Schädigungen im zentralen Nervensystem treten nicht nur bei der Multiplen Sklerose (MS), sondern auch bei einer Vielzahl weiterer entzündlicher Schadensparadigmen auf. Allgemeines Kennzeichen dieser primär wie auch sekundär entzündlichen neurodegenerativen Erkrankungen ist das Auftreten von oxidativem Stress in Verbindung mit einer eingeschränkten Regeneration von Nervenzellen und einem übermäßiges Auftreten von Astrozyten. Allerdings ist bislang nicht bekannt, welche Faktoren für eine frühe neuronale Schädigung verantwortlich sind, und welche Faktoren zu einem übermäßigen Auftreten von Astrozyten beitragen. Vorarbeiten belegten, dass Apoptose-regulierende Systeme, wie z.B. der TRAIL-Signalweg, sowohl an der Immunregulation als auch an Schädigungsprozessen im Gehirn beteiligt sein können. Im Rahmen dieser Arbeit wurde gezeigt, dass eine auf das ZNS beschränkte Blockade des TRAIL-Signalwegs in der EAE, dem Tiermodell der MS, zu einer signifikanten Verminderung des Erkrankungsgrades führte. Darüber hinaus wurde eine reduzierte Enzephalitogenität von TRAIL-defiziente Myelin-spezifischen Lymphozyten belegt. Die Ergebnisse deuten darauf hin, dass der TRAIL-vermittelte Schädigungsmechanismus die Pathogenese der Neuroinflammation entscheidend mitbestimmt und die immunregulatorische Wirkung eine eher untergeordnete Rolle spielt. Dagegen stellte sich im Tiermodell der bakteriellen Meningitis heraus, dass TRAIL hier eine anti-inflammatorische Rolle im ZNS spielt, die vor allem durch eine TRAIL-R-abhängige apoptotische Minderung der Entzündungsreaktion vermittelt wird. Eine Beeinflussung der Migration von Effektorzellen durch TRAIL konnte in diesem Modell ausgeschlossen werden. Anscheinend hängt die therapeutische Modulation des TRAIL-Systems entscheidend von der jeweils zu Grunde liegenden Ätiopathogenese ab und kann nicht allgemein auf entzündliche ZNS-Erkrankungen übertragen werden. Als mögliche Ursache für eine verminderte Regenerationsfähigkeit endogener Stammzellen konnte hier ein endogener Mechanismus aufgedeckt werden, der als Antwort auf oxidativen Stress zu einem quantitativen Überwiegen von Astrozyten führt. Dabei zeigte sich, dass nicht toxische oxidative Bedingungen das Proliferationsvermögen von neuralen Stammzellen deutlich hemmten und dazu führten, dass anstelle von Neuronen vornehmlich Astrozyten entstehen. Dieses veränderte Differenzierungsvermögen ließ sich sowohl in vitro als auch in vivo experimentell nachvollziehen und wies darauf hin, dass durch milde Entzündungsprozesse hervorgerufene basale metabolische Veränderungen die neuronale und astrogliale Entwicklung aus neuralen Stammzellen reziprok reguliert wird. In weiteren Untersuchungen stellte sich heraus, dass die Histondeacetylase Sirt1 in neuralen Stammzellen als Sensor für das Redox-Potenzial dient. Schon geringe metabolische Änderungen induzierten die Bindung an den bHLH-Transkriptionsfaktor Hes1, die zu einer direkten Modulation des pro-neuronalen Transkriptionsfaktors Mash1 führten und die Differenzierung von neuralen Stammzellen zugunsten der astroglialen Entwicklung beeinflussten. Die Aufklärung dieses Mechanismus könnte somit zukünftig helfen, intrinsische Regenerationsprozesse nach Schädigung des ZNS zu verstärken und damit neue therapeutische Perspektiven bei neurologischen Erkrankungen zu öffnen. / Damage processes of the central nervous system (CNS) are not only found in Multiple sclerosis (MS) even in a variety of inflammatory diseases. A common feature of these inflammatory neurodegenerative disorders is the existence of oxidative stress in combination with a failure of neuronal replenishment and the predominant occurrence of astrocytes (known as astrogliosis). So far, factors, which are responsible for early neuronal damage and overwhelming generation of astrocytes, are not known. Recent studies could show that the tumor necrosis factor related apoptosis-inducing ligand (TRAIL) might be involved in immunregulation as well as damage processes in the CNS. Here, it could be shown that blockade of TRAIL in the CNS of animals suffering from experimental autoimmune encephalomyelitis (EAE) significantly ameliorates the disease. Furthermore, transfer of myelin-specific TRAIL-deficient T cells into wild type recipients lead to a significantly attenuated disease score. These findings underline the contribution of TRAIL to irreversible CNS damage. In the adult mammalian brain, multipotent and self-renewing neural progenitor cells (NPCs) have the capacity to generate new neurons, astrocytes and oligodendrocytes. NPCs may thus serve as a regenerative tool by which brain damage could be compensated. However, repair processes in response to all forms of neuronal injury, be they inflammatory, ischemic, metabolic, traumatic or other, are characterized by the failure of neuronal replenishment and the predominant occurrence of astrocytes. The common molecular pathways underlying this phenomenon are only poorly understood. Here, it could be shown that subtle alterations of the redox state, found in different brain damage scenarios, substantially regulate the fate of murine NPCs via the histone deacetylase silent mating type information regulation 2 homolog 1 (Sirt1). Mild oxidative conditions suppress proliferation of NPCs and direct their differentiation towards the astroglial at the expense of the neuronal lineage (and vice versa). Under oxidative conditions, NPCs upregulate Sirt1 in vitro and in vivo, which then binds to the transcriptional repressor Hes1 and finally downregulates the pro-neuronal basic helix-loop-helix transcription factor Mash1. Furthermore, it could be shown that targeted modulation of Sirt1 activity mimics the effects of subtle redox alterations. The results provide evidence for an as yet unknown metabolic master switch, which determines the fate of NPCs. Targeting these mechanisms may minimize undesired aspects of reactive astrogliosis as well as improve the success of therapeutic neural stem cell implantation.

Rural accessibility is a pressing issue in many parts of the world. Improved geographical accessibility to basic social service facilities for rural populations is a goal of most governments in developing countries. Development of a trail-based transport system is a key way to improve rural accessibility in mountainous and rugged terrain where trails criss-cross with numerous rivers. The present study focuses on Nepal, a developing country with rural accessibility challenges and a very challenging physical environment. This thesis reviews the existing accessibility patterns in rural areas of Nepal and proposes various approaches for identifying poorly served geographical areas and optimizing of location of additional new trail bridges to provide “best” links to social services. The methodology in this study is based on the concept of the gravity-based spatial interaction and accessibility models. GIS applications are used in different ways, such as in creating, acquiring, integrating spatial and attribute datasets, and spatial analysis and visualization of the output results. Amongst the different types of social services, health care and education centers are considered the most pressing services and hence are the objects of analysis. The main difference between health care service centers and educational facilities is that schools are usually very widespread across the district and serve for the school age population. Health service centers are sparsely and inequitably distributed, however, they serve the whole population at large. The results of the analysis show a fairly clear indication of problems relating to rural transport and access to social service centers in rural Nepal. This is attributed, in part, due to insufficient provision of social service centers and the lack of trail bridges over river crossing locations. The estimated numbers of trips over potential new bridges based on spatial integration modeling provides a basis for prioritization of river crossing locations for allocation of new trail bridges. The poorly served areas across the study district are identified on the basis of the results of the potential accessibility modeling. The trail network nodes with relatively low accessibility values are of prime concern and the subject of contemplation in the trail bridge planning decision-making process.

Rural accessibility is a pressing issue in many parts of the world. Improved geographical accessibility to basic social service facilities for rural populations is a goal of most governments in developing countries. Development of a trail-based transport system is a key way to improve rural accessibility in mountainous and rugged terrain where trails criss-cross with numerous rivers. The present study focuses on Nepal, a developing country with rural accessibility challenges and a very challenging physical environment. This thesis reviews the existing accessibility patterns in rural areas of Nepal and proposes various approaches for identifying poorly served geographical areas and optimizing of location of additional new trail bridges to provide “best” links to social services. The methodology in this study is based on the concept of the gravity-based spatial interaction and accessibility models. GIS applications are used in different ways, such as in creating, acquiring, integrating spatial and attribute datasets, and spatial analysis and visualization of the output results. Amongst the different types of social services, health care and education centers are considered the most pressing services and hence are the objects of analysis. The main difference between health care service centers and educational facilities is that schools are usually very widespread across the district and serve for the school age population. Health service centers are sparsely and inequitably distributed, however, they serve the whole population at large. The results of the analysis show a fairly clear indication of problems relating to rural transport and access to social service centers in rural Nepal. This is attributed, in part, due to insufficient provision of social service centers and the lack of trail bridges over river crossing locations. The estimated numbers of trips over potential new bridges based on spatial integration modeling provides a basis for prioritization of river crossing locations for allocation of new trail bridges. The poorly served areas across the study district are identified on the basis of the results of the potential accessibility modeling. The trail network nodes with relatively low accessibility values are of prime concern and the subject of contemplation in the trail bridge planning decision-making process.

This work deals with the utilization of Nature Trails for activation of children in their free time. The key issue of this work is to create a ficticious nature trail which may serve for general public while going for a walk. This way it is possible to strengthen and improve good relation between children, adults, and nature {--} by using interesting and easy-reached methods. The Nature Trail for Cyclists is designed in the northern part of Protected Landscape Area Třeboňsko and it is about 30 kilometres long with 16 information points. This Trail is supplemented by worksheets for children of younger school-age {--}these worksheets could possibly be used in the education process. In the practical part, results of children who followed the Nature Trail and fulfilled the assigned tasks were processed and assessed. The designed Nature Trail will be offered to Protected Landscape Area Třeboňsko to realize it.

A leucemia mielóide crônica (LMC) é uma doença mieloproliferativa e sua patogênese está associada à expressão de um neogene, bcr-abl, que codifica uma proteína tirosina quinase Bcr-Abl. Esse trabalho tem como objetivos o estudo dos mecanismos envolvidos na resistência à morte das células Bcr-Abl positivas e a identificação de alterações gênicas nessas células. Dados de expressão gênica global obtidos por \"microarray\" mostraram uma superexpressão nas células HL-60.Bcr-Abl com relação a HL-60 dos genes faim e nipa, que foi confirmada por qRT-PCR em diferentes linhagens celulares Bcr-Abl positivas. Já os genes de trail e osm, apresentaram uma diminuição significativa em HL-60.Bcr-Abl, que foi confirmada para trail, porém osm não teve seu resultado validado. A avaliação da expressão dos genes em células de pacientes portadores de LMC, em diferentes fases da doença também foi estudada. Com esses resultados, o presente estudo visa a melhor compreensão de como alterações na expressão desses genes contribuem na fisiopatologia da LMC. / Chronic myelogenous leukemia (CML) is a stem cell disease characterized by the presence of the Bcr-Abl oncoprotein, which is the cause of the malignant transformation and the extreme resistance to apoptosis displayed by CML patients. Our aim was to analyze the alteration in global gene expression in Bcr-Abl expressing cells. Data obtained from microarray analysis showed significant up-regulation of nipa and faim in HL60.Bcr-Abl and down-regulation of osm and trail. These results were further confirmed by Real-Time PCR to nipa, faim and trail, but not for osm expression in HL-60.Bcr-Abl cells. To evaluate the potential of some of the modified genes as therapeutic targets or prognostic markers for CML, we also analyzed the expression of these genes in samples from CML patients.

Das Ovarialkarzinom ist eines der tödlichsten Malignome in der Gynäkologie und birgt eine große therapeutische Herausforderung. Trotz Platin und Taxan haltiger Chemotherapie liegt die Rezidivrate des Ovarialkarzinoms bei 70%. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gilt aufgrund seiner Eigenschaft spezifisch in Krebszellen Apoptose zu induzieren ohne normalen Körperzellen zu schaden in der Krebsforschung als vielversprechendes Therapeutikum. Seit einiger Zeit ist jedoch ersichtlich, dass 50% der Zelllinien und die Mehrheit aller primären humanen Krebszellen resistent für TRAIL induzierte Apoptose sind (Koschny, Walczak et al. 2007) und zunächst sensitiviert werden müssen. In dieser Studie konnte gezeigt werden, dass primäre Ovarialkarzinomzellen die mit Hilfe von EpCAM Dynabeads aus der Aszites von Krebspatientinnen isoliert wurden, sowohl mit Bortezomib (Proteasominhibitor) als auch mit PIK75 (PI3K- Inhibitor)spezifisch für TRAIL induzierte Apoptose sensitiviert werden konnten. Desweiteren konnte gezeigt werden, dass diese Kombinationstherapie normale hämatopoietische Zellen nicht beschädigt. Dies bekräftigt vor allem die Eigenschaft von TRAIL, krebszellspezifisch Apoptose zu induzieren. Wichtig ist vor allem, dass diese Kombinationstherapie sogar Chemotherapie resistente primäre Ovarialkarzinomzellen in Apoptose führen konnte.

Les précédents travaux menés au laboratoire avaient permis d’obtenir des lipides cationiques biolabiles dérivés d’un constituant naturel des membranes cellulaires, la DOPC, en masquant temporairement sa charge négative par l’introduction d’un substituant, clivable sous stimuli acide ou enzymatique. Ce concept s’était révélé efficace pour la délivrance, in vitro et in vivo, d’acides nucléiques, avec un impact toxicologique minimisé. Ce doctorat est la transposition de ce système à une approche thérapeutique du cancer, à l’aide de constructions dérivées d’alkylphospholipides (APLs), des lipides antitumoraux. De nombreuses prodrogues biolabiles (pro-APLs) ont été développées à partir de trois APLs prometteurs : miltéfosine, périfosine et érufosine. L’évaluation et l’optimisation de l’activité biologique des pro-APLs ont conduit à des formulations performantes pour la délivrance in vitro d’un ADN thérapeutique TRAIL et la production in situ d’APLs, pour une combothérapie antitumorale. / Previous work in the laboratory had resulted in biolabile cationic lipids derived from a naturally cell membrane component, DOPC, by temporarily masking its negative charge by the introduction of a cleavable substituent, under acidic or enzymatic stimuli. This concept was particularly efficient for the delivery, in vitro and in vivo, of nucleic acids such as DNA plasmid or siRNA, with a minimized toxicological impact for cells. The present study is the transposition of this system to a therapeutic approach to cancer, using constructions derived from alkylphospholipids (APLs), a recent class of antitumor lipids. Biolabile prodrugs (pro-APLs) have been developed from three promising APLs: miltefosine, perifosine and erufosine. The biological evaluation of pro-APLs activity and the optimization of various parameters led to efficient formulations for the in vitro delivery of a therapeutic DNA plasmid, related to TRAIL, and the in situ APLs production for a potential antitumor combotherapy.

Master of Landscape Architecture / Department of Landscape Architecture/Regional and Community Planning / Hyung Jin Kim / Walkability is a challenge for most suburban metropolitan areas. Specifically, the Kansas City suburban cities of Overland Park, Olathe, Leawood, and South KCMO have sprawled and disconnected urban patterns and a low average walkability score of 37 out of 100 (Walk Score, 2013, https://www.redfin.com/how-walk-score-works/). The Indian Creek Trail, an existing recreational trail that extends throughout the southern Kansas City neighborhoods, has the potential to improve walkability. It connects major destinations, including residential communities, businesses, and commercial districts throughout the suburban neighborhoods. Many studies have analyzed suburban sprawl and walkability, but few studies have identified the possibility of enhancing existing trail systems to provide for greater mobility, connectivity, and activity. The study examines the feasibility of reusing an existing trail system to act as a catalyst to promote walkability in the Kansas City suburbs. The goal of the project to create a paradigm shift in the way people think about transport and development. The purpose is to identify how centering walkable strategies around an active transportation network can promote walkability in sprawled suburban areas. The question: How can focusing improvement around existing trail infrastructure enhance walkability in suburban areas? has guided the project and helped define strategies for improvement. This project identifies the Indian Creek Trail’s current and potential uses from an in depth community and spatial analysis. Surveys, interviews, and observations were conducted within 13 major destination areas along the Indian Creek Trail. The results were then analyzed to create an evidence‐based design framework that will address walkable concerns. The project results showed there were three primary causes for walkable limitations along the trail network: current transportation trends, suburban development patterns, and social perceptions. Understanding these important aspects of walkability helped identify a framework for improvement. The findings from the analysis determined the site restrictions and prospects of creating a walkable environment along the Indian Creek Trail. The results identified primary locations of needed intervention and revealed major opportunities for connection. The design then applied walkable components based on analysis findings to create nodes of complete communities. Design decisions were tailored to amend community needs and alter traditional transport perceptions. The objective of the designs was to address specific walkable limitations to create reasonable solutions in suburban areas. The project identifies 5 primary components of walkability that can be used to create a walkable plan. Future studies would revolve around implementing the designs and analyzing the effectiveness to create a model that can be applied to enhance walkability for other suburban areas. Ultimately, the results could establish how improved walkability can promote multi‐modal transportation opportunities where population, density, diversity, and funding do not allow for typical transportation or development enhancements.

Call number: LD2668 .T4 1984 B87 / Master of Science

Master of Arts / Department of Geography / Kevin S. Blake / Monuments and memorials are how we record history on the landscape. History is created, preserved, and remembered by those who envision, design, and ultimately pay a visit to, these sites. The Oregon Trail is replete with interpretive sites relating to various events and people who lived along or traveled this route. From Independence, Missouri to Fort Laramie National Historic Site in Wyoming along the Great Plains section of the trail, Plains Indians are represented in thirty-two sites that convey various versions of history. The majority of these sites, twenty-seven, either ignore the Plains Indians or turn them into a stereotypical form of Sioux. These two representations give a sense that “No One is Home” or that “Siouxification” has occurred, a process by applying Sioux cultural traits to non-Sioux Plains Indians. The other five sites are categorized as “Getting It Right.” These sites either portray an accurate or close-to-accurate representation of the Indians and their role along the Oregon Trail. “No One is Home” is found all throughout the trail; “Siouxification” is clustered in the eastern study area; and “Getting It Right” primarily in the eastern portion.