The main aim of this thesis was to discover and design new ligands for difficult, under-explored and clinically relevant protein targets. A number of protein-protein interaction complexes (PPIs) are introduced as the target focus for the methods employed and developed herein. This thesis is separated into two sections to independently address both peptides and small molecules as screening agents. The project examines both approaches through comprehensive library design strategies and screening by NMR spectroscopic methods. ATAD2 is the first PPI investigated and was expressed and purified in good yield and was also isotopically labelled with Nitrogen-15 for enhanced sensitivity and orthogonal ligand and protein-observed NMR methods. A known pentapeptide was synthesised by solid-phase peptide synthesis (SPPS) using Fmoc chemistry for target validation and tool compound development. A one-bead one-compound (OBOC) tripeptide library was synthesised by SPPS in good yield and purity, determined using single-bead labelling techniques with a fluorescent dye (TMR) and HPLC analysis. This library contained 3072 unique tripeptides with 12 central non-natural, lysine derivatives flanked by 16 natural L amino acids. The library screening technique was based on using a fluorescently labelled protein and Confocal Nanoscanning to detect binding. However, fluorescent labelling of ATAD2 was unsuccessful due to difficult protein handling conditions, therefore this library was not screened. The advent of small molecule, high affinity inhibitors of this target protein generated by GSK shifted focus to a different PPI target, the ubiquitin conjugating enzyme, UbE2L3. A novel 'on-protein peptide building' approach was introduced with the aim of screening a library of fluorinated dipeptides and extending the most potent via the 'N' and 'C' terminus to increase the affinity. A proof-of-concept tetrapeptide to survivin was synthesised by SPPS by incorporation of a non-natural, fluorinated amino acid in the known tetrapeptide sequence. This fluorinated derivative showed target binding activity by 19F NMR spectroscopy. The tripeptide and dipeptide truncates were synthesised by SPPS and binding was still observable by 19F NMR. This method was extended to screening a library of synthesised fluorinated dipeptides by 19F NMR against UbE2L3. A single dipeptide was identified with low affinity and the dipeptide was extended C and N terminally by SPPS to increase affinity. However, there were no tripeptides identified for this protein using this method. The proof of concept tetrapeptide was a success, therefore further protein targets are required to conclusively assess the viability of the approach. Fragment based screening is then introduced as a second approach to novel ligand discovery. Coupled with cheminformatics analysis and in silico library design, we created an in-house fluorinated fragment library consisting of 109 fluorinated fragments using three parallel methods. Compounds were purchased and quality checked by LCMS, HPLC and 19F-NMR. These fragment libraries were screened in a 19F NMR assay against the UbE2L3 and NusE/NusB protein targets. In a primary mixture screen, two fragment hits were identified against the NusE/NusB PPI and there were no fragment hits identified against the UbE2L3 protein. The two fragments against NusE/NusB were validated using orthogonal ligand-binding NMR methods. A mini-series, consisting of six commercially available analogues, were purchased and two fragment analogues showed increased affinity and were active against E. coli in a bacterial inhibition assay. The dissociation constants of the six active compounds were determined by 15N-HSQC NMR titration experiments and shown to be in 100-500 μM range. The binding sites of each compound were also determined by 15N-HSQC chemical shift mapping. These fragment hits represent a novel chemical scaffold identified against the NusE/NusB PPI and demonstrate the potential druggability of this new, complex target. The use of fluorine as a sensor for binding detection is evaluated by incorporating into both peptides and fragments. Through the use of novel library design strategies, a campaign to discover novel ligands of difficult protein targets is presented.

This present study sought to evaluate the effectiveness of two types of school library displays: a display with books only, called Display, and a display with books, posters, models, copy, and realia, called Display +. The effectiveness of these displays was to be measured in two ways: a) through the observation of the attaction power, holding power and viewer participation in a display and b) through measuring the circulation of displayed books. Before commencing the study a literature search was conducted. The result of the literature search yielded four authors, Goldhor (1972; 1981), Aguilar (1983), Watson (1985), and Baker (1986), who had researched the relationship between circulation and displays. Each of these studies used the measurable effect of circulation increasing, decreasing or remaining constant to determine the effect of the display. This present study used a similar methodology and monitored the circulation of books on both types of displays. However, this study sought to go beyond the effect of circulation in determining the effectiveness of displays because the previous studies had not taken into account the library user who is affected by the display but is unable to borrow a book from the display. The literature search turned towards the area of museum exhibits and displays and the methodology employed to evaluate these exhibits and displays. Shettel (1968), Warren (1972), Screven (1976), Linn (1976), Clowes and Wolfe (1980), and Miles (1982) used attraction and holding power as measures of museum exhibit and display effectiveness. Similarly, library users can be attracted and their attention held by library displays. To the variables of attraction and holding power this study added the variable of participation, picking up books or other items in the display not necessarily with the intent of borrowing the books. In order to construct a Display + and control as far as possible the elements in the display a literature search of books and articles relating to the design elements of displays was conducted, and findings applied in the construction of the display. Shettel's (1968) methodology of unobtrusive observation was employed in this study with the added benefit of videotaping the observations. The hypotheses were set out in three groups, those relating to a single display, those comparing the effectiveness of Display and Display +, and those relating to circulation. The results of this study found in general that the attraction power of Display + exceeded the attraction power of Display but the holding power and participation in Display was greater than that of Display + indicating that the designer of library displays should pay particular attention to the purpose of displays in their libraries. The results of the circulation hypothesis confirmed the results of Goldhor (1972;1981), Aguilar (1983), Watson (1985), and Baker (1986) that more books circulated when they were displayed than when they were on the library shelves.

A highly combinatorial structure-based protein engineering method for obtaining enantioselectivity is reported that results in a thorough modification of the substrate binding pocket of Candida antarctica lipase A (CALA). Nine amino acid residues surrounding the entire pocket were simultaneously mutated, contributing to a reshaping of the substrate pocket to give increased enantioselectivity and activity for a sterically demanding substrate. This approach seems to be powerful for developing enantioselectivity when a complete reshaping of the active site is required. Screening toward ibuprofen ester 1, a substrate for which previously used methods had failed, gave variants with a significantly increased enantioselectivity and activity. Wild-type CALA has a moderate activity with an E value of only 3.4 toward this substrate. The best variant had an E value of 100 and it also displayed a high activity. The variation at each mutated position was highly reduced, comprising only the wild type and an alternative residue, preferably a smaller one with similar properties. These minimal binary variations allow for an extremely condensed protein library. With this highly combinatorial method synergistic effects are accounted for and the protein fitness landscape is explored efficiently.

In the last one hundred years Toronto’s cultural identity has been completely transformed. Once a quiet and thoroughly conservative Anglo-Saxon town, Toronto has become a thriving and dynamic multicultural city. Today a majority of the city’s residents are visible minorities and almost half are foreign-born; the largest of any city in the world. Never before have so many ‘different’ people shared place. While successive waves of immigration have had a profound and measurable impact on Toronto’s cultural and social character, the impact on its public spaces and institutions remains more illusive. This thesis proposes an architectural design for an intercultural library and language centre that seeks to give voice to the principles of diversity that have energized Toronto, while acknowledging the city’s history of divisiveness and political indifference to immigrants. Set adjacent to the Bickford Centre, an existing ESL school dedicated to serving new immigrants, the proposed intercultural library and language centre will face the Christie Pits Park, the site of Toronto’s worst race riot. Three lines of inquiry structure this thesis. The first is an in-depth sociodemographic investigation of immigration to Toronto. This is followed by an analysis of the meaning and significance of critical intercultural gathering spaces in the city. Finally, the thesis, through the design of the language centre, seeks to explore the capacity of architecture to simultaneously unite and provide amenity for a multicultural city population.

In the last one hundred years Toronto’s cultural identity has been completely transformed. Once a quiet and thoroughly conservative Anglo-Saxon town, Toronto has become a thriving and dynamic multicultural city. Today a majority of the city’s residents are visible minorities and almost half are foreign-born; the largest of any city in the world. Never before have so many ‘different’ people shared place. While successive waves of immigration have had a profound and measurable impact on Toronto’s cultural and social character, the impact on its public spaces and institutions remains more illusive. This thesis proposes an architectural design for an intercultural library and language centre that seeks to give voice to the principles of diversity that have energized Toronto, while acknowledging the city’s history of divisiveness and political indifference to immigrants. Set adjacent to the Bickford Centre, an existing ESL school dedicated to serving new immigrants, the proposed intercultural library and language centre will face the Christie Pits Park, the site of Toronto’s worst race riot. Three lines of inquiry structure this thesis. The first is an in-depth sociodemographic investigation of immigration to Toronto. This is followed by an analysis of the meaning and significance of critical intercultural gathering spaces in the city. Finally, the thesis, through the design of the language centre, seeks to explore the capacity of architecture to simultaneously unite and provide amenity for a multicultural city population.

In the face of technological developments, economic demands, and cultural desires that can encourage buildings devoid of character and permanence, we need to look for attributes of architecture that evoke strength and elude the undulations of time. / Master of Architecture

This thesis covers the reconstruction and the redesign of the modeling library VehProLib,which is constructed in the modeling language Modelica with help of the modeling toolWolfram SystemModeler. The design choices are discussed and implemented. This thesisalso includes the implementation of a turbocharger package and an initial study of the justificationof the ideal gas law in vehicle modeling. The study is made with help of Van derWaals equation of states as a reference of non-ideal gas model. It will be shown that for themean-value-engine-model, the usage of ideal gas law is justified.

The purpose of this essay is to explore the importance of library design to students, whether the interior design of a library has any effect on their experience when using its services, and what the students themselves believe is most important for the library to do to stay afloat in a society that is constantly evolving and becoming more digital. The study will also bring up UX (User Experience) as a method for library design. The theories used in this study are the third place theory, as well as a comparison to the ideals of the Learning Commons model. In order to find out how the students view the library and the impact of its design, five interviews with five different students at Linneaus University in Växjö were conducted. The results show that the library generally inspires the students to feel motivated and at ease in a place that is comfortable and safe. It also shows that the design and the general atmosphere of the library does play a specific role in the students’ overall experience of the library as it impacts many of the choices they make while they’re there, such as where to sit or which places to avoid. The majority of the students are mostly happy with the library as it is except for minor inconveniences, and merely wishes for the library to continue in the same way in the future while adapting to any new changes that may come in its way.

Magister Bibliothecologiae - MBibl / The use and design of library spaces in higher education is a theme that has come to the forefront of user needs in the past few years. Academic libraries are redesigning their spaces to accommodate the 21st century user. The 21st century user is often labeled as Generation Y and requires a different set of knowledge and skills. In today’s knowledge economy, core skills include creativity, problem solving and collaboration. Libraries are creating space to accommodate the needs of these new users. They are developing group work areas, relaxation or pause areas, technology hubs and discussion rooms. This study has investigated how to redesign academic libraries, using Cape Peninsula University of Technology (CPUT) Cape Town branch as a pilot study. The researcher used the concept of library "as place" or "3ʳᵈ place" as a theory. The framework interrogated the ten qualities of a good library space. The researcher used a mixed method research design to conduct this study. A questionnaire of which multiple copies were made, interviews and internal statistics were used to gather data. The results of the study reflected that the library is functional, can be adapted, the space is accessible and varied, it is conducive to motivating and inspiring people, it does promote interactivity between users and library services, and is environmentally suitable, flexible and has a wow factor. All of these characteristics conform to McDonald’s ten qualities of a good library space.

This thesis investigates architectural design with a focus on technology and parametric, or computational, design strategies in relation to environmental simulation and sustainability. While numerous studies of new digital and parametric design technologies have been undertaken, few discuss their potential application or synergy with sustainable or environmentally focused design. However, there is increasing interest in bridging the perceived gap between these areas of focus in architectural design, as will be discussed in a section on recent symposia related to performance and design technologies. The research project seeks to apply insight gained from these studies to a design project to be located in the Greenpoint neighborhood of Brooklyn, New York. The project type is a library and research center which would serve as a knowledge base and community hub for the study and discussion of environmental protection, sustainability, and conservation. As a hybrid archive, learning center, forum, and repository of information, it would aim to serve as a catalyst for the ongoing attempts to remediate the environmental conditions of nearby Newtown Creek and adjacent land, which has been subjected to severe environmental degradation as a result of a century and half of industrial activities related to oil refining and storage. The eastern portion of Greenpoint along Newtown Creek has been designated a superfund site as a result of millions of gallons of oil spillage occurring over an uncertain length of time, much of which remains below ground today. Additionally, the surrounding water bodies have been polluted from the discharge of excess wastewater due to overflow of the city’s combined sewer system during large storms. Thus the community and city face numerous environmental challenges and would be well served by a facility which would provide a research base and meeting place. The project also engages with an additional set of conditions related to the site. Recent zoning changes have been approved which will convert the formerly industrial East River waterfront to a dense residential zone. While the zoning aims to establish a public space along the waterfront, it will also likely result in residential towers vastly out of scale and context with adjacent neighborhood, which includes an important historic district, and a diverse population. The project seeks to place instead, at the tip of the peninsula which was once named for its greenness, a public space dedicated to its restoration.