Kynurenine 3-monooxygenase is a FAD-dependent aromatic hydroxylase (FAH) which is a widely suggested therapeutic target for controlling the balance of bioactive metabolite levels produced by the mammalian kynurenine pathway (KP). Prior to starting this work no structural information was known for the enzyme, with studies of the human form complicated by the presence of a C-terminal transmembrane helix. The bacterial Pseudomonas fluorescens enzyme (PfKMO) lacks the transmembrane region and has been previously characterised by Crozier-Reabe and Moran [1, 2]. Therefore PfKMO, which shares 32 % sequence identity with the human enzyme, was selected as a target for structure solution. Initial substrate bound PfKMO crystals showed poor X-ray diffraction. Subsequent growth optimisation and the generation of a C252S/C461S PfKMO mutant (dm2) yielded crystals suitable for structure solution. Selenomethioninelabelled substrate bound dm2 crystals were used to solve the first structure to a resolution of 3.40 Å. With just one protein molecule per asymmetric unit, a high solvent content was responsible for the poor diffraction properties of this crystal form. The overall fold resembled that of other FAH enzymes with a Rossmann-fold based FADbinding domain above a buried substrate binding pocket. Interestingly PfKMO possesses an additional, novel C-terminal domain that caps the back of the substrate-binding pocket on the opposite side to the flavin. Residues proposed to be involved in substrate binding were identified and shown to be highly conserved among mammalian KMO sequences. Subsequently single crystals of substrate-free dm2 PfKMO were obtained and showed significantly stronger diffraction due to new lattice packing in an orthorhombic space group bearing four molecules per asymmetric unit. The structure was solved to a resolution of 2.26 Å and revealed a clear conformational change of the novel C-terminal domain. This movement opens a potential route of substrate/product exchange between bulk solvent and the active site. The investigation of a set of C-terminal mutants further explored the relevance and mechanics of the conformational change. In addition the presence of chloride ions in the substrate-free crystal growth solution caused a small number of localised subtle alterations to the structure, with a potential chloride binding site identified adjacent to the flavin cofactor. This may have relevance for the observed inhibition of PfKMO activity by monovalent anions – a feature widely common to FAH enzymes [3]. The first discovered KMO inhibitors were analogues of the substrate L-Kyn, however one such compound (m-NBA) was recently shown to instigate uncoupled NADPH oxidation leading to the release of cytotoxic hydrogen peroxide [1]. A set of substrate analogues were tested and characterised for inhibition of PfKMO. The picture was shown to be complex as some substrate analogues completely inhibited the enzyme whilst the binding of some still stimulated low-levels of NADPH oxidation. Crystallographic studies with m-NBA and 3,4-dichlorobenzoylalanine (3,4-CBA) bound revealed indistinguishable structures from that of substrate-bound PfKMO. These studies suggest that the analogue 3,4CBA is a potent PfKMO inhibitor whose therapeutic potential may be re-visited. The previous most potent KMO inhibitor whose structure was not analogous to the substrate was Ro 61-8048 [4], which unfortunately did not pass pre-clinical safety tests. A novel series of 1,2,4-oxadiazole amides based on the structure of Ro 61-8048 was created by Gavin Milne (PhD, University of St Andrews) and tested on PfKMO. Rounds of refinement led to the discovery and refinement of low nanomolar competitive inhibitors of the bacterial enzyme. PfKMO was co-crystallised with each of the four most potent compounds forming a third different lattice arrangement, which yielded structures to resolutions of 2.15-2.40 Å. The structures displayed conformational changes resembling the substrate-free fold possibly caused by displacement of a crucial substrate-binding residue, R84. Overall the wealth of structural data obtained may be transferable to predictions about the structural features of human KMO and to the rational design of therapeutic inhibitors. The potent novel inhibitors tested may additionally present a new exciting development for the therapeutic inhibition of human KMO.

Towards the end of the 7th century A.D., Iraq was in a state of near civil war, caused by social and political malaise. Factional and tribal feuds and fierce antagonism to the Umayyad reign threatened the survival of the dynasty as the unifying force of the empire. Into this situation, al-Ḥasan b. Muḥammad b. al-Ḥanafiyya (d.c. 100/718), a grandson of 'Alī, introduced a peace formula which was intended to pacify the rival religio-political parties. This idea found adherence especially among religious scholars, who quickly broadened its basis, attracting followers to its pacific message. Despite an unstable record of relations with the court, the movement basically supported with its ideology the legitimacy of the Umayyad reign. The popularity of the movement, especially in some scholarly circles in Kufa, led to the formation of a school of religious thought, which had relied on the basic political and religious attitudes of the early Murji'a, but transformed it into a comprehensive theological system. Although not responsible for the actual forging of Murji'ite attitudes, Abū Ḥanīfa had emerged as the eponymous epitome of the movement and the theological school. The first chapter, "Irjā', The Development of the Idea", investigates several possibilities as the source of this notion, among them the alleged Qur'ānic origin, and the Kitāb al-Irjā' attributed to al-Ḥasan b. Muḥammad b. al-Ḥanafiyya. The second chapter, "The Formation of the Murji'a as a ReligioPolitical Movement" surveys the social and the historical background of the Kufan milieu, the formation of the Murji'ite circle and the social elements it was comprised of, and the position of the movement in political and religious affairs in the first two decades of the 8th century .A.D. The third and last chapter, "The Transformation of the Murji'a from a Political into a Religiously-Oriented School" studies and analyses what is believed to be genuine Murji'ite treatises of religious thought, in comparison to sources of a contemporary rival school and the heresiographers. Special emphasis was laid in the analysis on the subject of theology as a medium for political views.

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<p>Examensarbetet handlar om en jämförelsestudie av beräkningseffektivitet med avseende på energi- och tidsförbrukning mellan grafikkort och processorer i persondatorer och PlayStation 3.</p><p>Problemet studeras för att göra allmänheten uppmärksam på att det går att lösa en del av energiproblematiken med beräkningar genom att öka energieffektiviteten av beräkningsenheterna.</p><p>Undersökningen har genomförts på ett explorativt sätt och studerar förhållandet mellan processorer, grafikkort och vilken som presterar bäst i vilket sammanhang. Prestandatest genomförs med molekylberäkningsprogrammet F@H och med filkomprimeringsprogrammet WinRAR. Testerna utförs på MultiCore- och SingleCorePCs och PS3s av olika karaktär. I vissa test mäts effektförbrukning för att kunna räkna ut hur energieffektiva vissa system är.</p><p>Resultatet visar tydligt hur den genomsnittliga effektförbrukningen och energieffektiviteten för olika testsystem skiljer sig vid belastning, viloläge och olika typer beräkningar.</p> / <p>The thesis is a comparative study of computational efficiency in terms of energy and time consumption of graphics cards and processors in personal computers and Playstation3’s.</p><p>The problem is studied in order to make the public aware that it is possible to solve some of the energy problems with computations by increasing energy efficiency of the computational units.</p><p>The audit was conducted in an exploratory way, studying the relationship between the processors, graphics cards and which one performs best in which context. Performance tests are carried out by the molecule calculating F@H-program and the file compression program WinRAR. Tests performed on MultiCore and SingleCore PC’s and PS3’s with different characteristics. In some tests power consumption is measured in order to figure out how energy-efficient certain systems are.</p><p>The results clearly show how the average power consumption and energy efficiency for various test systems at differ at load, sleep and various calculations.</p><p> </p>

Examensarbetet handlar om en jämförelsestudie av beräkningseffektivitet med avseende på energi- och tidsförbrukning mellan grafikkort och processorer i persondatorer och PlayStation 3. Problemet studeras för att göra allmänheten uppmärksam på att det går att lösa en del av energiproblematiken med beräkningar genom att öka energieffektiviteten av beräkningsenheterna. Undersökningen har genomförts på ett explorativt sätt och studerar förhållandet mellan processorer, grafikkort och vilken som presterar bäst i vilket sammanhang. Prestandatest genomförs med molekylberäkningsprogrammet F@H och med filkomprimeringsprogrammet WinRAR. Testerna utförs på MultiCore- och SingleCorePCs och PS3s av olika karaktär. I vissa test mäts effektförbrukning för att kunna räkna ut hur energieffektiva vissa system är. Resultatet visar tydligt hur den genomsnittliga effektförbrukningen och energieffektiviteten för olika testsystem skiljer sig vid belastning, viloläge och olika typer beräkningar. / The thesis is a comparative study of computational efficiency in terms of energy and time consumption of graphics cards and processors in personal computers and Playstation3’s. The problem is studied in order to make the public aware that it is possible to solve some of the energy problems with computations by increasing energy efficiency of the computational units. The audit was conducted in an exploratory way, studying the relationship between the processors, graphics cards and which one performs best in which context. Performance tests are carried out by the molecule calculating F@H-program and the file compression program WinRAR. Tests performed on MultiCore and SingleCore PC’s and PS3’s with different characteristics. In some tests power consumption is measured in order to figure out how energy-efficient certain systems are. The results clearly show how the average power consumption and energy efficiency for various test systems at differ at load, sleep and various calculations.