<p>Für das Verständnis der Strukturbildung bei Proteinen ist es wichtig, allgemein geltende Prinzipien der Stabilität und Faltung zu verstehen. Bisher wurde viel Arbeit in die Erörterung von Gesetzmäßigkeiten zu den Faltungseigenschaften von globulären Proteinen investiert. Die große Proteinklasse der solenoiden Proteine, zu denen z. B. Leucine-Rich Repeat- (LRR-) oder Ankyrin-Proteine gehören, wurde dahingegen noch wenig untersucht. Die Proteine dieser Klasse sind durch einen stapelförmigen Aufbau von sich wiederholenden typischen Sequenzeinheiten gekennzeichnet, was in der Ausbildung einer elongierten Tertiärstruktur resultiert. In der vorliegenden Arbeit sollte versucht werden, die Stabilität und Faltung eines LRR-Proteins mittels verschiedener biophysikalischer Methoden zu charakterisieren. Als Untersuchungsobjekt diente die für die Infektion ausreichende zentrale LRR-Domäne des Invasionsproteins Internalin B (InlB₂₄₁) des Bakteriums <i>Listeria monocytogenes</i>. Des weiteren sollten die Integrität und die Stabilitäts- und Faltungseigenschaften der sogenannten Internalin-Domäne (InlB₃₂₁) untersucht werden. Hierbei handelt es sich um die bei allen Mitgliedern der Internalinfamilie vorkommende Domäne, welche aus einer direkten Fusion des C-terminalen Endes der LRR-Domäne mit einer Immunglobulin (Ig)-ähnlichen Domäne besteht.</p> <p>Von beiden Konstrukten konnte eine vollständige thermodynamische Charakterisierung, mit Hilfe von chemisch- bzw. thermisch-induzierten Faltungs- und Entfaltungsübergängen durchgeführt werden. Sowohl InlB₂₄₁ als auch InlB₃₂₁ zeigen einen reversiblen und kooperativen Verlauf der chemisch-induzierten Gleichgewichtsübergänge, was die Anwendung eines Zweizustandsmodells zur Beschreibung der Daten erlaubte. Die zusätzliche Ig-ähnliche Domäne im InlB₃₂₁ resultierte im Vergleich zum InlB₂₄₁ in einer Erhöhung der freien Enthalpie der Entfaltung (8.8 kcal/mol im Vergleich zu 4.7 kcal/mol). Diese Stabilitätszunahme äußerte sich sowohl in einer Verschiebung des Übergangsmittelpunktes zu höheren Guanidiniumchlorid-Konzentrationen als auch in einer Erhöhung der Kooperativität des Gleichgewichtsübergangs (9.7 kcal/mol/M im Vergleich zu 7.1 kcal/mol/M). Diese Beobachtungen zeigen dass die einzelnen Sequenzeinheiten der LRR-Domäne nicht unabhängig voneinander falten und dass die Ig-ähnliche Domäne, obwohl sie nicht direkt mit dem Wirtszellrezeptor während der Invasion interagiert, eine kritische Rolle für die <i style='mso-bidi-font-style:normal'>in&nbsp;vivo</i> Stabilität des Internalin B spielt. Des weiteren spiegelt die Kooperativität des Übergangs die Integrität der Internalin-Domäne wieder und deutet darauf hin, dass bei beiden Proteinen keine Intermediate vorliegen.</p> <p>Kinetische Messungen über Tryptophanfluoreszenz und Fern-UV<span style='color:red'> </span>Circulardichroismus deuteten auf die Existenz eines relativ stabilen Intermediates auf dem Faltungsweg der LRR-Domäne hin. Faltungskinetiken aus einem in pH&nbsp;2 denaturierten Zustand zeigten ein reversibles Verhalten und verliefen über ein Intermediat. Eine Erhöhung der Salzkonzentration des sauer-denaturierten Proteins führte zu einer Kompaktierung der entfalteten Struktur und resultierte im Übergang zu einem alternativ gefalteten Zustand. Bei der Internalin-Domäne deuteten kinetische Messungen des Fluoreszenz- und Fern-UV Circulardichroismus-Signals während der Entfaltung möglicherweise auf die Präsenz von zwei Prozessen hin. Der erste langsame Entfaltungsprozess kurz nach dem Übergangsmittelpunkt zeigte eine starke Abhängigkeit von der Temperatur, während der zweite schnellere Prozess der Entfaltung stärker von der Guanidiniumchlorid-Konzentration abhing. Renaturierungskinetiken zeigten das Auftreten von mindestens einem Faltungsintermediat. Kinetische Daten aus Doppelsprungexperimenten lieferten für die Erklärung der langsamen Faltungsphase zunächst keinen Hinweis auf dass Vorliegen einer Prolinisomerisierungsreaktion. Die vollständige Amplitude während der Renaturierung konnte nicht detektiert werden, weswegen von einer zweiten schnellen Phase im Submillisekundenbereich ausgegangen werden kann.</p> <p>Die Ergebnisse der Faltungskinetiken zeigen, dass die InlB-Konstrukte als Modelle für die Untersuchung der Faltung von Solenoidproteinen verwendet werden können.<span lang=EN-GB style='mso-ansi-language: EN-GB'><o:p></o:p></span></p> / <p class=MsoBodyText><span lang=EN-GB style='mso-ansi-language:EN-GB'>To understand the processes of protein structure formation, it is necessary to investigate protein stability and protein folding kinetics. The focus of many folding studies has been directed at small, globular proteins. The larger class of solenoid proteins, including leucine-rich repeat (LRR) and ankyrin proteins, has not been extensively investigated. These proteins contain tandem repeat motifs, and their tertiary structure consists of a regular linear array of modules that stack to form non-globular elongated or supercoiled structures. In the present work, the folding and stability of the central LRR domain of the invasion protein internalin B (InlB₂₄₁) from the bacterium <i>Listeria monocytogenes</i> was characterized using different biophysical techniques. In addition, the integrity, stability and folding behavior of the so-called internalin-domain (InlB₃₂₁) was investigated. In this single domain, which is found in all members of the internalin-family, an immunoglobulin (Ig)-like domain is directly fused to the C-terminal end of the LRR domain.<span style='color:red'><o:p></o:p></span></span></p> <p class=MsoBodyText><span lang=EN-GB style='mso-ansi-language:EN-GB'>A complete thermodynamic characterization of the stability of both constructs was performed, using chemical- and temperature-induced folding and unfolding transitions. The reversible and cooperative equilibrium transition of InlB₂₄₁ and InlB₃₂₁ allowed the use of a two-state model for the description of the data points. The additional Ig-like domain present in InlB₃₂₁ resulted in an increase of the unfolding free energy (8.8 kcal/mol compared to 4.7 kcal/mol). This resulted both, from a shift of the transition midpoint to higher denaturant concentration, and from an increase in the <i>m</i>-value, the denaturant dependence of the unfolding free energy (9.7 kcal/mol/M compared to 7.1 kcal/mol/M). These observations suggest that the unravelling of the individual structural repeats in the LRR region is a cooperative process and that the tight fusion with the Ig-like domain leads to a dramatically increased stability <i>in vivo</i> without interfering with the functionality of the protein. In addition, the cooperativity of the equilibrium transition reflects the integrity of the internalin-domain, and suggests that both InlB fragments unfold without significantly populated equilibrium intermediates.<o:p></o:p></span></p> <p class=MsoBodyText><span lang=EN-GB style='mso-ansi-language:EN-GB'>Kinetic measurements with tryptophan fluorescence and far-UV circular dichroism are indicative for the existence of a relative stable intermediate on the folding pathway of the LRR domain. Refolding kinetics from an acid-denatured state showed a reversible behavior and passes off an intermediate. An increase in the salt concentration of the acid-denatured protein results in a transition of the unfolded structure to a compact and alternatively folded state. Unfolding kinetics of the internalin-domain measured by fluorescence and far-UV circular dichroism are indicative for the possible presence of two processes. The first slow unfolding process after the transition midpoint showed a strong dependence on temperature, whereas the second and faster unfolding process showed a stronger dependence on the denaturant concentration. Renaturation kinetics indicated the existence of at least one folding intermediate. Preliminary double-mixing experiments revealed no evidence for a rate-limiting proline isomerization reaction. It was not possible to detect the complete amplitude of the renaturation reaction, suggesting existence of a second faster phase occuring in the submillisecond range.<o:p></o:p></span></p> <p class=MsoBodyText><span lang=EN-GB style='mso-ansi-language:EN-GB'>The results on folding kinetics prove the InlB constructs to be suitable models for the investigation of solenoid protein folding by techniques of high structural resolution.<o:p></o:p></span></p>

Dans cette thèse, nous proposons une étude détaillée des mécanismes responsables de la perte de données dans les mémoires à changement de phase enrichies en germanium (Ge-rich PRAMs), à savoir la dérive de la résistance au cours du temps et la recristallisation de la phase amorphe. Nous commençons par une présentation du contexte dans lequel s'inscrit cette étude an donnant un aperçu rapide du marché des mémoires à semiconducteur et une comparaison des mémoires non volatiles émergentes. Les principes de fonctionnement de la technologie PRAM sont introduits, avec ses avantages, ses inconvénients, ainsi que la physique régissant le processus de cristallisation dans les matériaux à changement de phase, avant de décrire les problèmes de fiabilité qui nous intéressent.Une caractérisation électrique complète de dispositifs intégrant des alliages de GST enrichi en germanium est ensuite proposée, en commençant par la caractérisation des matériaux utilisés dans nos cellules, introduisant alors les avantages des alliages enrichis en Ge sur le GST standard. Les performances électriques des dispositifs intégrant ces matériaux sont analysées, avec une étude statistique des caractéristiques SET & RESET, de la fenêtre de programmation, de l'endurance et de la vitesse de cristallisation. Nous nous concentrons ensuite sur le thème principal de cette thèse en analysant la dérive en résistance de l'état SET de nos dispositifs Ge-rich, ainsi que les performances de rétention de l'état RESET.Dans la dernière partie, nous étudions les mécanismes physiques impliqués dans ces phénomènes en fournissant une étude détaillée de la structure des cellules, grâce à l'utilisation de la Microscopie Électronique en Transmission (MET). Les conditions et configurations expérimentales sont décrites, avant de présenter les résultats qui nous ont permis d'aller plus loin dans la compréhension de la dérive en résistance et de la recristallisation de la phase amorphe dans les dispositifs Ge-rich. Une discussion est finalement proposée, reliant les résultats des caractérisations électriques avec ceux des analyses TEM, conduisant à de nouvelles perspectives pour l'optimisation des dispositifs PRAMs. / In this thesis we provide a detailed study of the mechanisms responsible for data loss in Ge-rich Ge2Sb2Te5 Phase-Change Memories, namely resistance drift over time and recrystallization of the amorphous phase. The context of this work is first presented with a rapid overview of the semiconductor memory market and a comparison of emerging non-volatile memories. The working principles of PRAM technology are introduced, together with its advantages, its drawbacks, and the physics governing the crystallization process in phase-change materials, before describing the reliability issues in which we are interested.A full electrical characterization of devices integrating germanium-enriched GST alloys is then proposed, starting with the characterization of the materials used in our PCM cells and introducing the benefits of Ge-rich GST alloys over standard GST. The electrical performances of devices integrating those materials are analyzed, with a statistical study of the SET & RESET characteristics, programming window, endurance and crystallization speed. We then focus on the main topic of this thesis by analyzing the resistance drift of the SET state of our Ge-rich devices, as well as the retention performances of the RESET state.In the last part, we investigate on the physical mechanisms involved in these phenomena by providing a detailed study of the cells' structure, thanks to Transmission Electron Microscopy (TEM). The experimental conditions and setups are described before presenting the results which allowed us to go deeper into the comprehension of the resistance drift and the recrystallization of the amorphous phase in Ge-rich devices. A discussion is finally proposed, linking the results of the electrical characterizations with the TEM analyses, leading to new perspectives for the optimization of PRAM devices.

Os SIG estão se popularizando cada vez mais e isso tem se dado principalmente através da Internet. Os assim chamados SIG-Web no entanto, quando desenvolvidos com as tecnologias tradicionais de web, apresentam as mesmas fraquezas daquelas, a saber: sincronicidade e pobreza na interação com o usuário. As tecnologias usadas para Rich Internet Applications (RIA) são uma alternativa que resolvem esses problemas. Na presente dissertação será demonstrada a factibilidade do seu uso para o desenvolvimento de SIG-Web, oferecendo um conjunto de códigos e estratégias para desenvolvimentos futuros, a partir de um conjunto básico de operações a se realizar em um SIG-Web. Adicionalmente será proposta a UWE-R, uma extensão a uma metodologia de engenharia web existente, para modelagem de RIA e SIG-Web. / GIS are getting more popular, mainly due to the Internet. Nonetheless the so called Web-GIS, when developed using traditional web technologies, inherit the same weaknesses from those, i.e.: sinchronicity and poor user interaction. Rich Internet Applications (RIA) technologies are an alternative for those issues. In the present work the feasibility of their usage for Web-GIS will be demonstrated, providing a set of codes and strategies for future developments, taking into account a basic set of Web-GIS operations. Additionally UWE-R, an extension to a web engineering methodology will be proposed for RIA modeling and Web-GIS.

Made available in DSpace on 2014-12-17T14:10:27Z (GMT). No. of bitstreams: 1 BrunoMSW_DISSERT.pdf: 2493064 bytes, checksum: 67d2a8f0addf9c48ec5976ed766a8e15 (MD5) Previous issue date: 2012-10-15 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Malaria is a disease of global distribution, recognized by governments around the world as a serious public health problem, affecting more than 109 countries and territories and endangering more than 3.3 billion people. The economic costs of this disease are also relevant: the African continent itself has malaria-related costs of about $ 12 billion annually. Nowadays, in addition to chloroquine, Plasmodium falciparum is resistant to many drugs used in the treatment of malaria, such as amodiaquine, mefloquine, quinine and sulfadoxine-pyrimethamine; resistance of Plasmodium vivax to treatments, although less studied, is also reported. Nature, in general, is responsible for the production of most known organic substances, and the plant kingdom is responsible for the most of the chemical diversity known and reported in the literature. Most medicinal plants commercialized in Brazil, however, are of exotic origin, which makes the search for endemic medicinal plants, besides a patent necessity, a fascinating subject of academic research and development. This study aimed to: (i) verify the antimalarial activity of ethanolic and hydroalcoholic extracts of Boerhavia paniculata Rich. And acetonic extract of Clethra scabra Pers. in Swiss albino mice infected by Plasmodium berghei NK65, (ii) observe possible combined effects between the course of infection by P. berghei NK65 and administration of these extracts in Swiss albino mice, and (iii) conduct a preliminary study of the acute toxicity of these extracts in Swiss albino mice. All extracts notable pharmacological activities - with parasite infections inhibitions ranging from 22% to 54%.These characteristics suggest that the activities are relevant, although comparatively lower than the activity displayed by the positive control group (always above 90%). The general framework of survival analysis demonstrates an overall reduction in survival times for all groups. Necroscopy has not pointed no change in color, shape, size and/or consistency in the evaluated organs - the only exception was the livers of rats submitted to treatment to hydroalcoholic extracts: these organs have been presented in a slightly congestive aspect with mass increasing roughly 28% higher than the other two groups and a p-value of 0.0365. The 250 mg/Kg ethanolic group has been pointed out by the Dunn s post test, as the only class with simultaneous inequalities (p<0.05) between positive and negative control groups. The extracts, notably ethanol extract, have, in fact, a vestigial antimalarial activity, although well below from the ones perceived to chloroquine-treated groups; nevertheless, the survival times of the animals fed with the extracts do not rise by presence of such therapy. Both the toxicopharmacological studies of the synergism between the clinical course of malaria and administration of extracts and the isolated evaluation of toxicity allow us to affirm the absence of toxicity of the extracts at the level of CNS and ANS, as well as their non-influence on food and water consumption patterns, until dosages of 500 mg/Kg. Necroscopic analysis leads us to deduct a possible hepatotoxic effect of hydroalcoholic extract at dosages of 500 mg/Kg, and an innocuous tissue activity of the ethanol extract, in the same dosage. We propose a continuation of the studies of these extracts, with protocol modifications capable of addressing more clearly and objectively their pharmacological and toxicological aspects / A mal?ria ? uma doen?a de distribui??o global, reconhecida por governos de todo o mundo como grave problema de sa?de p?blica, ocorrendo em mais de 109 pa?ses e territ?rios e pondo em risco mais de 3,3 bilh?es de pessoas. Os custos econ?micos da doen?a s?o tamb?m relevantes: apenas o continente africano tem um ?nus de cerca de US$12 bilh?es anuais. Hodiernamente, al?m da cloroquina, o Plasmodium falciparum apresenta resist?ncia aos diversos medicamentos usados na rotina, como amodiaquina, mefloquina, quinina e sulfadoxina-pirimetamina; a resist?ncia de Plasmodium vivax, apesar de menos estudada, tamb?m ? relatada. A natureza, de um modo geral, ? a respons?vel pela produ??o da maioria das subst?ncias org?nicas conhecidas, sendo o reino vegetal respons?vel pela maior parcela da diversidade qu?mica conhecida e registrada na literatura. A maioria das plantas medicinais comercializadas no Brasil, contudo, ? de origem ex?tica, o que torna a busca por plantas medicinais end?micas, al?m de uma patente necessidade, um fascinante assunto de pesquisa acad?mica e de desenvolvimento. Este trabalho teve por objetivo: (i) verificar a atividade antimal?rica dos extratos etan?lico e hidroalco?lico de Boerhavia paniculata Rich. e acet?nico de Clethra scabra Pers. em camundongos albinos Swiss infectados por Plasmodium berghei NK65; (ii) observar poss?veis efeitos combinados entre o curso da infec??o por P. berghei NK65 e a administra??o destes extratos em camundongos albinos Swiss; e (iii) realizar um estudo da toxicidade aguda destes extratos em camundongos albinos Swiss. Notam-se, em todos os extratos, atividades farmacol?gicas not?rias com inibi??es da parasitemia variando de 22% a 54% - caracter?sticas estas que sugerem atividades relevantes, apesar de comparativamente inferior ? atividade apresentada pelo grupo controle positivo (sempre superior a 90%). O quadro geral da an?lise de sobreviv?ncia demonstra uma redu??o global dos tempos de sobrevida para todos os grupos testados. A necroscopia n?o apontou, em um quadro geral, qualquer altera??o de cor, forma, tamanho e/ou consist?ncia nos ?rg?os avaliados nos estudos a ?nica exce??o recaiu sobre os f?gados dos animais submetidos ao extrato hidroalco?lico: estes se apresentaram sob um aspecto levemente congestivo, com aumento de massa cerca de 28% superior aos outros dois grupos e um p-valor de 0,0365. O grupo etan?lico 250 mg/Kg foi apontado, pelo p?s-teste de Dunn, como a ?nica classe com desigualdades simult?neas (p< 0,05) entre os grupos controles positivo e negativo. Os extratos analisados, notadamente o extrato etan?lico, apresentam, de fato, uma atividade antiplasm?dica resquicial, embora muito abaixo da percebida para grupos tratados com cloroquina; n?o obstante, os tempos de sobrevida dos animais submetidos aos tratamentos com os extratos n?o se elevam mediante a presen?a de tal terap?utica. Tanto o estudo t?xico-farmacol?gico do sinergismo entre a evolu??o cl?nica da mal?ria e a administra??o dos extratos quanto a avalia??o isolada de toxicidade nos permitem afirmar a aus?ncia de toxicidade dos extratos em n?vel de SNC e SNA, bem como a n?o influ?ncia destes nos padr?es de consumo h?drico e alimentar, at? as doses de 500 mg/Kg. A an?lise necrosc?pica nos leva ? dedu??o de um poss?vel efeito hepatot?xico do extrato hidroalco?lico, em doses de 500 mg/Kg, e uma atividade tecidual in?cua do extrato etan?lico, em mesma dosagem. Propomos uma continua??o dos estudos destes extratos, com modifica??es protocolares capazes de abordar, de forma mais clara e objetiva, seus aspectos farmacol?gicos e toxicol?gicos

Os SIG estão se popularizando cada vez mais e isso tem se dado principalmente através da Internet. Os assim chamados SIG-Web no entanto, quando desenvolvidos com as tecnologias tradicionais de web, apresentam as mesmas fraquezas daquelas, a saber: sincronicidade e pobreza na interação com o usuário. As tecnologias usadas para Rich Internet Applications (RIA) são uma alternativa que resolvem esses problemas. Na presente dissertação será demonstrada a factibilidade do seu uso para o desenvolvimento de SIG-Web, oferecendo um conjunto de códigos e estratégias para desenvolvimentos futuros, a partir de um conjunto básico de operações a se realizar em um SIG-Web. Adicionalmente será proposta a UWE-R, uma extensão a uma metodologia de engenharia web existente, para modelagem de RIA e SIG-Web. / GIS are getting more popular, mainly due to the Internet. Nonetheless the so called Web-GIS, when developed using traditional web technologies, inherit the same weaknesses from those, i.e.: sinchronicity and poor user interaction. Rich Internet Applications (RIA) technologies are an alternative for those issues. In the present work the feasibility of their usage for Web-GIS will be demonstrated, providing a set of codes and strategies for future developments, taking into account a basic set of Web-GIS operations. Additionally UWE-R, an extension to a web engineering methodology will be proposed for RIA modeling and Web-GIS.

Nationer är komplexa varumärken i kontrast till organisationers eller företags varumärken. De omfattar en rad aspekter såsom exempelvis turism, näringsliv och politik. Trots det, är det minst lika viktigt för ett land att skapa ett gott rykte kring sitt varumärke. Att sponsra en film är ett av alla tillvägagångssätt att nå ut med sitt varumärke till omvärlden. Det gjorde Singapores turistnämnd, när de sponsrade filmen Crazy Rich Asians. Hollywoodfilmen släpptes år 2018 och blev en succé i många länder. Denna studie har undersökt på vilket sätt en geografiskt distanserad publik tolkat landets varumärke genom filmen. Syftet med studien är att framhäva på vilket sätt en geografiskt distanserad publik tolkar ett nationsvarumärke i film. Fem svenska studenter deltog i en fokusgrupp. Studien kom fram till att (1) Singapores varumärke uppmärksammades tydligt av en geografiskt distanserad publik genom filmen, men att (2) vissa singaporianska kulturer och traditioner som framhävs tolkades på ett icke-önskvärt sätt. Studiens resultat understryker vikten av vilken kulturell kontext som filmen presenteras i. / Nations brands are complex in contrast to corporational- or organizational brands. There are numerous different aspects that need to be considered when building a strong nation brand for example within sectors revolving tourism, politics and infrastructure. Sponsoring a movie is one way for a nation to market themselves and reach out to a larger audience worldwide. In 2018 Singapore Tourism Board, STB, sponsored the movie Crazy Rich Asians, a movie that became a Hollywood success worldwide. This study aims to examine in which ways a geographical distanced audience responded to the movie and how their interpretation could help to construct Singapore's brand image. The purpose of the study is to highlight in what way a geographically distanced audience read a nation brand trough film. Five Swedish students participated in a focus group discussion on this matter after watching the movie Crazy Rich Asians. The study reveals that (1) a geographically distanced audience did create a brand image of Singapore through the movie. (2) Some of the Singaporean cultures and traditions that exposed in the movie were not read in a desirable way. The result of the study highlights the importance of which culture context a movie is presented in.

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Das Ziel der kognitiven Neurowissenschaften ist es, Struktur-Funktions-Beziehungen im Gehirn aufzudecken. Durch Fortschritte in der funktionellen Bildgebung und der Graphentheorie konnten zentrale Knotenpunkte im Gehirn identifiziert werden, welche neuronale Informationen integrieren und dementielle Prozesse erklären können. Datenbankgetriebene metaanalytische Methoden wurden genutzt, um tausende Bildgebungsstudien auszuwerten und das funktionelle Profil von Hirnregionen zu dekodieren. Das Systems-Level Decoding zielt darauf ab, eine Seed-Region und mit ihr verbundene kortikale Regionen funktionell zu dekodieren. In Studie 1 wurden thalamische Subregionen und in Studie 2 drei Subregionen des Intraparietalen Sulcus (hIP) als Seed-Regionen verwendet. Studie 3 untersuchte Unterschiede in der Rich-Club-Struktur zwischen Alzheimer-Patienten, Patienten mit milder kognitiver Beeinträchtigung und gesunden Probanden. Es wurden zwei große, Thalamus-zentrierte Systeme identifiziert, die mit autobiographischem Gedächtnis und Nozizeption assoziiert sind; für den hIP wurden neun Systeme, die mit Prozessen wie Arbeitsgedächtnis und numerischem Denken zusammenhängen, gefunden. Studie 3 fand Hinweise, dass periphere Regionen bei Patienten im Vergleich zu gesunden Kontrollen stärker aktiviert sind als Rich-Club-Regionen. Das Systems-Level Decoding lieferte neue Erkenntnisse über die Einbettung des Thalamus und des hIP in kortikale funktionelle Systeme. Allerdings waren die Ergebnisse hinsichtlich der funktionellen Charakterisierung thalamischer Kerne und der Aktivitätsunterschiede in Rich-Club- und peripheren Regionen zwischen Patienten und gesunden Kontrollpersonen begrenzt. Diese Ergebnisse lassen sich möglicherweise durch Limitationen des metaanalytischen Ansatzes erklären. Das Systems-Level Decoding ist insgesamt ein vielversprechender Ansatz für die Formulierung von Hypothesen über Struktur-Funktionsbeziehungen innerhalb der Netzwerkarchitektur des menschlichen Gehirns. / In cognitive neuroscience, there is great interest in unraveling structure-function relationships in the human brain. Advances in functional neuroimaging and graph theory methods have identified key brain nodes relevant for neuronal information integration and functional deficits in degenerative diseases like Alzheimer's. Database-driven meta-analytical methods have also evaluated knowledge from thousands of neuroimaging studies, to decode the functional profile of brain regions. The systems-level decoding aims to identify brain systems that provide insight into the functional characteristics of a seed region and its connected cortical regions. In Study 1, thalamic subregions were used as seed regions. Study 2 applied systems-level decoding to three distinct regions in the intraparietal sulcus (hIP). In Study 3, we attempted to substantiate activation differences in the Rich Club structure between Alzheimer's patients, patients with mild cognitive impairment, and healthy subjects. Two major, thalamus-centered systems associated with autobiographical memory and nociception were identified. Additionally, nine large systems associated with processes such as working memory, numerical cognition, and recognition memory were uncovered for the hIP. Finally, evidence showed that peripheral regions in patients are more activated than central Rich Club regions compared to healthy controls. Systems-level decoding provided significant new insights into the embedding of the thalamus and intraparietal sulcus in functional systems. However, results were limited in the functional characterization of thalamic nuclei and activity differences in Rich Club and peripheral regions between patients and healthy controls. Limitations of the meta-analytical approach may explain these findings. The systems-level decoding represents a promising approach for formulating hypotheses about brain structure-function relationships within the functional network architecture.

This research examines the relationship between the development of a portfolio of interactive digital techniques and compositions, and its impact on user experiences of time and place. It is designed to answer two research questions: (i) What are some effective methods and techniques for evoking an enhanced awareness of past time and place using interactive digital technologies (IDTs)? (ii) How can users play a role in improving the development and impact of interfaces made with IDTs? The principal creative and thematic element of the portfolio is the concept of the palimpsest, and its artistic potential to reveal visual and aural layers that lie behind the landscapes and soundscapes around us. This research thus contributes to an evolving cadre of creative interest in palimpsests, developing techniques and compositions in the context of testing, collating user experience feedback, and improving the ways in which IDTs enable an artistic exploration and realisation of hidden layers, both aural and visual, of the past of place. An iterative theory-composition-testing methodology is developed and applied to optimise techniques for enabling users to navigate multiple layers of content, as well as in finding methods that evoke an increased emotional connection with the past of place. This iterative realisation cycle comprises four stages - of content origination, pre-processing, mapping and user interaction. The user interaction stage of this cycle forms an integral element of the research methodology, involving the techniques being subjected to formalised user experience testing, both to assist with their further refinement and to assess their value in evoking an increased awareness of time and place. Online usability testing gathered 5,451 responses over three years of iterative cycles of composition development and refinement, with more detailed usability labs conducted involving eighteen participants. Usability lab response categories span efficiency, accuracy, recall and emotional response. The portfolio includes a variety of interactive techniques developed and improved during its testing and refinement. User experience feedback data plays an essential role in influencing the development and direction of the portfolio, helping refine techniques to evoke an enhanced awareness of the past of place by identifying those that worked most, and least, effectively for users. This includes an analysis of the role of synthetic and authentic content on user perception of various digital techniques and compositions. The contributions of this research include: • the composition portfolio and the associated IDT techniques originated, developed, tested and refined in its research and creation • the research methodology developed and applied, utilising iterative development of aspects of the portfolio informed by user feedback obtained both online and in usability labs • the findings from user experience testing, in particular the extent to which various visual and aural techniques help evoke a heightened sense of the past of place • an exploration of the extent to which the usability testing substantiates that user responses to the compositions have the potential to establish an evocative connection that communicates a sense close to that of Barthes' punctum (something that pierces the viewer) rather than solely that of the studium • the role of synthetic and authentic content on user perception and appreciation of the techniques and compositions • the emergence of an analytical framework with the potential for wider application to the development, analysis and design of IDT compositions

LHCb is a high-precision experiment for the study of CP violation and rare decays in B physics. It has two Ring Imaging Cherenkov (RICH) counters for particle identification. The RICH system uses Hybrid Photon Detectors (HPD) for single photon detection. This thesis describes tests performed on individual HPDs for quantum efficiency and vacuum quality. It then presents work done monitoring HPD vacuum quality through regular ion feedback measurements after they were mounted into the RICH. Also discussed is HPD vacuum degradation and how replacement and repair of deteriorated HPDs was implemented using data from the vacuum monitoring. Preparations for an upgrade to LHCb have started. The upgrade will extend the discovery potential of the LHCb by increasing the rate of data collection. This thesis presents particle identification and avour tagging studies using upgrade simulations. Flavour tagging using kaons was then reoptimised for upgrade conditions and this work is described with discussions of the results.