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Dissertação (mestrado)—Universidade de Brasília, Instituto de Ciências Humanas, Departamento de Geografia, Programa de Pós-Graduação em Geografia, 2015. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2016-03-31T16:36:20Z No. of bitstreams: 1 2015_PriscilaCâmaradeAraújo.pdf: 3124057 bytes, checksum: 2b221e051c7eb29ebbdd1ca4d015077d (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2016-04-01T20:46:24Z (GMT) No. of bitstreams: 1 2015_PriscilaCâmaradeAraújo.pdf: 3124057 bytes, checksum: 2b221e051c7eb29ebbdd1ca4d015077d (MD5) / Made available in DSpace on 2016-04-01T20:46:24Z (GMT). No. of bitstreams: 1 2015_PriscilaCâmaradeAraújo.pdf: 3124057 bytes, checksum: 2b221e051c7eb29ebbdd1ca4d015077d (MD5) / O planejamento da ordenação territorial é imprescindível para o crescimento das cidades. Os Planos Diretores têm papel fundamental no estabelecimento de diretrizes para ocupação dos espaços. A implantação do Trem de Alta Velocidade brasileiro aumenta as possibilidades de relações entre centros urbanos e impacta a ordenação do território, especialmente as áreas de implantação das estações. Nesse sentido, a modelagem digital torna-se uma ferramenta importante no planejamento da ocupação dos terrenos, tendo em vista que os Modelos Digitais de Terreno (MDT) e os Modelos Digitais de Superfície (MDS) fornecem informações do terreno e dos elementos sobre a superfície. Para o desenvolvimento deste trabalho, foi escolhida a região do Campo de Marte (SP), uma das regiões previstas para implantação de uma estação do TAV Brasil, com o objetivo testar uma metodologia de trabalho que auxilie na estimativa das potencialidades de verticalização em torno da estação, modelando uma simulação de mudança de gabarito na área. Utilizando ortofotos e o MDS produzidos em 2010/2011, pela a Empresa Paulista de Planejamento Metropolitnao (Emplasa) e, disponibilizados pela Empresa de Planejamento e Logística (EPL) do governo federal, foi feito o mapeamento das ruas e edificações da área de influência indireta do Campo de Marte e a construção do MDT. Foi calculado o volume de ocupação atual da área pela diferença dos valores de elevação obtidos pelo MDS e MDT para dentro da área da estrutura predial multiplicado pela área desta estrutura. Os resultados obtidos foram a classificação das edificações atuais e a verificação de que a área de estudo ainda possui um grande potencial de verticalização permitido pelo plano diretor (cerca 5 milhões de metros cúbicos). / The growth of cities is dynamic and constant and is essential to planning the territorial ordination. The Directive Plans play a fundamental role in the establishment of guidelines and strategies for the space occupation. The implementation of the brazilian High Speed Train increase the chance of relations between urban centers and impacts land use planning. In this sense, digital modeling becomes an important tool in planning the occupation of the land, given that the Digital Terrain Models (DTM) and the Surface Digital Models (MDS) provide the land information and evidence on the surface .To develop this work, it was chosen the region of Campo de Marte (SP), one of the areas provided for implementation of a station TAV Brazil, aiming to predict the potential for occupation around the station. Using orthophotos and MDS produced in 2010/2011 by the Paulista Company of Metropolitan Planning (Emplasa) and made available by the federal government Company for Planning and Logistics (EPL), has done the mapping of streets and buildings in the area of indirect influence of the Campo de Marte and the construction of the MDT. We calculated the volume of the current occupation of the area by the difference in elevation values obtained by MDS and MDT and into the area of the building structure multiplied by the area of this structure. The results were the classification of current buildings and verification that the study area still has great potential for vertical expansion allowed by the directiver plan (about 5 million cubic meters), and when simulated (to a height of 87 meters) the triples value.

Sambandet mellan emotionella uttryck och tonhöjdsegenskaper i tal har tidigare undersökts, men få studier har gjorts av andra ljudegenskaper av emotionella uttryck. Denna studie undersöker volym och talhastighetens påverkan på människors förmåga att sortera emotionella uttryck, och om det finns andra variabler som används när denna information plockats bort. Hypotesen är att det blir svårare att sortera när denna information inte längre finns tillgänglig. Till studien rekryterades 62 deltagare, varav 56 av dessa användes i analysen. Deltagarna randomiserades till en kontrollgrupp och tre experimentgrupper, i vilka volym, talhastighet, samt volym och talhastighet normaliserats till respektive variabels medianvärde. De fick lyssna på och sortera ljudfiler där skådespelare gestaltade olika emotionella tillstånd. Multidimensionell skalning (MDS) användes för att skapa en karta över avståndet mellan emotioner och multipla regressioner utfördes för att hitta förklaringar till MDS-lösningarna. Resultatet tyder på att det är svårare att urskilja de emotionella uttrycken när volym och talhastighet normaliserats. Vad i ljudet som används istället undersöks med multipel regression. Resultaten kopplas till befintliga emotionsmodeller och slutsats dras om att volym och talhastighet verkar vara viktiga för sortering av emotionella ljud.

Understanding the structure-function relationship of proteins such as G protein-coupled receptors (GPCRs) requires detailed information on their three-dimensional (3D) structure and dynamics. Recent progress in the structural elucidation of receptor-G protein or -arrestin complexes yields valuable starting points to studying their function and dynamics. I investigated the dynamic process of β2 adrenergic receptor-G protein recognition and binding using molecular dynamics (MD) simulations. MD simulation is a well-established technique to monitor the time-resolved motions of proteins and is used to investigate the dynamics of GPCRs. In order to start MD simulations, the structures that are often incompletely resolved have to be further completed. Finally, the results from computational analysis have to be subjected to experimental validation. To promote broad applicability of that workflow, I automated critical steps such as modeling of missing segments or interactive analysis and visualization of the results of MD simulations. Web-tools allow researchers besides different methodological expertise to apply unfamiliar techniques on their biological systems of interest without the need to download software or databases. To facilitate usage, I included visualization allowing intuitive understanding and analysis. We developed the NGL molecular web-viewer, which accesses hardware-accelerated graphics through WebGL. This and other recent developments, reviewed by Mwalongo and others, opened up new possibilities for web molecular graphics and render- ing techniques, superseding plugin- and Java-based viewers and making them comparable with desktop tools, such as PyMOL, VMD, or UCSF Chimera. Here, I implemented and applied tools for interactive modeling of missing segments into single-particle cryo-electron microscopy (cryo-EM) density maps, for interactive analysis of structure-functional dynamics, and more general to promote interdisciplinary research. To allow non-expert users access to bioinformatics methods and biophysical techniques, all tools were generated as web-services allowing interactive analysis and visualization.:Introduction 1 GPCRs as a prime example in structural and pharmaceutical biology 2 Modeling missing segments into cryo-EM density maps 3 Research goal I: Web service for modeling of missing segments into cryo-EM density maps 4 From static to dynamics to investigate GPCR function 5 The complexity of sharing MD simulations 6 Research goal II: Interactive visual sharing of MD simulations Manuscripts 1 FragFit: a web-application for interactive modeling of protein segments into cryo-EM density maps 2 MDsrv: viewing and sharing molecular dynamics simulations on the web. 3 Bringing Molecular Dynamics Simulation Data into View Summary 1 Modeling of missing fragments into cryo-EM density maps 2 InteractiveanalysisofMDsimulationsontheweb . . . . . . References Appendix A Additional Manuscripts 1 SL2: an interactive webtool for modeling of missing segments in proteins 2 GPCR-SSFE 2.0-a fragment-based molecular modeling web tool for Class A G-protein coupled receptors. 3 A fragment based method for modeling of protein segments into cryo-EM density maps 4 Structural Insights into the Process of GPCR-G Protein Complex Formation 5 Sharing Data from Molecular Simulations Appendix B Darstellung des eigenen Beitrags Selbständigkeitserklärung Curriculumvitae & Publikationen Danksagung

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Die akute myeloische Leukämie (AML) und das myelodysplastische Syndrom (MDS) stellen heterogene myeloische Neoplasien dar, deren Übergang in einander fließend ist. Während bei der AML ein Differenzierungsblock sowie eine unkontrollierte Proliferation myeloischer Vorläuferzellen dominieren, zeichnet sich das MDS vorrangig durch Dysplasien und variable Zytopenien, sowie ein erhöhtes Risiko der Transformation in eine AML aus. Trotz unseres zunehmenden Verständnisses dieser Erkrankungen ist die Prognose für AML und MDS Patienten noch immer häufig ungünstig. Auch mit der Entwicklung neuer zielgerichteter Therapiekonzepte behält die allogene hämatopoetische Stammzelltransplantation ihre große Bedeutung in der Therapie von AML und MDS. Insbesondere bei Patienten mit prognostisch ungünstigen Merkmalen stellt sie häufig die einzige kurative Therapieoption dar. Entsprechend kommt einer Risikostratifizierung bei Diagnose sowie im Krankheitsverlauf zur individuellen Therapieentscheidung eine große Bedeutung zu um personalisierte Behandlungen zu ermöglichen. Diese kann durch klinische Variablen, Immunphänotypisierung und zyto- oder molekulargenetische Veränderungen erfolgen. Diese Arbeit beschäftigt sich mit neuen klinischen, molekularen und durchflusszytometrischen Markern um die bestehenden Risikoklassifikationssysteme für Patienten mit AML und MDS weiter zu verfeinern und legt ein besonderes Augenmerk auf Patienten, die eine allogene Stammzelltransplantation erhalten. Der erste Abschnitt dieser Arbeit zeigt die prognostische Relevanz der leukämischen Stammzellpopulationen – definiert über die CD34+/CD38- Zellpopulation bzw. die GPR56 Expression - bei Diagnosestellung. Sowohl in der AML als auch im MDS scheint ein hoher Anteil leukämischer Stammzellen eine Subgruppe von Patienten mit ungünstiger Prognose unabhängig von aktuellen Risikostratifikationen und auch trotz Durchführung einer allogenen Stammzelltransplantation identifizieren zu können. Im zweiten Abschnitt wird ein Überblick über die zunehmende Relevanz der Risikostratifikation im Krankheitsverlauf - im Sinne der Bestimmung einer messbaren Resterkrankung (MRD) – erörtert und mit der Expressionshöhe von BAALC und MN1 mögliche neue Marker zur MRD Bestimmung vorgestellt. Der dritte Abschnitt zeigt, dass auch die Wahl des Konsolidierungskonzeptes die initiale molekulargenetische Risikostratifizierung beeinflussen kann. Während eine hohe Expression der AML-assoziierten Gene BAALC und MN1 bei AML Diagnose mit einer ungünstigen Prognose einhergeht, wenn die Patienten mit einer Chemotherapie behandelt werden, scheint eine allogene Stammzelltransplantation diesen prognostischen Einfluss aufzuheben. Außerdem wird die Relevanz einer allogenen Stammzelltransplantation bei älteren Patienten mit der prinzipiell eher günstigen molekulargenetischen Konstellation NPM1 mutiert/FLT3-ITD Wildtyp diskutiert. Im vierten Abschnitt wird der Einfluss klinischer Parameter auf die Prognose von AML und MDS Patienten diskutiert. Patienten mit einer sekundären (nach anderen myeloischen Erkrankungen) oder therapieassoziierten AML (nach vorausgegangener zytostatischer Therapie) weisen unter konventioneller Chemotherapie eine sehr ungünstige Prognose auf. Im Gegensatz dazu legen die Ergebnisse nahe, dass das Überleben nach allogener Stammzelltransplantation – wenn das genetische Risiko beachtet wird - nicht wesentlich schlechter ist als das von Patienten mit de novo AML. Außerdem wird gezeigt, dass sowohl das Vorliegen einer Adipositas zum Zeitpunkt der Diagnose einer AML als auch ein Gewichtsverlust zwischen Diagnose und allogener Stammzelltransplantation mit einer ungünstigen Prognose einhergehen. Zuletzt werden zwei Konditionierungsintensitäten vor Stammzelltransplantation in MDS Patienten verglichen und gezeigt, dass vor allem bei jüngeren Patienten intensivere Protokolle bessere Ergebnisse erzielen. Zusammenfassend zeigt diese Arbeit neue Möglichkeiten auf, die Risikostratifizierung für Patienten mit myeloischen Erkankungen sowohl bei Diagnose als auch im Krankheitsverlauf zu verbessern und leistet somit einen wichtigen Beitrag zur weiteren Personalisierung der Therapie von AML und MDS.:1. INTRODUCTION / EINLEITUNG 5 1.1 AML 5 1.1.1 DIAGNOSIS AND DISEASE CLASSIFICATION 5 1.1.2 RISK STRATIFICATION AT DIAGNOSIS 6 1.1.3 TREATMENT 8 1.2 MDS 9 1.2.1 DIAGNOSIS AND DISEASE CLASSIFICATION 9 1.2.2 RISK STRATIFICATION AT DIAGNOSIS 10 1.2.3 TREATMENT 12 1.3 ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION 13 2. FREQUENCY OF LEUKEMIA INITIATING CELL POPULATIONS AT DIAGNOSIS OF AML AND MDS 14 2.1 BACKGROUND 14 2.2 OWN CONTRIBUTION 14 Prognostic Impact of the CD34+/CD38- Cell Burden in Patients with Acute Myeloid Leukemia receiving Allogeneic Stem Cell Transplantation. Am J Hematol 2017; 92: 388-396. 15 High expression of the stem cell marker GPR56 at diagnosis identifies acute myeloid leukemia patients at higher relapse risk after allogeneic stem cell transplantation in context with the CD34+/CD38- population. Haematologica 2020. 105: 229260 15 The pre-treatment CD34+/CD38- cell burden as prognostic factor in MDS patients receiving allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2019; 25: 1560-1566. 15 3 MEASURABLE RESIDUAL DISEASE DETECTION IN AML 37 3.1 BACKGROUND 37 3.2 OWN CONTRIBUTION 37 High Blood BAALC Copy Numbers at Allogeneic Transplantation Predict Early Relapse in Patients with Acute Myeloid Leukemia. Oncotarget 2017; 8:87944-87954. 38 Prognostic impact of blood MN1 copy numbers before allogeneic stem cell transplantation in patients with acute myeloid leukemia. HemaSphere 2019; 3: e167. 38 4. THE USE OF ALLOGENEIC HSCT IMPACTS THE RELEVANCE OF GENETIC PROGNOSTICATORS AT AML DIAGNOSIS 59 4.1 BACKGROUND 59 4.2 OWN CONTRIBUTION 59 Outcomes of older patients with NPM1 mutated and FLT3-ITD negative acute myeloid leukemia receiving allogeneic transplantation. HemaSphere 2020. 3; 4: e326. 59 Allogeneic stem cell transplantation mitigates the adverse prognostic impact of high diagnostic BAALC and MN1 expression in AML. Ann Hematol 2020. 99: 2417-2427. 60 5. CLINICAL AND TREATMENT-ASSOCIATED PROGNOSTICATORS IN AML AND MDS 76 5.1 BACKGROUND 76 5.2 OWN CONTRIBUTION 77 ELN risk stratification and outcomes in secondary and therapy-related AML patients consolidated with allogeneic stem cell transplantation. Bone Marrow Transplant. 2020 Nov 19. doi: 10.1038/s41409-020-01129-1. [Online ahead of print] 77 Nutritional status at diagnosis and weight changes impact outcomes in acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation HemaSphere 2021. 5:2(e532). 77 Comparison of non-myeloablative and reduced-intensity allogeneic stem cell transplantation in older patients with myelodysplastic syndromes. Am J Hematol 2019; 94:1344-1352. 77 6. CONCLUSION / ZUSAMMENFASSUNG 106 7. REFERENCES / REFERENZEN 108 8. INDEX OF ABBREVIATIONS / INHALTSVERZEICHNIS 114 9. EIDESSTATTLICHE ERKLÄRUNG ZUR VORGELEGTEN HABILITATIONSSCHRIFT 116 10. COMPLETE LIST OF PUBLICATIONS / PUBLIKATIONSVERZEICHNIS 117 11. CURRICULUM VITAE / LEBENSLAUF 129 12. ACKNOWLEDGEMENTS / DANKSAGUNG 132

High-dimensional data sets can be difficult to visualize and analyze, while data in low-dimensional space tend to be more accessible. In order to aid visualization of the underlying structure of a dataset, the dimension of the dataset is reduced. The simplest approach to accomplish this task of dimensionality reduction is by a random projection of the data. Even though this approach allows some degree of visualization of the underlying structure, it is possible to lose more interesting underlying structure within the data. In order to address this concern, various supervised and unsupervised linear dimensionality reduction algorithms have been designed, such as Principal Component Analysis and Linear Discriminant Analysis. These methods can be powerful, but often miss important non-linear structure in the data. In this thesis, manifold learning approaches to dimensionality reduction are developed. These approaches combine both linear and non-linear methods of dimension reduction.

An integral concern across care settings is the prompt intervention for patients suffering with pain. Long-term care (LTC) settings present with unique challenges to assess and manage pain in resident populations. Pain assessment is especially challenging, because residents have varying degrees of cognition to communicate their pain, and clinician/staff knowledge of pain symptoms may be lacking. The purpose of this research was to improve the measurement of pain and outcomes of care for the elderly residing in skilled nursing care, especially those with cognitive-impairment. The specific aims of this study were to: 1) Determine the magnitude of the relationship between pain behaviors and a measurement model hypothesized for pain; 2) Test the construct validity of a pain measurement model; 3) Examine the concomitance of pain and cognition in a three-year longitudinal analysis. The research questions answered: 1) Is there a difference in the prevalence of pain in cognitively intact versus cognitively-impaired residents; 2) Can a theoretically derived model of pain aid in detecting pain across all cognitive levels; and 3) Do pain and cognitive status concomitantly correlate? The goal was to examine the covariance model of concomitance of pain and cognition to more accurately construct theoretical models of pain to then include additional resident care factors in future research. Traditional self-reports of pain are often under-assessed and under-treated in the cognitively-impaired (CI) elderly resident. Having additional measures to detect pain beyond self-reports of pain intensity and frequency increases the likelihood of detecting pain in populations with complex symptom presentation. Data collected from skilled nursing facilities offer exceptional opportunities to study resident demographics, characteristics, symptoms, medication use, quality indicators, and care outcomes. The Minimum Data Set-Resident Assessment Instrument (MDS-RAI) 2.0, a nationally required resident assessment tool, must be completed on every resident in a Medicare LTC facility within 14 days of admission, quarterly, annually and with significant changes in resident status. Because the MDS is widely used and recognized in LTC settings, core items from MDS [i.e., pain frequency (J2a) and pain intensity (J2b)] along with additional MDS items hypothesized to signify pain were analyzed in the pilot measurement model. Ten core items from MDS were used: 1) Inappropriate behavior frequency (E4da); 2) Repetitive physical movements; 3) Repetitive verbalizations (E1c); 4) Sad facial expressions (E1l); 5) Crying (E1m); 6) Change in mood (E3); 7) Negative statements (E1a); 8) Pain frequency (J2a); 9) Pain intensity (J2b); and 10) Cumulative pain sites scores. All indicators of pain were significant at the <.01 level. A longitudinal cohort design was used to answer if a concomitance exists between pain and cognition. Data were collected from MDS annual assessments from 2001, 2002 and 2003 for residents across the United States. The sample consisted of 56,494 residents age 65 years and older with an average age of 83 [plus or minus] 8.2 years. Descriptive statistics, ANOVA and a covariance model were used to evaluate cognition and pain at the three time intervals. ANOVA indicated a significant effect (<.01) for pain and cognition with protected t-tests indicating scores decreased significantly over time with resident measures of pain and cognition. Results from this study suggest that: 1) Using only pain intensity and frequency, pain prevalence was found in 30% of the pilot population, while 47.7% of cognitively intact residents had documented pain and only 18.2% of the severely CI had documented pain, supporting previous research that pain is potentially under-reported in the CI; 2) Parsimonious measurements models of pain should include dimensions beyond self-reports of pain (i.e., cognitive, affective, behavioral and inferred pain indicators); 3) Model fit was improved by using specific MDS items in the pain construct; 4) Longitudinal analysis revealed relative stability for pain and cognition measures over time (e.g., larger stability or consistency was found in cognitive measures than the measures of pain over the three-year period); 5) Crossed-legged effects between pain and cognition were not consistent; 6) A concomitant relationship was not found between pain and cognition. The relationship was significant (<.01), but associations were weak (r=0.03 to 0. 08). Pain or cognition should not be used as a predictor of the other in theoretical models for similar populations. The MDS is a reliable instrument to follow resident attributes, quality of care, and patient outcomes over time. The development of more accurate assessments of pain may improve resident care outcomes. Ineffectively intervening on the pain cycle is posited to cause secondary unmet needs that affect the resident's quality of life. Findings support the importance of improving clinical outcomes in the management of pain in the elderly residing in long-term care. Deficits in the treatment of pain highlight the impetus to support health policy change that includes pain treatment as a top health priority and a quality indicator for federally funded programs supporting eldercare.