This paper puts forward a new approach to the revitalization of vacant and neglected buildings and spaces by introducing the use of temporary pop-up environments. The initial research establishes groundwork for pop-up environments and temporary use, while pointing to their potential. Records from specialists, Florian Haydn, Robert Temel, and Philipp Oswalt, exhibit various types of temporary uses and interim strategies. Strategies are displayed in their selection of sites and operation. These strategic approaches will support transitioning space and present interim projects, which have the prospect of utilizing space as a secondary means, while a more primary use of space is in development. The case studies will demonstrate the temporary use strategies and social factors, which may establish new meaning to facilitate change. By presenting possibilities of repurposing through temporary and interim uses, there is the opportunity for renewal and averting the dependence on massive (re)development, sustaining a city’s heritage.

As digital books begin to take center stage in our lives the importance of the old printed book still lingers on. A large number of the books printed on the paper media still have much to offer to readers for various reasons (e.g. less famous authors of prose, old books with interesting and original problems). To help individuals in digitizing and reusing their physical and digital books we decided to build a framework that will help people convert physical and digital books to other formats taking into consideration four dimensions: learning outcomes or methodology, target device characteristics, representation and the user. Our focus is on textbooks in history. Consequently, we do not consider some problems like math formulas. This work has the potential of helping people deal with the huge backlog of physical books that can become invisible as the digital books take off. To show that our platform can help in repurposing books for student study activities, we have developed some transformations. The transformations we have implemented shows that the framework can be used to add study aids to books, optimize books for a target platform (e-reader device and application combination), and supplement available features of a target platform and maintain consistency across various audio/visual devices and e-book formats. One of the important steps in the thesis was determining the study activities that we would support as examples in our implementation. We have chosen to implement support for the survey, question, read and review activities of the SQ3R reading technique. We have also implemented support for additional activities like search. The chosen activities and the support implemented for these activities are examples and are not meant to be complete. Another important decision point was to decide which target platforms (e-reader device and application combination) we need to support. We decided to choose a few representatives and leave the rest as future work. The target devices were selected so as to have a variety of device capabilities like screen size, display technology (e.g. e-ink, VGA), and user interaction styles (e.g. touch-based, button based) combined with application capabilities (e.g. audio only, visual only, audio visual, grayscale, and color). The devices selected were: iPad, iPod, iPhone, Kindle 3rd generation, Kindle Fire, Sony PRS and a laptop. The e-reader applications are the ones that are available for these devices.

A quimioterapia disponível para o tratamento das leishmanioses conta com um número reduzido de fármacos, com efeitos adversos severos e progressivo aumento de resistência. O reposicionamento de fármacos oferece uma grande oportunidade para introdução de novas terapias. Antidepressivos orais têm demonstrado eficácia tanto in vitro quanto in vivo contra espécies de Leishmania spp. Neste estudo, o antidepressivo sertralina (SRT), e o fármaco ciclobenzaprina (CBP), um relaxante muscular de estrutura tricíclica análoga a antidepressivos, foram avaliados quanto a atividade contra Leishmania (L.) infantum. Estudos metabolômicos não dirigidos utilizando multiplataforma analítica, foram combinados a análises de parâmetros celulares, essenciais para obtenção de uma ampla descrição dos mecanismos de ação. A CBP mostrou uma atividade leishmanicida in vitro, com valor de CE50 de 4,3 ?M contra formas promastigotas e 8,6 ?M contra formas amastigotas intracelulares. O fármaco apresentou uma citotoxicidade (CC50) de 70,6 ?M em células NCTC, e um índice de seletividade similar a miltefosina. Os estudos de mecanismo de ação, sugeriram que a CBP se difunde pela membrana plasmática, causando diminuição do ??p e no interior citoplasmático, parece induzir um estresse do RE com liberação de Ca+2; concomitantemente, induz um desacoplamento brando da cadeia respiratória mitocondrial e depleção dos níveis de ATP. Com o efeito prolongado, a liberação de Ca+2 parece ativar a autofagia, e seu influxo para a mitocôndria potencializar os efeitos deletérios, diminuindo o ??m e aumentando a produção de ROS. A longo prazo, o CBP induz uma extensa alteração metabólica, caracterizada aumento dos níveis da maioria dos metabólitos identificados e atividade desregulada de transportadores de membrana, gerando alto gasto energético associado a condições insuficientes de produção de energia mitocondrial, resultando em morte celular. A sertralina também apresentou atividade leishmanicida in vitro, com valor de CE50 de 2 ?M contra formas promastigotas e 3,9 ?M contra formas amastigotas intracelulares. Sua toxicidade em células NCTC foi de 19,6 ?M, resultando em um índice de seletividade similar a miltefosina. Nossos estudos confirmaram a mitocôndria de Leishmania como alvo primário e, o efeito de desacoplamento da cadeia respiratória associado ao colapso energético, estresse oxidativo seguido da despolarização do ??m como a possível origem desta disfunção mitocondrial. Estudos metabolômicos evidenciaram que a extensão do desarranjo metabólico, abrange diminuição da capacidade de detoxificação do metabolismo tiol-redox, uma severa depleção do pool intracelular de aminoácidos e poliaminas, evidenciando uma completa deterioração do metabolismo energético, por meio de um mecanismo multialvo direcionado a vias metabólicas essências do parasita. Finalmente, este estudo descreve a atividade anti-Leishmania de dois fármacos orais aprovados, com mecanismos de ação letais e irreversíveis no parasita, encorajando o prosseguimento para futuros estudos pré-clínicos na leishmaniose visceral americana / The available chemotherapy for the treatment of leishmaniasis has a reduced number of drugs, with severe adverse effects and progressive increase of resistance. The drug repurposing offers a great opportunity for the introduction of new therapies. Oral antidepressants have been demonstrated efficacy both in vitro and in vivo against Leishmania spp. In this study, the antidepressant sertraline (SRT), and the drug cyclobenzaprine (CBP), a muscle relaxant with tricyclic structure analogous to antidepressants, were evaluated against Leishmania (L.) infantum. Untargeted metabolomic studies using multiplataform analysis were combined to cellular parameters to a broad description of the mechanisms of action. Cyclobenzaprine showed an in vitro leishmanicidal activity with an EC50 value of 4.3 ?M against promastigotes and 8.6 ?M against intracellular amastigote forms. The drug showed a cytotoxicity (CC50) of 70.6 ?M in NCTC cells, and a selectivity index similar to miltefosine. Mechanism of action studies suggested that CBP diffuses through the plasma membrane, causing a decrease of the ??p and inside the cytoplasm, the drug seems to induce an ER stress, with release of Ca+2; concomitantly, it induces a mild decoupling of the mitochondrial respiratory chain and depletion of ATP levels. With the prolonged effect, a release of Ca+ 2 appears to activate an autophagy, and its mitochondrial influx results in a potentiation of deleterious effects as decreasing of ??m and increasing ROS production. In long term, CBP induces an extensive metabolic alteration, characterized increased levels of most of the identified metabolites and unregulated activity of membrane transporters. These generates a high energy expenditure associated to limited conditions of mitochondrial energy production, resulting in the cellular death. Sertraline also showed in vitro leishmanicidal activity, with an EC50 value of 2 ?M against promastigotes and 3.9 ?M against intracellular amastigote forms. Its toxicity in NCTC cells was 19.6 ?M, resulting in a selectivity index similar to miltefosine. Our studies confirmed the mitochondria of Leishmania as the primary target, and the uncoupling of the respiratory chain associated with energy collapse, oxidative stress, and the depolarization of ??m as the possible origin of this mitochondrial dysfunction. Metabolomics evidenced an extended metabolic disarray caused by SRT encompassing a decrease in the scavenging capacity of the thiol-redox metabolism and a severe depletion of the intracellular pool of amino acids and polyamines. The complete deterioration of energetic metabolism was evident through a multi-target mechanism, affecting the main metabolic pathways of the parasite. Finally, this study describes an anti-Leishmania activity of two approved oral drugs with lethal and irreversible mechanisms of action in the parasite, encouraging future preclinical studies in American visceral leishmaniasis.

Les travaux présentés dans ce mémoire traitent de la conception des chaînes éditoriales Numériques XML : des logiciels de production documentaire qui outillent la rédaction de et l'assemblage de ces fragments pour former des documents. fragments La publication des documents s'opère par transformation de fragments XML en documents numériques aux formats standards. La composition des fragments permet d'instrumenter la rééditorialisation documentaire soit l'usage de contenus existants dans la rédaction de documents originaux. La production de documents rééditorialisés implique une modification de la représentation logique des documents de la forme classique d'arbre à celle de graphe de fragments liés entre eux. Ces travaux s'intéressent aux limites rencontrées lorsque la complexité du graphe devient un frein à la production de documents cohérents.Nous avons élaboré une théorie pour la conception des chaînes éditoriales qui s'appuie sur deux approches complémentaires s'articulant autour de la figure de l'atelier - soit l'environnement d'écriture des fragments - pour accompagner les rédacteurs dans l'édition de graphes complexes.La première approche est une articulation interne à l'atelier. Nous proposons de modéliser des fragments pragmatiques dont l'enjeu est d'assister les rédacteurs dans la gestion des fragments tout en enregistrant l'activité sur le graphe. Ces fragments participent à la documentarisation de l'activité puisqu'ils produisent et mettent à jour une documentation des actions opérées sur le graphe.La seconde approche est une articulation externe à l'atelier. Nous proposons de structure rle graphe documentaire dans plusieurs ateliers en fonction des projets éditoriaux (projets de documents à publier) et auctoriaux (projets d'organisation de la production). L'enjeu est d'éclater le graphe dans plusieurs ateliers afin d'en simplifier la perception et donc la manipulation.Nous avons participé aux développements de la suite Scenari afin d'expérimenter notre approche théorique. Les modèles de fragments pragmatiques de la tâche, du fragment commenté, et les responsabilités et cycles de vie sur les fragments ont été développés afin de documentariser l'activité. Les ateliers calques et fragments proxys ont été conçus afin de structurer le graphe. Nos expérimentations nous ont permis de synthétiser une méthodologie pour la conception de chaînes éditoriales exploitant des graphes complexes. Nos travaux se concluent sur une réflexion épistémologique sur la recherche technologique et plus particulièrement sur ses modalités de validité. / This thesis deals with the design of digital XML publishing chains : document production software which allows writing fragments and composing them in order to publish documents. Document publication is computed by transforming XML fragments into digital documents in standard formats. The composition of the fragments allows the repurposing of existing contents into new documents.The writing of repurposed documents involves a change in the logical representation ofdocuments from the classical form of the tree to a graph of linked fragments. This work is dedicated to the limitations encountered when the complexity of the graph becomes an obstacleto the writing of consistent documents.We developed a theory for the design of publishing chains which is based on two complementary approaches around the concept of the writing workspace - the space where the authors write the fragments - to assist writers in the editing of complex graphs.The first approach is internal to the workspace. We propose to model pragmatic fragments intended to assist authors in fragment management while recording graph activity.These fragments are involved in the activity documentarisation since they produce and maintaina documentation of the actions performed on the graph.The second approach is external to the workspace. We propose to structure the graph asseveral workspaces based on publishing and authorial projects. The challenge is to distribute the graph over several workspaces in order to simplify their perception and handling.We participated in the development of Scenari in order to experiment our theoretical approach. The pragmatic fragment models of the task, of the commented fragment, and of there sponsibilities and life cycles on fragments were developed to document the activity. The layerworkspaces and proxy fragments were designed to structure the graph. Our experiments allowed us to summarize a methodology for designing publishing chains which handle complex graphs. Our work is concluded with an epistemological approach in order to qualify and evaluate this technological research.

Philosophiae Doctor - PhD / Glioblastoma multiforme (GBM) remains the most malignant of all primary adult brain tumours. It is a highly invasive and vascularized neoplasm with limited treatment options and very low survival rate. GBM tumours are heterogeneous in nature with cellular hierarchy and at the apex of this hierarchy are the glioblastoma stem cells, known to promote tumourigenesis and resistance to chemotherapeutic agents and tumour recurrence. Currently, the standard care for GBM involves surgical resection, radiation, and chemotherapy treatment with temozolomide. Unfortunately, median survival after treatment is still daunting and tumour relapse is very frequent. Indeed, patients with recurrent glioblastoma have less than a year survival. To address this, novel therapies need to be developed with the early introduction of promising agents into clinical trials and subsequent approval for use. Importantly, for these novel therapies to be approved for GBM, they need to be safe, effective as well as being able to penetrate the blood-brain barrier (BBB). Due to the high cost and process time for the development of new drugs, existing approved drugs are currently being repurposed for new indications and this is gaining significance in clinical pharmacology as it allows rapid delivery of useful drugs from bench to bedside. Drugs of the antipsychotic class are well known to cross the BBB due to their neuroleptic action. To this end, the aim of this study was to identify and characterize the anti-cancer activities of novel phenothiazine-derivatives belonging to the antipsychotic class of drugs in glioblastoma. To achieve this, several novel phenothiazine-derivatives were initially screened for possible anti-cancer activity in the U87 and U251 malignant GBM cells. Two lead compounds, DS00326 and DS00329, were identified and their anti-cancer activities were determined in U87 and U251 cells as well as in primary patient-derived xenograft (PDX) glioblastoma cultures. DS00326 and DS00329 significantly inhibited glioblastoma cell viability, with minimal effects observed in the non-cancerous FG0 fibroblasts. The IC50 values of DS00326 and DS00329 for U251, U87 and PDX cells ranged from 1.61 to 12.53μM. Flow cytometry analyses showed that DS00326 and DS00329 treatment led to an increase in the G1 population of cells. Additionally, DS00326 and DS00329 induced double-strand DNA breaks, which lead to activation of the canonical DNA damage response pathway. Furthermore, DS00326 and DS00329 induced apoptosis as shown by morphological markers, flow cytometry with annexin V-FITC/propidium iodide staining, as well as western blotting with an antibody to detect levels of cleaved PARP. Interestingly, treatment with DS00326 and DS00329 also induced autophagy as evident by the increase of acidic vesicular organelles in cells following staining with acridine orange as well as an increase in levels of the autophagy marker LC3-II. Autophagy was seen as a pro-death pathway in the U87 and U251 cells as inhibition of autophagy led to a reversal of cytotoxicity and consequently increased cell survival. Moreover, it was demonstrated that DS00326 and DS00329 inhibited the PI3/Akt pathway while modulating the mitogen-activated protein kinases p38, ERK1/2 and JNK signalling pathways. Importantly DS00326 and DS00329 displayed anti-cancer stem cell activities by the inhibition of neurosphere formation and regulation of stem cell markers SOX2 and GFAP in PDX cells. Together, the findings from this study suggest that DS00326 and DS00329 may be effective in the treatment of glioblastoma and provide a strong rationale for further clinical studies exploiting phenothiazines and their derivatives as treatments for glioblastoma. / 2021-09-01

No description available.

No description available.

This master´s thesis called „Revitalization of object“ is compiled as a project documentation according to relevant technical regulations and norms. Object is designed as a four-story building including two below-ground stories and an attic. It is comprised of a brick wall system stemming from present stone foundations and a sloped framed roof. All ceilings are based on existing horizontal constructions. Object is newly laid out as a five-unit flat house with facilities included.

This study was an effort to construct and validate an instructional design framework for media content selection that incorporates re-purposing popular media to enhance mathematics and science instruction. The study resulted in the development and validation of a framework that was applicable with novice and expert instructional designers to be used as a stand - alone model or as a supplement to widely-used instructional design models. The framework was developed based on the literature review of four constructs: instructional design models, re-purposing popular media, learning theories and the new generation learners' characteristics, and multidisciplinary or integrated approaches to instruction. The findings of the literature review were used as the theoretical foundation for the construction of the framework for media content selection. During the final step of the study's Phase One, the researcher used the first iteration of the framework to develop a short instructional module that incorporated the re-purposing of popular media. This instruction focused on early mathematics (K-2) and the re-purposing of full-feature children animated films. The goal of this step was the development of documentation to record the process for media content selection that was later used to modify and revise the framework. As the next step, the framework was validated by subject matter experts in the field of instructional design. The framework was then further revised and modified. The findings of this study have implications on the areas that pertain to (a) instructional design models, (b) media selection, (c) media content selection, and (d) curriculum integration. Based on the findings of this study, recommendations to practitioners choosing to use the framework for media content selection were suggested and suggestions for future research were provided. / Ph. D.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and is recognized as the second leading cause of cancer-related deaths in North America. CRC follows a hierarchal tumor organization, the root being a small population of self-renewing and highly tumorigenic colon cancer stem cells (CSC). There is an epigenetic signature that exists within these colon CSCs contributing to their maintenance and dynamic plasticity. A key hallmark of this colon CSC epigenetic signature is the Histone-3 Lysine-9 di-methylation (H3K9me2) histone mark which is overrepresented in many types of cancer. Pharmacological modulation of this epigenetic signature (i.e through H3K9me2 modulation) serves as a novel way to selectively target and eliminate human CSCs while sparing normal progenitor cells. Direct inhibitors of key methyltransferases such as G9a, have been identified to have high specificity, however none of these inhibitors have shown success during early stages of clinical trials, leaving us to question the clinical relevance. My research has shown that the overexpression of histone methyltransferase G9a in colon cancer serves as a risk factor for patients and is associated with shorter-relapse free survival. G9a activity has been shown to be essential for the maintenance of embryonic-like transcriptional signature which promotes self-renewal, tumorigenicity and an undifferentiated state. This work provides insights into the role of G9a as a driver of a cancer stem cell phenotype. To combat the toxicity and issues associated with targeting the catalytic activity of G9a, I utilized a phenotypic screening pipeline consisting of thousands of clinically-approved compounds, and identified CSC-bioactive epigenetic inhibitors showing promise in CSC-like models. RNA-seq profiling, dose response treatments and molecular techniques were used to confirm the selectivity of these candidates to colon-CSC like cells with minimal impact on normal progenitors. The lead candidate compound, vanoxerine (VXN) restricts organoid-initiating capacity of patient derived colon CSCs in serial 3D organoid formation assays that I developed throughout my research project. Using two murine syngeneic models resembling microsatellite instability and stability in CRC, I found this compound to be successful in decreasing primary tumor volumes compared to vehicle control mice, through epigenetic reprogramming and infiltration of immune cells. Drug treated tumors that were harvested, dissociated and re-injected into secondary mice showed diminished tumor initiating capacity compared to vehicle controls. Furthermore, the target of vanoxerine, SLC6A3, was investigated and the expression pattern characterized revealed a new potential biomarker for colon cancer stem cells. This SLC6A3-G9a axis discovered for the first time in colon cancer and serves as a novel and important pathway to block H3K9me2 deposition in CRC, rewiring the CSC epigenome and suppressing neoplastic self-renewal and tumor-initiating functions. Together, the identified repurposed compound selectively targets and modulates the epigenetic signature of CSCs which diminishes the tumor initiating function of these cells. This hints at an interesting interaction between CRC stemness and tumor immunology, a promising future therapeutic avenue.