This dissertation presents new evidence about Anglo-Moroccan relations in the late eighteenth and early nineteenth centuries, with particular reference to the development of the links between the Gharb region of Morocco and Gibraltar and the establishment of the Moroccan consulate there. This evidence is used to re-evaluate prevailing arguments about Moroccan isolationism, especially during the reign of Mawlay Sulaymān (r. 1792-1822), linking this to the nature of the Moroccan sultanate's foreign and trade policy over the longer term. It is argued that the Sīdī Muḥammad b. 'Abd Allāh's (r. 1757-90) well-known 'opening up' of the country should be seen not just as a response to European expansion, but also as a continuation of the sultanate's historical development as a state based partly on the control of trade. It is further argued that Mawlay Sulaymān and his successor Mawlay 'Abd al-Raḥmān (r. 1822-59) essentially followed Sīdī Muḥammad's policy. With reference to this context, the dissertation analyses the development of the Moroccan consulate in Gibraltar, including re-dating its initial establishment. The example of the consulate is also applied to reconsidering dominant assumptions about the role of religious discourse in limiting Morocco's contact with the outside world by assessing the wider social and economic context in which it operated, specifically the growth of trade between Gibraltar and the Gharb and the related development of a group of both Jewish and Muslim Moroccan merchants who partly conducted it. The dissertation finally assesses the political importance of these trade links and commercial interests, and how they influenced the operation of power and authority in the Gharb. The overall case is presented in the context of a critique of civilisational or culturalist approaches to the study of reactions to European expansion and modernity that prioritise cultural difference between Western and, in this case, Muslim societies. It is argued that the Straits of Gibraltar - a ubiquitous symbol of the supposed dividing line between different civilisations - actually illustrate the importance of the interaction between different societies for accurately understanding their development and the agency of actors on both sides.

Le 5 juillet 1830, Husayn dey signe une reddition. Alger tombe aux mains de la puissance conquérante, et, mécaniquement, les Algériens sont dits français. Cette automaticité de la nationalité tire sa force d'un principe général du droit des gens : l'État annexant attribue sa nationalité aux sujets dont l'État annexé disparaît en tant que sujet de droit international. Cette mécanique du droit est aussi une charge narrative toute contenue dans cet énoncé : les Algériens sont français. Or, pour impérative que soit la formule, d'un strict point de vue juridique, elle n'en demeure pas moins un raccourci historique que je me propose d'examiner. L'examen de la question de la nationalité des Algériens fixés à l'étranger, principalement dans l'empire ottoman, restitue au moment 1830 son caractère premier : son indétermination. Ce déplacement de la pensée dans la migration pose la colonie comme un arbitraire narratif, cet après-coup écrasant ce moment d'indéterminations. Réinscrire les conflits de nationalité dans leurs dimensions internationales donne à voir tout ce que le droit de la nationalité a de pragmatique dans l'essai de définition de l'Algérien, sujet français. Nous interrogeons le droit et ses récits comme opérateur d'une transaction historique, et, partant tentons de mesurer l'incidence du droit sur nos historiographies. L'examen attentif de suppliques en nationalité permet alors de raconter une autre histoire, déduite non plus des énoncés élémentaires du droit mais du droit en action et en contexte. / On July 5th, 1830, Dey Husayn surrendered. Alger fell to the hands of the conquering power and, mechanically, Algerian were said to be French. This automatic granting of nationality emanated from a general principle of the law: the annexing State grants its nationality to the subjects whose State disappears as an object of international law. Such mechanics of the law also held a narrative power expressed in this statement: Algerians were French. No matter how imperious the formula was legally, it nevertheless accomplished a historical leap that I offer to re-explore. Examining the question of the nationality of Algerians established abroad, principally in the Ottoman Empire, renders to the moment of 1830 its initial dimension: that of indetermination. The intellectual displacement created by studying migration reveals the colony as a narrative arbitrary, an after-the-fact that crushes the moment of indeterminations. Re­exploring conflicts of nationality in their international dimensions reveals the pragmatic aspect of the law on nationality when it comes to defining the Algerian as a French subject. This work questions the law and its narratives as the operator of a historical transaction and it aims to explore the impact of the law on our historiographies. The careful examination of petitions for nationality allows to tell another story, a story no longer produced from elementary statements of the law, but from the law in action and in context.

This thesis is about Ibn Taymiyya's thinking on jihād and baghy. It aims to make an important contribution to the study of early Islamic political thought. It considers how the terms jihād and baghy have developed and been expanded from the structure established by the Qur'an and hadith. It also examines the relationship between jihād and baghy in Islamic law and reveals the pivotal role of the imām in politics. The main focus of this study is Ibn Taymiyya's thinking on jihād and the fatwās that resulted from it, using hitherto overlooked printed materials. It also seeks to explain why Ibn Taymiyya upheld jihād against the Mongols, the Franks and the heretic Shī'a. The thesis is divided into four chapters and structured as follows. The first chapter deals with the life of Ibn Taymiyya. This chapter moves beyond conventional biography to relate the story of Ibn Taymiyya's life to the main events that occurred during the Mongols' incursion. The second chapter identifies what Meccan and Medinan Qur'anic texts say about jihād, and examines whether jihād is a mechanism of self defense or an act of aggression; it also explains the relationship between jihād and the establishment of dār al-Islām, dār al-ḥarb and dār al-'ahd. The third chapter considers Ibn Taymiyya's view on jihād. The fourth chapter analyses Ibn Taymiyya's view on baghy, and aims to arrive at a clearer picture of the relationship between Ibn Taymiyya's concepts of jihād and baghy.

<p>Many human diseases are associated with the malfunction of enzymes in the aromatic amino acid hydroxylase family, e.g. phenylketonuria (PKU), hyperphenylalaninemia (HPA), schizophrenia and Parkinson's disease. The family of aromatic aminoacid hydroxylases comprises the enzymes phenylalanine hydroxylase (PheOH), tyrosine hydroxylase (TyrOH) and tryptophane hydroxylase (TrpOH). These enzymes require the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and atomic oxygen. In eukaryotes, the aromatic amino acid hydroxylases share the same organization with a N-terminal regulatory domain, a central catalytic domain and a C-terminal tetramerization domain. Aromatic amino acid hydroxylases that correspond to the core catalytic domain of the eukaryotic enzymes are found in bacteria. The main focus of this thesis is the structural characterization of a phenylalanine hydroxylase from the bacterium Pseudomonas aeruginosa (PaPheOH). </p><p>To initiate the structural characterization, the active site environment was investigated with X-ray absorption spectroscopy (XAS). The experimental data support a model where the active site iron is coordinated by four oxygen atoms and two nitrogen atoms. We suggest that two water molecules, His121, His126 and Glu166 coordinates the active site iron. In this model, Glu166 provides two of the oxygen atoms in a bidentate binding geometry. EXAFS and XANES studies indicate that structural rearrangements are induced in the second and third coordination shells in samples of PaPheOH with BH4 and/or L-Phe. </p><p>The 1.6 Å X-ray structure of PaPheOH shows a catalytic core that is composed of helices and strands in a bowl-like arrangement. The iron is octahedrally coordinated, by two water molecules and the evolutionary conserved His121, His126 and Glu166 that coordinates the iron with bidentate geometry. The pterin binding loop of PaPheOH (residue 81-86) adopts a conformation that is displaced by 5-6 Å from the expected pterin binding site. Consistent with the unfavourable position of the pterin binding loop is the observation that PaPheOH has a low specific activity compared to the enzymes from human and Chromobacterium violaceum. </p><p>The second part of this thesis focus on the crystallization and structure determination of the actin binding domain of a-actinin (ABD). a-Actinin is located in the Z-disc of skeletal muscle were it crosslinks actin filaments to the filamentous protein titin. The ABD domain of a-actinin crystallizes in space group P21 with four molecules in the asymmetric unit. The structure of the ABD domain has been solved to a d-spacing of 2.0 Å. The two CH-domains of ABD is composed of 5 a-helices each. The a-helices fold into a closed compact conformation with extensive intramolecular contacts between the two domains.</p>

Many human diseases are associated with the malfunction of enzymes in the aromatic amino acid hydroxylase family, e.g. phenylketonuria (PKU), hyperphenylalaninemia (HPA), schizophrenia and Parkinson's disease. The family of aromatic aminoacid hydroxylases comprises the enzymes phenylalanine hydroxylase (PheOH), tyrosine hydroxylase (TyrOH) and tryptophane hydroxylase (TrpOH). These enzymes require the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and atomic oxygen. In eukaryotes, the aromatic amino acid hydroxylases share the same organization with a N-terminal regulatory domain, a central catalytic domain and a C-terminal tetramerization domain. Aromatic amino acid hydroxylases that correspond to the core catalytic domain of the eukaryotic enzymes are found in bacteria. The main focus of this thesis is the structural characterization of a phenylalanine hydroxylase from the bacterium Pseudomonas aeruginosa (PaPheOH). To initiate the structural characterization, the active site environment was investigated with X-ray absorption spectroscopy (XAS). The experimental data support a model where the active site iron is coordinated by four oxygen atoms and two nitrogen atoms. We suggest that two water molecules, His121, His126 and Glu166 coordinates the active site iron. In this model, Glu166 provides two of the oxygen atoms in a bidentate binding geometry. EXAFS and XANES studies indicate that structural rearrangements are induced in the second and third coordination shells in samples of PaPheOH with BH4 and/or L-Phe. The 1.6 Å X-ray structure of PaPheOH shows a catalytic core that is composed of helices and strands in a bowl-like arrangement. The iron is octahedrally coordinated, by two water molecules and the evolutionary conserved His121, His126 and Glu166 that coordinates the iron with bidentate geometry. The pterin binding loop of PaPheOH (residue 81-86) adopts a conformation that is displaced by 5-6 Å from the expected pterin binding site. Consistent with the unfavourable position of the pterin binding loop is the observation that PaPheOH has a low specific activity compared to the enzymes from human and Chromobacterium violaceum. The second part of this thesis focus on the crystallization and structure determination of the actin binding domain of a-actinin (ABD). a-Actinin is located in the Z-disc of skeletal muscle were it crosslinks actin filaments to the filamentous protein titin. The ABD domain of a-actinin crystallizes in space group P21 with four molecules in the asymmetric unit. The structure of the ABD domain has been solved to a d-spacing of 2.0 Å. The two CH-domains of ABD is composed of 5 a-helices each. The a-helices fold into a closed compact conformation with extensive intramolecular contacts between the two domains.

ABD-Derived Affinity Proteins (ADAPTs) is a novel class of small engineered scaffold proteins based on albumin-binding domain (ABD) of streptococcal protein G. High affinity ADAPT  binders against various therapeutic targets can be selected.  In this thesis, we report a development of ADAPT-based radionuclide imaging agents providing high sensitivity and specificity of molecular imaging of HER2 expression in disseminated cancers. We investigated the feasibility of the use of ADAPTs as imaging agents and influence of molecular design and radiolabeling chemistry on in vivo targeting and biodistribution properties of the tracers. In Paper I we demonstrated the feasibility of the use of anti-HER2 ADAPT6 molecule as a high contrast imaging agent; In Paper II we evaluated the influence of composition of histidine-containing tag on in vivo biodistribution of ADAPT-based tracers labeled with 99mTc using 99mTc(CO)3 binding to histidine-containing tags and 111In using DOTA chelator at N-terminus; In Paper III we evaluated the influence of different aspects of N-terminus leading sequence on targeting including effect of sequence size on clearance rate and effect of the composition of the sequence on biodistribution profile; In Paper IV, we evaluated the influence of residualizing properties and positioning of the label on biodistribution and targeting; and In Paper V, we compared tumor-targeting properties of the ADAPT6 labeled at C-terminus with 99mTc using N3S chelator and 111In using DOTA chelator. In conclusion, ADAPTs constitute a very promising class of targeting probes for molecular imaging providing high contrast. Molecular design of the ADAPT proteins and chelators/linkers for labeling has an appreciable effect on their imaging properties.

This essay sheds light on a specific religious reformist within the Islamic tradition. This contemporary reformist is none other than Abd al-Karim Soroush, whose theory on fundamental building blocks within the Islamic tradition, such as revelation and prophethood, has sparked the interests of philosophers, theologians, and scholars of religion in general, and Islamic religious tradition in particular. By conducting a content-based analysis of his own work The Expansion of Prophetic Experience: Essays on Historicity, Contingency and Plurality in Religion the essay aims to a) examine his views on revelation and prophethood, b) explore his theory in relation to Islamic jurisprudence and ethics, and c) investigate any legal and ethical problematizations that his theory poses within the Islamic tradition. In an effort to revive the essence of Islam and reform the approach to the Quran and Islamic tradition, Soroush breaks down prophethood into two components: prophetic mission and prophetic experience. According to Soroush, both the prophetic mission and experience are tied to the era in which Muhammad (peace be upon him) operated. Such a contextual approach entails viewing and interpreting the Quran as a canonized book that reflects Muhammad's intuitive experiences and their continuous interaction with the cultural, social, and economic conditions prevalent during his time. By categorizing different aspects of the Quran into essentialism and accidentialism, Soroush argues that traditional legal and ethical derivations belong to the accidental category, which implies that they should not be viewed as static but rather dynamic and subject to reinterpretation in light of the contemporary context. To consider the traditional interpretation of Islamic jurisprudence and ethics as a secondary aspect in relation to the primary aspect of Islam, namely its essence, and to strip jurisprudence of its centrality and authority has both advantages and disadvantages within the Islamic tradition. The advantage may lie in a more rational and accepting approach towards religious pluralism and women's rights. The disadvantage can manifest in challenges related to Muslim identity formation and the arbitrary definition of essential Islam that his theory may entail.

Established biopharmaceuticals such as antibodies and derivatives thereof are relatively large. In cancer therapy, this creates a steep drug concentration gradient within tumors, leaving cells far from blood vessels effectively untreated. Continuous pseudo treatments should foster the development of drug resistance and might lead to eventual disease relapse. Drug concentration gradients can be operationalized as tissue penetration efficiencies, which are functions of molecular size. However, small particles are also subject to potent renal clearance, collapsing the therapeutic window beyond clinical applications. In this master’s thesis, spatial bispecificity was engineered into a single albumin binding domain (ABD). Resulting ABD derived affinity proteins (ADAPTs) are saved from urinary excretion by the grace of HSA, but in the more static microenvironment of tumors, following HSA dissociation, they are capable of tissue penetration efficiencies bestowed only upon smaller particles. To this end, phage display was used to raise ADAPTs against the cancer associated proteins human epidermal growth factor receptor 2 (HER2) and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), but also the inflammation marker C-reactive protein (CRP). Via Sanger sequencing, 9 variants were picked for protein production and characterization, among which two spatially bispecific binders were found. ADAPTs were also evaluated for aggregation tendencies, structural conformity to library design, and thermal stability. One ADAPT, binding HER2, passed all tests of initial characterizations. Deep sequencing was used to analyze selection output, from which many more binders should be screened in future experiments. / Etablerade bioläkemedel liksom antikroppar och deras derivat är relativt stora protein. Som cancerterapeutiska skapar de således branta koncentrationsgradienter utgående från tumörpenetrerande blodkärl. Detta riskerar att lämna vissa cancerceller utanför det terapeutiska fönstret. Det svaga selektionstryck som således verkar i tumörperiferin fostrar cancerceller till att utveckla resistens mot detsamma. Koncentrationsgradienten beror på proteinets vävnadspenetrarande förmåga, vilken är en funktion av proteinets storlek. Mindre proteiner borde därmed lättare ackumuleras i hela tumören och förebygga resistensutveckling. Problemet med små proteiner är deras mycket korta halveringstid i serum, en följd av relativt obehindrad filtrering ut i urinen via njurarna. I det här examensarbetet utvecklades rumsbispecifika bindare av cancerassocierade protein med hjälp av fagdisplayselektioner från ett proteinbibliotek baserat på en enda albuminbindande domän (ABD). Resulterande ABD deriverade affinitetsprotein (ADAPT) undkommer ovan nämnda filtrering tack vare sin naturligt starka interaktion med humant serumalbumin (HSA). I den mer långsamt flödande tumörmikromiljön tillåts ADAPTerna efter albumindissociation sedan utöva en bland bioläkemedel överlägsen vävnadspenetration. Tre parallella selektionsspår utfördes mot de cancerassocierade målproteinerna human epidermal growth factor receptor 2 (HER2) och carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) samt den utsöndrade inflammationsmarkören C-reaktivt protein (CRP). Via Sangersekvensering kunde flera kandidater identifieras. Bland 6 karakteriserade ADAPTer uppvisade samtliga hög HSA-affinitet, tre konstaterades interagera specifikt med sitt målprotein, och två verkade binda även rumsbispecifikt. ADAPTer utvärderades även för sin benägenhet att bilda aggregat, strukturell överensstämmelse med experimentell design, och värmestabilitet. Endast en bindare, mot HER2, klarade sig genom alla prövningar som proteinkarakteriseringen innebar utan underkänt. Även en högparallel sekvensering utav selektionsresultat utfördes, men utanför de tidsramar som tillät ytterligare karakterisering.

Cancer is still one of the most common causes of death world-wide and in parallel there is a need to update the repertoire of therapies that withstand resistance of recurrent cancers. Since the introduction of antibody therapies as anti-cancer pharmaceuticals, recognized as immunotherapy in health care, it has been an increasing field in cancer therapy, as a more targeted treatment compared to chemotherapy. Despite the great success, immunotherapy rely on parenteral administration, partly due to poor tissue penetration. If the treatment is administered intravenously, specialized personnel is required, in addition to that it can be inconvenient for the patient. Also, pharmaceuticals based on antibodies often require costly production steps which yields a high-priced treatment. To approach this problem, researchers have developed small affinity domains with the aim to increase tissue penetration while keeping a high specificity to its target. Albumin Binding Domain Derived Affinity Protein (ADAPT) is an example of a small affinity domain of only 7 kDa, which is based on albumin binding domain (ABD) from the streptococcal protein G. Recently, it was shown that the ADAPTs can be further engineered to bind albumin and another relevant target protein of interest simultaneously, which suggests a tolerable half-life in patient serum, alternative administration routes and lower production costs compared to antibody treatments. Furthermore, less side effects are expected due to higher specificity compared to chemotherapy. This work presents the characterization of novel ADAPT proteins that the target the cancer relatedproteins C-C motif ligand 7 (CCL7), vascular endothelial growth factor A (VEGF-A) and carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5). The new constructs were produced recombinantly in Escherichia coli (E. coli) and purified using affinity chromatography. Moreover, the results demonstrate bispecific binding with high affinity towards serum albumin and CCL7 and CEACAM5 respectively, while the ADAPT variants targeting VEGF-A remain to be further developed. Lastly, the importance of different amino acids for structural and binding properties of one CEACAM5 binder are stated. It reveals that the target binding relies on hydrophobic interactions which also can be connected to its poor structural attributes. Accordingly, this project adds new insights about the ADAPTs which can be useful in research towards future clinical applications aimed to improve cancer treatments.

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