. Hibernating bats in northern Arizona may be at low risk for white-nose syndrome based on population size, hibernation length, roosting behavior, and absolute humidity, but other variables (e.g. temperature) indicate the potential for white-nose syndrome impacts on these populations. / Dissertation/Thesis / Masters Thesis Biology 2020

This master’ thesis deals with the design of the front landing gear for Zlín 40 aircrafts. The main emphasis in the research part of the work is placed on the selection of a new nose landing gear and the subsequent design of the structure. For the structural design was prepared a new mass analysis and load cases. The load-bearing capacity of the structure is verified using analytical and numerical methods of FEM. An important step of the work is the design concept of structure. The aim of the work is to point out the new possibilities of the nose landing gear structure and verify its feasibility for the case of future implementation.

High grade gliomas remain a devastating disease, for which a curative therapy is virtually absent. The high medical need is unmet by novel treatment strategies and advances in chemo-and radiotherapy. Patients diagnosed for GBM face a median survival of 15 months after maximal standard-of-care therapy, and relapse is often observed due to micro-metastasis in the direct environment of resection. In part, current treatment modalities such as chemo-and immunotherapy are hampered in their efficacy due to the specialized TME. This area is adequately equipped to withstand the cytotoxic attack of chemo- and immunotherapy. Therefore, we hypothesized that modulation of the TME could decrease these defense mechanisms, and increase susceptibility to tumor lysis.In this respect, we focused on Gal-1 as an ideal target to modulate the TME in the context of GBM. Gal-1 exerts multiple tumor promoting functions. From pre-clinical research, we have learned that Gal-1 is an important mediator for the proliferation and migration of tumor cells, moreover Gal-1 could also promote angiogenesis in the TME, providing nutrients and oxygen for GBM to grow. Gal-1 also maintains the inherent defense mechanisms to chemo and immunotherapy. Gal-1 is crucial for the resistance mechanisms to TMZ by altering the EPR stress response. Moreover, and most important for our purposes, Gal-1 is also a crucial immune suppressor in the TME, which can induce apoptosis in activated T cells, and recruit Tregs. To target Gal-1 in the TME would be clinically most relevant if this could be performed via a non-invasive treatment modality. Therefore, we developed a nanoparticle complex that could deliver siGal-1 from the nasal cavity directly to the CNS, and even the TME. This nose-to-brain delivery bypasses systemic routes, with a higher (and more selective) local bioavailability in the CNS. The major pharmaceutical excipient in this nanoparticle complex consists of chitosan polymers. These polymers are highly interesting agents to promote nose-to-brain delivery due their muco-adhesive and epithelial barrier modulation properties. When applying these particles in vitro on GBM cells, a solid decrease of Gal-1 was noted, and the epithelial modulatory properties were confirmed. Furthermore, we observed a rapid transport from the nasal cavity to the brain upon intranasal administration of a highly-concentrated chitosan nanoparticle siGal-1 suspension and we could even observe the sequence-specific cleavage of Gal-1 mRNA, and a decrease of Gal-1 in the TME. This Gal-1 reduction could modulate the TME from immune suppression to immune activation, as demonstrated by decrease in suppressor cells, and increased stage of activation in rejective immune cells. Moreover, due to decreased Gal-1, also angiogenesis was alleviated, and a reduced size in vasculature was observed, mimicking a morphological vessel normalisation. Reversing the immune and vascular contexture of the TME by Gal-1 reduction seemed a prerequisite to increase the efficacy of TMZ, DC vaccination and PD-1 blocking. In combination experiments, we noticed that siGal-1 on top of these treatments, could further increase the efficiency of chemo and immunotherapy. The findings presented in this thesis can serve as a proof of concept for the feasibility to modulate and re-orchestrate the TME of GBM via intranasal administration. The intranasal administration of siGal-1 could represent a valuable clinically translational treatment to increase the efficiency of chemo- and immunotherapy for GBM patients. In our research facilities, a phase 0 as a first-in-human trial is actively pursued. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

For many years, the nasal route of administration as part of a therapeutic treatment has been used. This route of administration is easy to implement, especially due to its non-invasiveness the ease of administration that it affords for the patient. In addition, it is suitable for chronic treatment as well as for an emergency situation when the patient is unconscious. For instance, the administration of benzodiazepines, such as midazolam, may be done to stop convulsions in a patient.Traditionally, intranasal administration was mainly borrowed to target a local effect (e.g. treatment of a cold with a decongestant agent). Subsequently, its application for systemic delivery (e.g. treatment of migraine with triptans) was more and more frequently considered. However, the administration of a drug in the nasal cavities for systemic delivery still remains limited. Indeed, even if the intravenous route has several major limitations such as its invasiveness or the pain generated during administration, it remains more widely used than the intranasal route. This can be explained, on the one hand, by the knowledge that was relatively limited regarding the nasal delivery but also because of the unavailability of nasal devices allowing precise control of the nasal administration (i.e. accurate dose delivery, strong deposition in the nasal cavity, etc).Subsequently, the intranasal route has led to a third therapeutic targeting, namely, the “nose-to-brain pathway”. In that case, the nasal cavity was considered as an opportunity to access the central nervous system (CNS). Indeed, the nose-to-brain delivery allows reaching the brain while bypassing the blood-brain barrier which is known to be a major obstacle to the diffusion of drugs in the CNS. Moreover, the passage through the nasal cavity would allow the administration of sensitive molecules (e.g. biopharmaceuticals) while avoiding excessive enzymatic degradation.Therefore, the nose-to-brain pathway appears to be an attractive route for the delivery of unstable molecules, requiring an access to the brain to reach their site of action. In this context, the therapeutic target that has been selected was "cachexia". It is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. It usually results in particular from undernutrition and a generalized inflammatory state in the patient. In order to treat this syndrome and to restore the appetite in these patients, the goal was to use ghrelin (GHRL) as a model drug. GHRL is a peptide hormone that exhibits, among other effects, an orexigenic action. This biopharmaceutical needs to reach its receptors, located in the hypothalamus, to exert its therapeutic effect.In this study, the goal was to develop a formulation that was able to protect GHRL during its nasal administration, while increasing its residence time to promote its diffusion through the nasal olfactory epithelium.In the first part of the project, GHRL was mainly characterized in terms of stability (e.g. temperature and pH), but also in terms of surface charge. These results allowed selecting the most suitable strategy of formulation as well as the optimal storage conditions. After these preformulation evaluations, it was decided to work on the development of a liquid formulation. The first formulation was based on micelles composed of lipids with polyethylene glycol "DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol) -2000] (ammonium salt)" as hydrophilic group. This type of pegylated lipids have already shown, in many scientific studies, interesting properties in the context of intranasal administration, especially in terms of mucopenetration. With a slight adaptation of the protocol found in the literature, it was possible to obtain micelles of an adequate size (~15 nm). The micelles produced also showed good ability to encapsulate GHRL with an encapsulation rate of 98%, but micelles of DSPE-PEG failed to increase the GHRL diffusion through epithelial layer. This step is essential in order to obtain high GHRL levels in the brain. The formulation containing DSPE-PEG micelles has thus been abandoned.Still in the goal of combining lipid excipients with hydrophilic polymer, another formulation strategy based on liposomes coated with chitosan has been considered. Since GHRL has a positive charge at physiological pH, anionic liposomes have been developed to get a high loading. Three types of liposomes have been produced: anionic, neutral and cationic. The objective was to evaluate the influence of the liposomes charge on GHRL encapsulation. By working with anionic liposomes, the loading could be 46% higher than that obtained from the cationic liposomes. In order to evaluate a potential relation between the amount of GHRL that was encapsulated in the liposomes and the amount of GHRL that could potentially be degraded in the presence of enzyme, the three types of liposomes were exposed to trypsin. Following enzyme exposure, anionic liposomes showed enzymatic protection 4 times higher than cationic liposomes. These anionic liposomes have also shown high GHRL protection in the presence of another enzyme with another mechanism of digestion, namely, carboxylesterase-1. Subsequently, isothermal titration calorimetry tests were performed to better understand the interaction mechanisms between GHRL and anionic liposomes. This technique showed that hydrophobic interactions between both compounds were predominant. The coating of anionic liposomes by chitosans was performed and confirmed by an increase of the mean diameter (+48 nm) and charge (+6 mV) as well as by the modification of the morphology of the liposomes. This coating of liposomes with chitosans was supposed to confer additional properties to the formulation such as mucoadhesion and permeation enhancement. These both effects can be obtained thanks to the positive charge of chitosans which allows adhering to the mucins of the mucus, on the one hand, and thanks to the opening of the epithelial tight junctions that enhances drug permeation, on the other hand. The chitosan coating allowed increasing the fixation of the liposomes to mucins by about twenty percent compared to uncoated liposomes. In addition, the "absorption promoter" effect of chitosans was confirmed on cells culture. Then, the formulation was introduced into two distinct nasal devices intended for the administration of liquid nasal sprays, namely, the VP3 device from Aptar Pharma and the SP270 device from Nemera. The aerosols produced by each device allowed generating droplets characterized by a mean diameter higher than 10µm, leading to potential satisfactory impaction onto the olfactory region instead of diffusion throughout posterior region of the nasal cavities. In the second part of the work, a dry formulation was produced by spray-drying from the liquid dispersion of coated liposomes. The objective was to increase the stability of GHRL during storage as well as to enhance its remanence and diffusion through the olfactory epithelium. The optimized parameters allowed producing a powder characterized by a mean diameter higher than 10 μm with an acceptable yield. The powder produced exhibited a low residual moisture and showed good homogeneity in terms of GHRL content. Then, a comparative study was carried out between the powder and the liquid formulation to compare the GHRL stability over time during storage at different temperatures (4°C and 25°C) but also their ability to fix mucins. In both cases, the dry powder showed better results The powder was also re-dispersed in aqueous phase to evaluate the ability of the liposomes to be reconstituted without modifying their physicochemical properties (e.g. size distribution, charges, stability). It was demonstrated that the majority of the initial properties could be preserved after reconstitution (i.e. rate of encapsulation). Similarly to the liquid formulation, the powder was loaded into a specific device developed for the nasal administration of powders that allows targeting the olfactory region to optimize the nose-to-brain transfer. The device, "UDS - Unit Dose System " from Aptar Pharma, has shown excellent properties in terms of particle size distribution in the aerosol but also in terms of targeting the olfactory zone. The latest was studied by means of "nasal cast" that is a 3-printed model of artificial nasal cavities. After impaction in the different cavities of the cast, it was possible to quantify the amount of GHRL that was deposited in the olfactory zone. Using our optimized formulation in combination with the device developed by Aptar, it was shown that 52% of the powder was impacted onto the area corresponding to the olfactory region. Such data demonstrated the relative difficulty to target this section of the nasal cavities.Finally, the formulation loaded with fluorescent GHRL was intranasally administered in mice. It was demonstrated that GHRL could reach the brain after intranasal administration of the formulation and that the formulation was essential to allow this transfer to the brain.The administration of such biopharmaceutical by nose-to-brain with this formulation seems to be an interesting alternative to exploit. However, additional studies to quantify this transfer more precisely, to better define its kinetics and also to evaluate the efficacy of the treatment should be carried out. / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

Since white-nose syndrome (WNS) arrived in the northeastern U.S. in 2006, several affected bat species have exhibited marked population declines (> 90%). For areas such as Fort Drum in northern New York that are subject to regulatory mandates because of the presence of the endangered Indiana bat (Myotis sodalis), acoustic monitoring is now likely more effective than traditional capture methodologies. In the summers of 2011 and 2012, I implemented intensive acoustic sampling using Anabat detectors at Fort Drum to develop a summer acoustic monitoring protocol that is both cost efficient and effective at detecting species of high conservation or management interest, such as the Indiana bat and the little brown bat (Myotis lucifugus). Habitat analysis of radio telemetry data and occupancy models of acoustic data were congruent in confirming nocturnal spatial use of forested riparian zones by little brown bats.  Additionally, occupancy models of passive versus active sampling revealed that passive acoustic sampling is preferable to active sampling for detecting declining species in the post-WNS context. Finally, assessment of detection probabilities at various arrays of acoustic detector layouts in an expected area of use revealed that a grid of detectors covering a wide spatial extent was more effective at detecting Indiana and little brown bats than permanent stations, transects, or double transects. My findings suggest that acoustic monitoring can be affectively implemented for monitoring Indiana and little brown bats even in areas of severe decline. Future efforts should be aimed at determining effective sampling designs for additional declining species. / Master of Science

Diese aus drei verschiedenen Studien bestehende Arbeit trägt mittels Verknüpfung von Anatomie (Struktur) und Physiologie oder Verhalten (Funktion) zu einem besseren Verständnis von somatosensorischer Informationsverarbeitung bei. In der ersten Studie untersuchten wir wie das Nervensystem der Ratte sich an das kontinuierliche Nachwachsen und Ausfallen der Tasthaare anpasst. Unsere Ergebnisse zeigen, dass Barrel-Kortex Neurone nach Auslenkung von sowohl jungen oder alten Tasthaaren ähnliche neuronale Antworten aufweisen. Wir konnten auch beobachten, dass junge und alte Tasthaare gemeinsam im Follikel innerviert werden und im Kortex nicht separat topologisch repräsentiert sind. Diese Ergebnisse könnten erklären wie die Stabilität von Wahrnehmung während fortlaufenden körperlich-sensorischen Veränderungen gewährleistet wird. In der zweiten Studie identifizierten wir Details der kortikalen Nasen Repräsentation und konnten zeigen, dass die Organisation von Schicht 4 im Somatosensorischen Kortex in Nagetieren konserviert ist. Wir fanden auch eine Kopplung von Nervenzellaktivität mit der Atmung, was für eine koordinierte Verarbeitung von Tastsinn und Atmung im Nasen-Somatosensorischen Kortex spricht. In der dritten Studie charakterisierten wir die kortikale Repräsentation der Schnauze im Hausschwein und konnten zeigen, dass dessen makroskopische, drei-dimensionale Erscheinung viele Details aufweist, die auch bei der tatsächlichen Schnauze zu finden sind. Ähnlich wie bei unseren histologischen Beobachtungen im Nasen- Somatosensorischen Kortex von Nagern konnten wir im Hausschwein Kortex eine Verjüngung von Schicht 4 der mutmaßlichen Repräsentation des Nasenlochs beobachten. Zusammengefasst zeigt diese Arbeit i) einen potentiellen Mechanismus für Kontinuität der Wahrnehmung während körperlichen Veränderungen ii) Details der kortikalen Nasen-Repräsentation und dessen Verhältnis zur Atmung und iii) isomorphe Eigenschaften der kortikalen Schnauzen-Repräsentation im Hausschwein. / Topological mapping of body part representations in the brain have long been studied in neuroscience. In this thesis, three separate studies investigate such somatosensory representations by relating anatomy (structure) to physiology or behavior (function). In the first study we investigated whether and how the rat nervous system adapts to whiskers regrowth. We found that barrel cortex neurons displayed similar response properties to young and old whisker deflection and that both whiskers share their peripheral innervation in the same follicle. Our results further suggest that young and old whiskers do not form topologically distinct representations in the cortex. Such findings illuminate how perceptual stability is maintained despite the constant change of bodies and sensory structures. In the second study we identified the rodent nose somatosensory cortex and found that its tangential layer 4 organization is conserved across rodents. We also found significant respiration locked neural activity in the rat nose somatosensory cortex, suggesting coordinated processing of touch and respiration. In the third study we characterized the pig rostrum somatosensory cortex and found that its three-dimensional, gross organization matches the detailed structure of the actual rostrum appearance. We also found that layer 4 appears thinner in the putative nostril, similar to our results in the rodent nose somatosensory cortex. Collectively, our data i) reveal potential mechanisms for perceptual stability during bodily changes ii) identify the rodent nose somatosensory cortex and its relationship to respiration and iii) a striking isomorphism of the pig cortical rostrum representation with the pig snout.

Emerging infectious diseases of wildlife are among the greatest threats to biodiversity. Indeed, when pathogens are introduced into naïve host populations, they can impose novel selective pressures that may cause severe host declines or even extinction. However, disease impacts may vary both within and among host species. Thus, one of the key goals for management is to identify factors that drive variation in host susceptibility to infection, as they may improve our understanding of hosts' potential to develop disease resistance and/or tolerance and inform conservation strategies aimed at facilitating host persistence. For instance, Pseudogymnoascus destructans (Pd) - an invasive pathogenic fungus that causes white-nose syndrome (WNS) in hibernating bats - is highly virulent, has killed millions of bats in North America, and continues to spread at an alarming rate. Yet, the continued persistence of bat colonies in contaminated areas despite initial mass mortality events suggests variation in survival among infected individuals. I thus aimed to better understand intraspecific drivers of variation in bat susceptibility to WNS and their implications for population persistence and management in affected areas. Specifically, my objectives were to: 1) evaluate the extent to which variation in hibernaculum microclimate temperature and humidity affects Pd infection severity and disease progression in affected bats during hibernation, 2) compare how bats from colonies that vary in duration of exposure to Pd and from different age classes behaviorally respond to the infection, and examine how these behavioral changes affect host fitness and 3) model the population dynamics of remnant bat populations to assess the likeliness of persistence and the potential effectiveness of management interventions in affected colonies. I addressed these objectives through field research, experimental infection studies, and demographic modeling of the little brown myotis (Myotis lucifugus). In my dissertation, I first provide causal evidence of environmentally-driven variation in pathogen growth and infection severity on bats in the field. Both warmer and more humid microclimates contribute to the severity of the infection by promoting the production of conidia, the erosion of wing tissues, and, therefore, the transmission potential and virulence of Pd. I then document potential mechanistic links between Pd-induced behavioral change and host fitness. Higher infection levels, independent of bats' past exposure to Pd or age class, may cause individuals to groom longer, prolong euthermic arousals, accelerate the depletion of fat reserves, and ultimately increase mortality risk. Finally, I predict that populations will face a high risk of extirpation in the next decade or two if no management action is taken, but that interventions such as environmental control of Pd and hibernaculum microclimate manipulation can prevent short-term population collapse in remnant bat populations. Together, these studies provide key, mechanistic insight into the pathology of WNS and the probability of persistence of affected bat colonies, while highlighting the importance of prioritizing winter habitat preservation and enhancement for the conservation of hibernating bats. / Biology