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Onychomycosis is fungal infection of toe nails or fingernails caused by a fungal microbe that invades the nail bed. It is the most common disease of the nails and constitutes about a half of all nail abnormalities and may affect toenails or fingernails, but toenail infections are particularly common. It occurs in about 10 percent of the adult population. The most common symptoms of fungal nail infection are thickening and discoloration of the nail. Treatment of onychomycosis is challenging because the infection is embedded in the nail making it difficult for the drug to diffuse to the site of infection. Onychomycosis is an opportunistic infection in people with compromised immune function and in those with diabetes, psoriasis, HIV/AIDS etc. Onychomycosis affects patients’ physical and psychological health and has a negative impact on overall quality of life. Oral administration of antifungal agents has been the mainstay in treatment of onychomycosis such as griseofulvin, terbinafine and itraconazole, but has limitations of systemic adverse events and drug interactions, whereas several drugs have been approved for topical administration but their efficacy is limited by the low permeability of the nail plate. This study evaluated the preformulation transungual permeability of econazole nitrate and formulation development of a transungual topical patch utilizing penetration enhancers in combination with econazole nitrate to optimize the delivery and penetration through the nail. The objectives of this project were to: 1) determine the critical factors for the in vitro transungual delivery of econazole nitrate, 2) design and develop a transungual formulation containing econazole nitrate and selection of the penetration enhancers, and 3) characterize the physical characteristics and functional properties of a novel transungual formulation. There were ten penetration enhancers being screened in this project according to the enhancement for saturation solubility, in vitro nail penetration and in vitro skin permeation and penetration of the antifungal drug econazole nitrate. Unlike transdermal drug delivery, the selection requirements for skin penetration enhancer were to increase drug accumulation in the epidermis and decrease the amount in the dermis to avoid unnecessary systermic absorption (Palliyil, et al. 2013). Thiourea (TU) improved the solubility and nail penetration of econazole nitrate. It also produced enhancement in the transungual diffusion of the drug. It was selected as the nail permeation enhancer and skin penetration enhancer for econazole nitrate. In the pH study, pH 5 ammonium phosphate buffer was the most effective pH for both enhancing the amount of drug in the nail and decreasing keratin binding. This resulted in increased accumulated of free drug in the target nail. In the formulation screening study, pressure sensitive adhesives (PSA), polyisobutylene, polysiloxane and polyacrylate classes of adhesives, were screened to develop a monolithic drug-in-adhesive type nail patch. Increasing the concentration of TU from 1% to 2.5% resulted in drug crystallization in the dry patch, therefore the concentration of 1% (w/w) TU was selected for all further screening. The concentration of econazole nitrate, propylene glycol and triethyl citrate were screened at 2.5%, 10% and 10% accordingly to ensure high drug release rate with no drug crystallization. The in vitro drug release rate of EN from the patch was improved with propylene glycol and hydrophobic plasticizer triethyl citrate. Polyvinylpyrrolidone was added to the patch formulation to lower the pH of the patch. This resulted in a greater concentration of ionized EN. The nail permeation and penetration of EN were studied in vitro using human cadaver toenails mounted in Franz diffusion cells. Thiourea, when formulated in the novel nail patch, was shown to deliver higher amount of EN into target tissues with a shorter permeation lag time compared to formulations which did not utilize thiourea. / Pharmaceutical Sciences

Onychomycosis is the most common disease of nails and constitutes about a half of all nail abnormalities. The thickness of the nails become the major challenge in developing a topical formulation for treatment on OM. In this study, penetration enhancers are used to enhance the solubility and permeability of the drug enconazole nitrate into the nail and the skin. It turns out of all the penetration enhancers, thiourea is the best choice because it can improve the solubility and nail penetration of econazole nitrate at the same time. / Pharmaceutical Sciences

This thesis is missing page 157, the other copies of the thesis did not have the page either. -Digitization Centr / The polyomavirus enhancer is organized into three elements. One of these elements, Element 2, is particularly interesting because the activities of the factors which interact with it are highly regulated. There are at least three cellular proteins, PEA1, PEA2, and PEA3, which bind to adjacent sites in Element 2. These proteins are differentially active in mouse cells at different developmental stages and their activity is modulated by serum, tumor promoting agents and the products of several oncogenes. It is likely, therefore, that these cellular proteins play an important role in interpreting growth stimuli and other physiological cues in the mouse. A plasmid was contructed which can be used to test enhancer elements for their ability to activate both transcription and DNA replication. This plasmid includes the Py origin of replication and a minimal promoter, consisting of a TATA box only, controlling expression of a reporter gene. The activity of the PEA factors was studied by cloning the binding sites for these factors into this reporter plasmid as monomers, multiple tandem copies, and in paired combinations, and testing their ability to activate transcription and DNA replication in vivo. The results of these studies show that PEA1 and PEA3 can function independently and cooperatively to activate both replication and transcription. By contrast, PEA2 is unable to independently activate transcription and represses PEA1-activated transcription when the binding sites for these factors are located adjacent to one another. However, PEA2 functions cooperatively with PEA1 to activate DNA replication, and can weakly activate replication on its own. / Thesis / Master of Science (MS)

The usage of Unmanned Aerial Systems (UASs), such as quadcopters and hexacopters, has steadily increased over the past few years in both recreational and commercial use. This increased availability to purchase such systems has also given rise to many safety and security concerns. A common concern is that the misuse of a UAS can cause damage to airplanes and helicopters in and around airports. Another growing concern is the use of UASs for terrorist intentions such as using the UAS as a remote controlled bomb. There is clearly a need to be able to detect the presence of unwanted UASs in restricted areas. This thesis work presents the beginning work towards a method to detect the presence of these UASs using the blade pass frequency (BPF) of the motors and rotors of a home made quadcopter. A low cost uniform linear microphone array is first used to perform a simple delay-and-sum beamformer to spatially filter out noise sources. The beamformer output is then divided into sub-bands using three bandpass filters centered on the expected location of the fundamental BPF and its 2nd and 3rd harmonics. For each sub-band, an adaptive filter called an adaptive line enhancer is used to extract and enhance the narrowband signals. The response of the adaptive filters are then used to detect the quadcopter by looking for the presence of the 2nd and 3rd harmonics of the fundamental BPF. Static tests of the quadcopter out in a field showed promising results for this method with the ability to detect up to the 3rd harmonic 90ft away and the 2nd harmonic 130 ft away. / Master of Science / The usage of Unmanned Aerial Systems (UASs), such as quadcopters and hexacopters, has steadily increased over the past few years in both recreational and commercial use. This increased availability to purchase such systems has also given rise to many safety and security concerns. A common concern is that the misuse of a UAS can cause damage to airplanes and helicopters in and around airports. Another growing concern is the use of UASs for terrorist intentions such as using the UAS as a remote controlled bomb. There is clearly a need to be able to detect the presence of unwanted UASs in restricted areas. This thesis work presents the beginning work towards a method to detect the presence of a home made quadcopter based on the sound it produces. A series of microphone are first used to remove surrounding sounds that could interfere with the quadcopter’s sound. The output of this processes is then divided into smaller sections using three filters centered on the expected location of the most important and information rich parts of the quadcopter’s sound. For each section, a final filter is used to extract and enhance the signals of interest produced by the quadcopter. The response of these filters are then used to detect whether the quadcopter is present or not. Static tests of the quadcopter out in a field showed promising results for this method with the ability to detect the quadcopter 90 to 130 ft away.

3 domaines cellulaires définissent l'épiderme de la queue de Ciona intestinalis. Le domaine des lignes médianes, donne naissance à deux structures différenciées larvaires, la nageoire et système nerveux périphérique. Il a été montré que les voies de signalisation BMP et FGF sont respectivement les inducteurs des lignes médianes ventrale et dorsale. Ce travail a consisté en la caractérisation des mécanismes moléculaires, situés à l'interface des signaux inducteurs et des processus de différenciation, définissant l'identité cellulaire des lignes médianes. L'identification des relations épistatiques reliant 7 facteurs de transcription impliqués dans ce processus suggère un fonctionnement en réseau hiérarchisé et place Msxb comme gène clé. Cette hiérarchie est validée par: un atlas d'expression spatio-temporelle, la perte de fonction de Msxb, l'analyse des régions cis-régulatrices de la transcription. Nous avons identifié 2 types d'enhancers, contrôlant respectivement les gènes précoces et tardifs du réseau. L'expression précoce de Msxb dans les précurseurs dorsaux est controlée par un enhancer distinct régulé par la voie FGF relayée par Otx et Nodal. Cette signature transcriptionnelle est retrouvée dans les enhancers de gènes co-exprimés, et chez l'orthologue de Msxb chez une autre ascidie. Enfin, nous montrons que la partie la plus postérieure des lignes médianes constitue un troisième compartiment, déployant un programme génétique distinct. Ce travail nous renseigne sur la structure, les mécanismes moléculaires de formation des lignes médianes, l'existence d'une signature transcriptionnelle évolutivement conservée pour le gène clé de l'acquisition de ce destin cellulaire. / Ciona intestinalis tail epidermis has 8 rows of cells defining 3 domains. One of them, the midline domain, gives rise to differentiated cells which form the larval fin and part of peripheral nervous system. Previous work has shown that BMP and FGF signalling are the inducers of ventral and dorsal midlines respectively. My work consisted in the identification of molecular events which lead epidermal cells to adopt midline fate, from induction to tail differentiation. We identified 7 transcription factors involved in this process. Identification of epistatic relationships suggest that these genes are in a hierarchical network where Msxb is a key gene. This hierarchy is validated by 1) a spatio-temporal expression atlas, 2) loss of function of Msxb, 3) cis-regulatory regions analysis for each network gene. We identified 2 types of enhancers, one capable to decouple ventral / dorsal signals used by early genes, and the other used by later genes, acting as a global response in both midlines. We showed that the early expression of Msxb in dorsal precursors is controled by a distinct enhancer, regulated by FGF9/16/20 via Otx and Nodal. This transcriptional signature is found in enhancers of co-expressed genes and in Msxb orthologue in another ascidian. Finally, we showed the most posterior part of the midlines is controlled by a distinct genetic program than the one used in dorsal and ventral midlines. This work gives insight into midlines structure, the mechanisms involved in their formation and a conserved transcriptional signature for the key gene involved in midline cell fate.

L'étape initiale dans l'expression génique est la transcription de l'ADN génomique du gène en ARN. La transcription être initiée par l'assemblage d'ARN pol II autour du site de début de transcription, qui est également connues comme promoteurs. Cependant, la transcription est nécessite un autre gène distal des régions, des amplificateurs, qui sont augmenté ainsi la probabilité de la transcription. Amplificateurs et les promoteurs sont généralement définis par leur éloigné des sites d'initiation de la transcription et souvent distingués par les modifications des histones. Récemment, des études, il a été de plus en plus ont révélé de grandes similitudes entre les amplificateurs et les promoteurs. Les résultats antérieurs ont suggéré la possibilité que certains promoteurs de gènes peuvent afficher les fonctions activatrices. Cependant l'étendue de ce type de promoteurs et si elles fonctionnent réellement réglementé l'expression des gènes distales sont restés insaisissable.Mon projet est réalisé en vue de répondre à ces questions. En exploitant un essai amplificateurs reporter à haut débit, je démêler une partie sous-estimée du promoteur de base présentant une activité d'activateur, définie comme Epromoters. Ils présentent des propriétés distinctes par rapport à des amplificateurs et des promoteurs classiques distales, sont associés à la réponse au stress et d'interagir plus souvent avec d'autres promoteurs. En utilisant CRISPR complète / cas9 approche de suppression I a démontré que Epromoters sont généralement impliqués dans l'activation des gènes distales. Nos résultats identifient d'abord une nouvelle catégorie de promoteurs avec activité in vivo dans amplificateurs. / The initial step of gene expression is the transcription of genomic DNA of the gene into RNA. The transcription can only be initiated by the assembly of RNAPII machinery around transcription start site of a gene, known as core promoter. However, transcription also requires other gene-distal regulatory DNA regions, known as enhancers. Enhancers and promoters are traditionally distinguished by their histone modifications. Recently, there has been increasing number of studies revealing broad similarities between enhancers and promoters. Previous findings have suggested the possibility that some gene promoters display enhancer activity. However, the questions of how can we identify this type of promoter in genome-wide and whether they actually function to regulated the expression of distal genes are remained elusive.My project has carried out aiming to answer these above questions. Firstly, I have optimized the technique that has developed in the lab, named CapStarr-seq, which used as an approach to exploiting a high-throughput enhancer activity. Performing CapStarr-seq in human cell lines, I unraveled an underestimated proportion of promoter displaying enhancer activity, defined as Epromoters. They display distinct properties as compared to distal enhancers and classical promoters, are associated with stress response genes and interact more frequently with other promoters. Moreover, by using comprehensive CRISPR/Cas9 genomic deletion approach, I demonstrated that Epromoters are generally involved in the activation of distal genes. Taken together, our results first identify a new category of promoters with dual promoter and enhancer functions.