Scale 1 in = 30 miles. 1931 reprint of the 1795 original with added imagery to the map and surrounding space. The original print of this map was a published guide for emigrants to the Tennessee country, shortly to become a state. Designed to encourage prospective settlers to move to Tennessee, it contains indications of land quality, soil fertility, etc. It also displays a reference to Native American villages and their assumed boundaries. / https://dc.etsu.edu/rare-maps/1112/thumbnail.jpg

This map is revised from the earlier map of "The State of Tennessee" published in Carey's General Atlas in 1814, 1815, and 1816. New towns shown with various connecting roads are Franklin, Columbia, Pulaski, Vernon, Jefferson, McMinnville, Madison, Washington, Springfield, and Hendersonville in middle Tennessee. Sevierville, Newport, Warm Spring, and Blountsville are in east Tennessee. It was published in Mathew Carey, Carey's General Atlas (Philadelphia: Mathew Carey and Son, 1817). Scale 1 in = 27 miles. / https://dc.etsu.edu/rare-maps/1113/thumbnail.jpg

This map is much the same as "Tennessee" published in Carey and Lea's American Atlas in 1822. Like that map, it includes border text with information about the state below the map and on a separate appendix sheet. It has 52 counties, each colored separately. Many rivers are given, as are mountain ranges. Southeastern Tennessee has "Cherokee Lands" and Ross's. Roads through central and eastern parts of the state are drawn, with Nashville and Knoxville being crossroads of travel. No area beyond the state is mapped, except for lands in Alabama which fall within the Tennessee River. Franklin County is spelled "Eranklin" with Maury spelled "Murray." Unlike that map, it shows "Brainerd one of the Missionary Stations" in southeastern Tennessee. Drawn by F. Lucas Jr. Published in H.C. Carey and I. Lea, A Complete Historical, Chronological, and Geographical American Atlas (Philadelphia: H.C. Carey and I. Lea, 1823). Scale 1 in = 27 miles. / https://dc.etsu.edu/rare-maps/1114/thumbnail.jpg

This map depicts Tennessee in the 1830s with counties named and delineated. Topographical features are shown with various land routes, water routes, mountains, cities, towns, forts, post offices, and other details identified. Engraved by G.W. Boynton. Published in T.G. Bradford, An Illustrated Atlas, Geographical, Statistical and Historical of the United States and Adjacent Countries (Boston: Weeks, Jordan and Co., 1838). Scale 1 in = 30 miles. / https://dc.etsu.edu/rare-maps/1115/thumbnail.jpg

Tennessee State Geologist James Safford's map showing types of lands, soils, and crops of the various geological formations in Tennessee. Also shows topographical features as well as railroads, county boundaries, and towns. Prepared by order of the Bureau of Agriculture. Published in Joseph B. Killebrew, Tennessee: Its Agricultural and Mineral Wealth (1877). Scale 1 in = 12 miles. / https://dc.etsu.edu/rare-maps/1116/thumbnail.jpg

In dieser Dissertation wird der MEK5/ERK5- Signalweg als möglicher Angriffspunkt in der zielgerichteten Melanomtherapie identifiziert. Die Adressierung von ERK5 bietet eine Alternative, um einer Resistenzentwicklung gegenüber Inhibitoren des MAPK- Signalwegs entgegenzuwirken. Das maligne Melanom ist ein hochaggressiver Tumor mit steigender Inzidenz. Zunehmende Sonnenstunden im Rahmen des Klimawandels mit erhöhter Belastung der Haut durch UV-Strahlung werden die Problematik des malignen Melanoms für den Menschen in den nächsten Jahren weiter zunehmen lassen. Die Aktivierung des MEK5/ERK5- Signalwegs scheint eine Reaktion von Tumorzellen auf Therapiestress zu sein. Diese Aktivierung liefert den Melanomzellen einen Überlebensvorteil und verhindert ein langfristiges Therapieansprechen. ERK5 beeinflusst den Zellzyklus von Melanomzellen und ist somit möglicherweise von wichtiger Bedeutung in der Tumorgenese des malignen Melanoms. Patienten mit NRAS- Mutation profitieren auffallend weniger von einer gezielten MEKi-Therapie als solche mit BRAF Mutation. Für ersteres Patientenkollektiv steht aktuell lediglich die Immuntherapie zur Verfügung, wodurch oft nur ein kurzes, progressionsfreies Intervall erreicht werden kann und die Patienten häufig unter schweren Nebenwirkungen leiden. Grund für die problematische Behandlung könnte das häufige Auftreten einer basalen ERK5- Aktivierung in NRAS- mutierten Melanomen sein. Diese Arbeit liefert eine positive Prognose über den Nutzen einer ERK5- Inhibition als Erweiterung des Therapieschemas. Diese These gilt auch für Melanompatienten mit einer BRAF- Mutation. Patienten, die an einem malignen Melanom erkrankt sind, weisen zu 80% eine Mutation in einem dieser beschriebenen Onkogene auf. Die Arbeit lässt darauf schließen, dass eine ERK5- Inhibition in der Therapie von beiden Gruppen erfolgreich sein könnte und somit das Leben nahezu aller Melanompatienten betrifft. / In this thesis, targeting the MEK5/ERK5- pathway is identified as a possible treatment option for maligant melanoma in order to prevent the development of resistances against inhibitors of the MAPK- pathway. The malignant melanoma is a highly aggressive tumor with an increasing incidence. A rising amount of sun exposure due to climate change will lead to increasing skin damage among the population and thus the malignant melanoma may emerge as an important medical problem throughout the following decade. The activation of the MEK5/ERK5 pathway seems to be a cellular response to therapeutic stress. It therefore results in sustained proliferation and survival in melanoma cells and prevents an efficiant therapy in the longterm. ERK5 has influence on the cell cycle progression of melanoma cells and could be of utmost importance for the tumorigenesis in malignant melanoma. Patients suffering from NRAS- mutant melanoma benefit remarkably less from MAPK-pathway targeting regimens than those with BRAF- mutation. In these cases immunotharpy remains as the only valuable treatment option yet barely achieving a short progression free survival with severe side effects. The obstacle of effective therapy could be the frequently found occurrence of a basal ERK5- activity especially observed in NRAS- mutant melanoma cells. Our data imply that MEKi/ERK5i co-treatment could provide a new therapeutic approach as an adjunct to targeted therapy of malignant melanoma improving its overall effectiveness. This discovery does not only apply for NRAS- mutant melanoma but also for patients with BRAF- mutation. In 80% of malignant melanoma the driver mutation can be found in one of these two oncogenes suggesting the majoryty of melanoma patients might benefit from MEK5/ERK5- Inhibition.

In the United States, the floodplain maps used in the administration of the National Flood Insurance Program are created and maintained by the Federal Emergency Management Agency. Currently, a nationwide map modernization program is underway to convert the existing paper floodplain maps into a digital format, while continuing to improve the maps and expand the scope of the studies. The flood zones depicted on these maps are developed through engineering studies, using a variety of accepted methods to model and predict flood-prone areas. These methods are classified as detailed, limited detailed, or approximate, corresponding to varying levels of expense and accuracy. Current flood map revision activities across the nation typically consist of developing new hydraulic models, or reusing existing hydraulic model results in conjunction with new, more detailed LiDAR terrain models. This research develops a profile synthesis method for redelineation of approximate flood boundaries, and evaluates the method's performance and usability. The profile synthesis method is shown to perform reliably on simple floodplain geometry, recreating a water surface profile based only on its floodplain boundaries. When applied to a real-world floodplain studied in a previous flood insurance study, the profile synthesis method is shown to perform adequately, with results comparable to an approximate hydraulic model developed in HEC-RAS. Methods similar to this profile synthesis method for reuse of existing approximate zone boundaries have not been widely documented or evaluated; nevertheless, methods such as this are believed to be common in the revision of approximate zone flood boundaries. As such, this work explores concepts which will be of interest to individuals actively involved in flood map revision and modernization. / Master of Science

La fonction barrière de la peau dépend en grande partie d’une différenciation appropriée des kératinocytes épidermiques. Au cours de ce processus, de nombreux changements ont lieu dans ces cellules tels que la diminution de la prolifération, le remodelage du cytosquelette, des changements dans l’expression génique, la dégradation du noyau et des organites de même que la formation d’une structure bien particulière : l’enveloppe cornée. Il est important que de tels évènements soient régulés de façon adéquate puisqu’un débalancement au sein de ces derniers peut mener à l’apparition de conditions pathologiques. La Dual Leucine zipper-bearing Kinase (DLK) est une Mitogen-Activated Protein Kinase Kinase Kinase dont l’expression est très forte au niveau de la couche granuleuse, soit la dernière couche de cellules vivantes avant la couche cornée de l’épiderme. Des études précédentes ont révélé que la surexpression de la DLK dans des kératinocytes en culture avait pour effet d’induire la différenciation terminale. Toutefois, les mécanismes par lesquels la DLK régule ce processus restent encore méconnus faisant en sorte que l’objectif général de cette thèse consiste à mieux les définir. L’hypothèse à la base de ces travaux est que la DLK est requise pour la différenciation des kératinocytes et que celle-ci y participe en favorisant la stabilisation des microtubules de même que l’expression ou l’activité de facteurs de transcription impliqués dans ce processus. Dans un premier temps, un modèle de peau reconstruite in vitro dans lequel l’expression de la DLK a été réduite par interférence à l’ARN a été développé. Il a été noté que la diminution de la DLK avait pour effets d’affecter la distribution de protéines de l’enveloppe cornée telles que la filaggrine et la transglutaminase 1 de même que d’inhiber la formation des couches granuleuse et cornée. Des analyses en immunofluorescence et en microscopie électronique ont permis d’observer des défauts au niveau des jonctions serrées et des desmosomes dans les peaux sous-exprimant la DLK révélant un rôle de cette kinase dans le bon maintien de ces deux types de jonctions cellulaires. L’impact de la DLK sur les microtubules a été étudié dans des kératinocytes en culture transduits à l’aide de vecteurs adénoviraux menant à la surexpression de la DLK de même que dans les peaux reconstruites présentant une expression réduite de cette kinase. Ces études ont permis de conclure que la DLK était non seulement en mesure d’induire la réorganisation et la stabilisation des microtubules en périphérie cellulaire, mais que celle-ci était également requise à la réalisation de ces processus. Afin de mieux décrire les mécanismes par lesquels la DLK assure la réorganisation des microtubules en périphérie cellulaire, les effets de la surexpression ou de la sous-expression de la DLK sur les protéines LIS1 et HSP27 (pour Heat shock protein 27 kDa), des régulateurs de la distribution des microtubules, ont été étudiés. Ces analyses ont permis de définir la DLK en tant qu’élément nécessaire à la bonne distribution en périphérie cellulaire de LIS1 et HSP27. Des études plus poussées ont révélé que l’expression de la DLK dans des kératinocytes en culture était non seulement en mesure d’induire la redistribution en périphérie cellulaire d’HSP27, mais également l’insolubilisation et la phosphorylation de cette protéine de choc thermique. Il a également été démontré que l’ensemble de ces processus dépendaient de l’activité de ERK (pour Extracellular-signal Regulated Kinase). Dans le but de définir l’importance des microtubules dans le processus de différenciation des kératinocytes, des peaux reconstruites ont été traitées avec un agent induisant la dépolymérisation de cette composante cytosquelettique soit plus précisément le nocodazole. Un tel traitement produit un phénotype similaire à celui des peaux reconstruites sous-exprimant la DLK suggérant les microtubules comme d’importants effecteurs de la différenciation induite par la DLK. Dans la perspective de mieux définir les effets de la DLK sur la signalisation cellulaire et l’expression génique globale, nous avons eu recours à l’étude de la phosphorylation d’importants médiateurs de la signalisation moléculaire intracellulaire de même qu’à des analyses en micropuce à ADN d’échantillons provenant de peaux reconstruites sous-exprimant la DLK. Cette démarche a permis de révéler une hausse de la phosphorylation de ERK1/2, de JNK1/2/3, de GSK3 (pour Glycogene Synthase Kinase 1) et du récepteur à l’EGF (pour Epidermal Growth Factor). Les analyses en micropuce à ADN ont permis de révéler une réduction dans l’expression de nombreux gènes impliqués dans la formation de l’enveloppe cornée. Finalement, la réduction de c-Jun et de C/EBPα a pu être observée dans les noyaux de peaux reconstruites sous-exprimant la DLK révélant ainsi l’importance de cette kinase dans la régulation de ces facteurs de transcription dans un contexte de différenciation des kératinocytes. Globalement, nos travaux montrent que la DLK est requise pour la différenciation des kératinocytes et que celle-ci y contribue en assurant la réorganisation des microtubules en périphérie cellulaire, la consolidation des desmosomes et des jonctions serrées de même la régulation positive des facteurs c-Jun et C/EBPα. / Skin barrier function greatly depends on proper keratinocyte differentiation in the epidermis. During this process, many changes occur within the cell such as decrease in cell proliferation, cytoskeleton reorganization, changes in gene expression, nucleus and organelles elimination as well as cornified envelope formation. Keratinocyte differentiation must be finely orchestrated since misregulation of this process may lead to pathological conditions. The Dual Leucine zipper-bearing Kinase (DLK) is a Mitogen-Activated Protein Kinase Kinase Kinase showing a strong expression in the granular layer, the last layer composed of living cells before reaching the cornified layer. Previous studies revealed DLK capacity to induce keratinocyte terminal differentiation process. However, how DLK promotes such an event remains unknown. The main objective of this thesis is to identify mechanisms and potential effectors of the DLK-induced keratinocyte differentiation. Our hypothesis is that DLK is required for keratinocyte differentiation by promoting microtubule stabilization as well as the expression or the activity of transcription factors involved in this process. In order to test our hypothesis, a tissue-engineered skin (TES) model with a reduced DLK expression was produced using a RNA interference approach. Impaired distribution of cornified envelope proteins such as filaggrin and transglutaminase 1 as well as reduced granular and cornified layers were observed in TES with reduced DLK expression. In those samples, immunofluorescence and electron microscopy analyses pointed out desmosomal and tight junctional defects suggesting a role for DLK in the maintenance of these types of cell junctions. The impact of DLK expression on microtubules was also studied in TES with reduced DLK expression and in keratinocytes in culture overexpressing DLK following gene transduction using adenoviral vectors. These studies led to the conclusion that DLK not only promotes but is also required for microtubules reorganization and stabilization to cell periphery. To explain DLK capacity to induce such a process, effects of DLK depletion or overexpression on microtubule regulators such as LIS1 and HSP27 were investigated by immunofluorescence staining. These analyses revealed that DLK induces and is required for LIS1 and HSP27 relocalization to cell periphery. In additional studies, our results show that DLK expression in normal human keratinocytes in culture not only promotes HSP27 distribution to cell periphery but also induces HSP27 insolubilization and phosphorylation in an ERK-dependent manner. In order to more precisely define the role of microtubules in keratinocyte differentiation process, TES were treated with nocodazole, a microtubule depolymerizing agent. The effect of such a treatment was to reproduce the phenotype of DLK-depleted TES suggesting that microtubules are important effectors of DLK-induced keratinocyte differentiation. In an attempt to describe the impact of DLK on global gene expression, RNA samples of DLK-depleted TES were studied using microarray analyses. This approach revealed a reduction in the expression of many genes coding for cornified envelope proteins. Reductions of c-Jun and C/EBPα immunofluorescence staining were also noted in TES with a reduced DLK expression suggesting this kinase as a c-Jun and C/EBPα regulator in the context of keratinocyte differentiation. Globally, our works show that DLK is required for keratinocyte differentiation since it promotes microtubule reorganization to cell periphery, desmosomes and tight junction consolidation as well as c-Jun and C/EBPα localization to the nucleus.

The classical Riemann Mapping Theorem has many discrete analogues. One of these, the Finite Riemann Mapping Theorem of Cannon, Floyd, Parry, and others, describes finite tilings of quadrilaterals and annuli. It relates to several combinatorial moduli, similar in nature to the classical modulus. The first chapter surveys some of these discrete analogues. The next chapter considers appropriate extensions to infinite tilings of half-open quadrilaterals and annuli. In this chapter we prove some results about combinatorial moduli for such tilings. The final chapter considers triangulations of open topological disks. It has been shown that one can classify such triangulations as either parabolic or hyperbolic, depending on whether an associated combinatorial modulus is infinite or finite. We obtain a criterion for parabolicity in terms of the degrees of vertices that lie within a specified distance of a given base vertex. / Ph. D.

Using the genome database of the phytopathogenic fungus, Alternaria brassicicola, we identified a gene with high homology to the cell wall integrity-associated mitogen-activated protein (MAP) kinase, Slt2 in the yeast, Saccharomyces cerevisiae. This MAP kinase consists of a predicted 1,251-bp open reading frame, and encodes a 416-amino-acid protein weighing 47501 Da. This homolog was designated AbSlt2 (A. brassicicola Slt2) and gene disruption knockout (KO) mutants were generated in an A. brassicicola wild type background. Several altered phenotypes were found in the mutants compared to the wild type. During growth in various liquid and solid media, the abslt2 mutants displayed slightly aberrant hyphal growth and were unable to develop at the same rate as wild type. Furthermore, scanning electron microscopy (SEM) analysis revealed the abslt2 mutants showed decreased penetration ability, underdeveloped appresoria, and altered morphology on the leaf surface of the host plant, Brassica oleracea (cabbage) when compared to wild type. Abslt2 mutant hyphae exhibited slower growth in planta ultimately resulting in highly reduced virulence. Complementation of the disruption mutant with the wild type gene fully restored pathogenicity. Therefore, AbSlt2 is a new pathogenicity and developmental factor in A. brassicicola. / Master of Science