Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT... Show moreHuntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4. In September 2015, the first-in-human study looking into the safety of an intrathecally administered antisense oligonucleotide therapy to reduce mutant HTT (mHTT) protein was launched in HD patients, where the drug proved to be safe and the intended mHTT lowering was demonstrated. The aim of this thesis is to find biomarkers corresponding with disease state and measuring progression in different stages of HD, which in turn can be used as suitable objective surrogate clinical trial endpoints. We put special emphasis on longitudinal study designs, as these provide the most useful clinical progression and parameter change associations. Although previous neuroimaging studies have shown potential markers, findings remain inconsistent or lacking association with disease state. As such, further exploration of neuroimaging techniques is of great relevance. Using different approaches to evaluate the potential usefulness of specific markers, we demonstrate biomarkers that may assist in the objective assessment of a potential disease-modifying intervention. Show less
The Sarcheshmeh Copper Mine was the world’s second largest open pit copper deposit in the 1970s. Currently, it is the largest in the Middle East and retains its place as one of the biggest copper... Show moreThe Sarcheshmeh Copper Mine was the world’s second largest open pit copper deposit in the 1970s. Currently, it is the largest in the Middle East and retains its place as one of the biggest copper processing complexes in the world. This thesis examines the formation of the modern copper mining industry in Iran, with particular focus on the establishment of Sarcheshmeh Copper Mine. It is elaborated within the theory of developmental state and accentuates an assortment of factors including political stability, relatively autonomous institutions with equitable performance, conversant technocrats committed to the national interest, a development-oriented state, and the growth of oil revenue.It then aimed to highlight the significance of the structure of mine ownership and the presence of the state in transforming the social policy, industrial relations, and mode of management in the Sarcheshmeh Copper Mine. These factors were instrumental in the formation of a working class, which was inspired by working-class power to indicate the role of the workers’ background and the company’s welfare policy in the workers’ response to the political unrest during the 1979 Revolution. Show less
Cardiovascular diseases are the primary cause of death in the world with atherosclerosis as primary underlying cause. Atherosclerosis is characterized by cholesterol accumulation in the vessel wall... Show moreCardiovascular diseases are the primary cause of death in the world with atherosclerosis as primary underlying cause. Atherosclerosis is characterized by cholesterol accumulation in the vessel wall and inflammation of the vessel wall of medium to large size arteries. Both cholesterol accumulation and inflammation are pathogenic in the context of atherosclerosis. Current treatment regimens are tailored to reduce cholesterol levels in the blood. However, even a successful lowering of cholesterol is in many patients not sufficient to prevent a major cardiovascular event due to unresolved inflammation. Therefore, the immune system provides an interesting therapeutic target for the treatment of atherosclerosis. In this thesis we have explored the effect on atherosclerosis of several immunomodulatory strategies in pre-clinical models.As cholesterol is not soluble in water, cholesterol is transported in the bloodstream in particles called lipoproteins. The low-density lipoprotein (LDL) carries the highest concentration of cholesterol and accumulates in the vessel wall where a pathogenic specific immune response against LDL is instigated. In this thesis we have used several strategies to modulate the specific immune response against LDL, inducing LDL-specific regulatory T cells, antibodies, and cytotoxic T cells. Through immunoproteasomal inhibition we assessed the effect of general immune inhibition on atherosclerosis. Show less
The focus throughout this thesis will be on gathering fundamental studies of the detailed structure and composition of the electrode/electrolyte interface effect on the rate and mechanism of key... Show moreThe focus throughout this thesis will be on gathering fundamental studies of the detailed structure and composition of the electrode/electrolyte interface effect on the rate and mechanism of key electrocatalytic reactions. The first part (Chapter 2 and 3) of this PhD thesis is about the studies of the non-Nernstian dependence on pH of the step-related voltammetric peak on platinum surface. The combined experimental and computational studies prove the existence of the co-adsorbed alkaline metal cation (Li, Na, K, and Cs) and hydroxyl at step sites of a platinum electrode. The co-adsorbed alkaline metal cation weakens the hydroxyl adsorption which yielding the anomalous non-Nernstian dependence on pH of the step-related “hydrogen peaks”. The second part starts from Chapter 4 changes first to the study of adsorption processes on a Pd monolayer-modified Pt(111) surface. Chapter 5 deals with the mechanism of electrocatalytic oxidation of formic acid and reduction of carbon dioxide on this Pd monolayer-modified Pt(111) electrode. The work in Chapter 6 explores the effects of electrolyte composition and catalysts surface structure on formic acid oxidation reaction. Show less
Sustainable energy from wind and solar is most readily available near the sea. Seawater electrolysis would thus be a highly promising method for intermittently storing surplus electricity from... Show moreSustainable energy from wind and solar is most readily available near the sea. Seawater electrolysis would thus be a highly promising method for intermittently storing surplus electricity from these sources, in the form of hydrogen. Unfortunately, the direct use of seawater in electrolysers brings with it a selectivity problem, caused by the chloride salts in such water. Instead of forming oxygen at the anode, which is environmentally harmless and thus the desired product, the formation of toxic chlorine becomes possible in seawater, and this reaction has to be avoided. This thesis is focussed on how the anodic evolution of oxygen and chlorine compete, and how selectivity between these two reactions may be optimized for the benefit of seawater electrolysis, and electrocatalysis in general. Show less
Most small-molecule drugs are designed to interact with their biological targets under equilibrium binding conditions, whereby the desired drug-protein interaction is a rapid and reversible (non... Show moreMost small-molecule drugs are designed to interact with their biological targets under equilibrium binding conditions, whereby the desired drug-protein interaction is a rapid and reversible (non-covalent) process. As an extension to maximizing the strength of these noncovalent molecular interactions, a less conventional strategy termed ‘covalent interactions’ has recently gained reputation in the field of drug discovery. In this thesis a covalent strategy is applied and shown to be compatible with a target-directed, structure-guided discovery paradigm, with a focus on adenosine receptors as drug targets. The development and application of chemical tools and strategies are described to study three subtypes of ARs, A1R, A2AR and A3R. We set up a work flow of in vitro pharmacological assays as a robust tool for measuring and quantifying covalent modulation. Besides, we developed affinity-based probes, which allow monitoring of GPCR expression in cell fragments. Combined, this research approach may ultimately aid in the discovery and development of novel adenosine receptor-based therapeutics that lack potential side effects as much as possible. Show less
In Savage Embraces: James Purdy, Melodrama, and the Narration of Identity, Looi van Kessel explores the ways in which the early works of the American author James Purdy undermine the notion of a... Show moreIn Savage Embraces: James Purdy, Melodrama, and the Narration of Identity, Looi van Kessel explores the ways in which the early works of the American author James Purdy undermine the notion of a stable and true identity. Writing in the 1950s and 60s, a time in which identity politics enjoyed increased purchase in the United States, Purdy imagines characters who feel the urge to act out their sexual desires without having to conform to oppressive identity categories. In so doing, Purdy is searching for a language that shows how identity is produced through narration. To tease out this language, Looi approaches Purdy’s writing through the mode of melodrama—a mode that focuses on the aesthetic dramatization of tensions in the plot—while also bringing his work in conversation with current queer thinking. Ultimately, this dissertation attempts to bring the disparate fields of narrative theory and queer theory in a meaningful relation with one another. Show less
This thesis explores different avenues to develop insurmountable antagonists for CC Chemokine Receptors, such as CCR1, CCR2 and CCR5. These receptors, which belong to the large family of G protein... Show moreThis thesis explores different avenues to develop insurmountable antagonists for CC Chemokine Receptors, such as CCR1, CCR2 and CCR5. These receptors, which belong to the large family of G protein-coupled receptors (GPCRs), are implicated in a variety of inflammatory and immune diseases, including atherosclerosis, rheumatoid arthritis and cancer. Thus, numerous drug candidates have been developed over the years to target them. Despite promising preclinical data, most of these candidates have failed in clinical trials due to lack of efficacy, making necessary the development of novel tools and concepts to better study and target these receptors. Thus, throughout this thesis we have explored different mechanisms to achieve insurmountable inhibition, which include intracellular allosteric modulation, covalent inhibition and long residence time. Moreover, the crystal structure presented in this thesis provides a new template for the rational design of future antagonists. Finally, with the identification of several selective or multitarget intracellular ligands for CCR1, CCR2 and CCR5, we are expanding the toolbox to further modulate chemokine receptors. Overall, the results of this thesis may contribute to the development of novel chemokine receptor antagonists, and GPCRs in general, with improved in vivo efficacy. Show less
In this thesis, the role of plant-mediated soil legacy effects in shaping aboveground plant-insect interactions was investigated. This work shows that soil legacy effects on plant-insect... Show moreIn this thesis, the role of plant-mediated soil legacy effects in shaping aboveground plant-insect interactions was investigated. This work shows that soil legacy effects on plant-insect interactions are a common phenomenon in nature, both in individual responding plant species and their associated herbivores, as well as in responding plant communities and associated herbivores. This thesis elucidates two potential mechanisms how soils can influence aboveground insects. First, soils can alter the way plants defend them selves in terms of secondary chemistry and phytohormonal defenses. Second, soils can also directly impact aboveground insects by changing the insect microbiome. This work shows that a large part of the insect microbiome is taken up directly from the soil microbiome, and leads to exciting new research directions on the longterm and evolutionary implications of soils for aboveground insects. Show less
Large carnivore population is globally declining as a result of the fragmentation of habitat, large prey depletion and retaliatory killing by pastoralists. Despite Kenya declaring approximately 8... Show moreLarge carnivore population is globally declining as a result of the fragmentation of habitat, large prey depletion and retaliatory killing by pastoralists. Despite Kenya declaring approximately 8 percent of the land as wildlife protected areas, there are less than 2000 lions left in the wild. This trend is worrying and Kenya Wildlife Service developed conserve and manage large carnivores’ strategy. This justify the reason for Nairobi Lion Research Project. Understanding the factors influencing human–lion conflicts would reduce retaliatory killing of lions and improve conservation of lions. Therefore, the aim of this study is to ensure conservation of lions in NNP and in the surrounding areas, specifically in relation to human–lion conflicts. It focuses on population size and pride structure, home ranges and movements, prey choice and diets and examine socio-economic aspects of lion–livestock conflicts and application of LED flashlights. I found that Nairobi National Park has high lion’s density per100 km2, small home range and avoid the urban fringe of Nairobi City. They supplement diet with very small prey (<5 kg). Partial fencing of parks is not a solution to human-lion conflicts and LED flashlight technology is effective in reducing nocturnal livestock depredation at bomas by lions. Show less
All life on earth contains DNA, which is used to store biological information. Organisms compact their DNA in order for it to fit inside their cell(s). Specialized proteins, which are referred to... Show moreAll life on earth contains DNA, which is used to store biological information. Organisms compact their DNA in order for it to fit inside their cell(s). Specialized proteins, which are referred to as nucleoid-associated proteins (NAPs), help organize the DNA to keep it compact but accessible for transcription. These NAPs often function as DNA benders, bridgers and wrappers. In most eukaryotic and archaeal species, histones are important NAPs that are able to bend or wrap the DNA duplex around its core. In this thesis, the histones from archaea are described in terms of their interaction with DNA. We describe archaeal histones on a molecular level and analyze their primary structure. We also characterize recombinant expressed archaeal histones using single molecule techniques such as tethered particle motion and magnetic tweezers. Experiments using these techniques show that some archaeal histones form a rod-shaped structure together with DNA in solution. This hypernucleosome strongly compacts DNA. Furthermore, we discuss the impact of hypernucleosome formation on transcription regulation in archaea. Show less
This thesis presents an investigation into how geopolitical change and religious control are reflected in the composition of copper-alloy costume artefacts, recovered from Roman and early medieval... Show moreThis thesis presents an investigation into how geopolitical change and religious control are reflected in the composition of copper-alloy costume artefacts, recovered from Roman and early medieval contexts. It engages with the challenging topic of portable X-ray Florescence Spectrometry use in archaeology, especially as applied to corroded copper-alloy artefacts. The relevance is twofold. Firstly it helps us better understand the globalising effects of the Roman Empire on distant cultures and the emergence of the western economy after the end of antiquity. This is investigated by detecting changes in craft production, considered a proxy for understanding changes in past economies and societies. Secondly it advances a methodology for the study of copper-alloy objects. Subsequently the composition of Roman brooches from Germania Inferior, suggested a strong link between brass and Roman military production. This connection was also seen in other parts of the Roman world, suggesting a degree of centralisation or control. The earliest roman objects found in the Baltic States, far north of the Limes frontier, are also in this 'Roman' alloy. These objects had a lasting impact on the peoples of this region. They adopted and adapted them stylistically to suit their local preferences for centuries after they first appeared. Show less
DNA encodes the genetic instructions for living organisms. However, damage to the DNA is inevitable, because DNA itself is an unstable molecule and environmental factors such as UV-radiation or X... Show moreDNA encodes the genetic instructions for living organisms. However, damage to the DNA is inevitable, because DNA itself is an unstable molecule and environmental factors such as UV-radiation or X-rays cause damage to the DNA. A certain type of DNA damages can block DNA replication, an essential step before cell can divide. The polymerases that normally replicate DNA are incredibly efficient and virtually flawless on undamaged DNA, but they cannot replicate damaged DNA. In multi-celled organisms, the most important defense mechanism against this is Translesion DNA synthesis (TLS). TLS protects against various negative consequences of damage to the DNA. For this, TLS utilizes specialized TLS polymerases that can replicate damaged DNA.My experiments show that the strong evolutionary conservation of TLS is explained by the dual functions of TLS: guarding replication potential and genome stability. TLS suppresses genomic instability, by preventing conversion of replication blocks to double-stranded DNA breaks (DSBs). Without functional TLS, DSBs arise and result in larger and more harmful mutations. TLS is beneficial for organisms because it supports continuous reproduction and growth. Although DNA damage is always present and unavoidable, TLS guards against the formation of mutations that would otherwise lead to cancer, aging and congenital disease. Show less
In the research presented in this thesis, the effects of humidity on a series of Ru-complex molecular layers is investigated with the Conductive Atomic Force Microscopy technique. One specific... Show moreIn the research presented in this thesis, the effects of humidity on a series of Ru-complex molecular layers is investigated with the Conductive Atomic Force Microscopy technique. One specific molecule out of this series called '2-Ru-N' shows remarkable humidity sensitive diode behavior: in low humidity it behaves as a conventional resistive tunneling junction, wheras in high humidity, it behaves as a diode. The rectification ratios found for 2-Ru-N are among the highest reported for molecular junctions in the literature. By comparing the behavior of 2-Ru-N with its other counterparts, a model is presented that is based on two localized molecular orbitals that are misaligned during the addition of water. This is due to the water pulling on the counter-ions that are found in the molecular layer and hence, effectively gate one of the two localized molecular orbitals, resulting in a misalignment and thus, a diode-like behavior. Show less
This dissertation is inspired by the question how national authorities can be motivated to advance the fight against impunity by investigating and prosecuting those responsible for mass atrocities... Show moreThis dissertation is inspired by the question how national authorities can be motivated to advance the fight against impunity by investigating and prosecuting those responsible for mass atrocities through their domestic justice systems. Whereas international scholarship has often sought to answer such questions by looking at international criminal courts, this study proposes instead to turn our gaze towards the Inter-American Court of Human Rights.Since the days of the Cold War, the Inter-American human rights system has been an important ally for victims and civil society groups pushing their governments to recognize and investigate serious and systemic violations of human rights and bring the perpetrators to justice. It has thus been involved in the fight against impunity for decades.This dissertation examines both the legal doctrines developed by the Inter-American Court of Human Rights to further the fight against impunity and the practical contributions of those doctrines to domestic accountability processes in Latin America. It argues that the Inter-American system has made important contributions to several aspects of domestic accountability processes. However, in order to understand these contributions, we have to step outside the compliance framework often employed in legal scholarship to the study of international courts. Show less
This thesis explores the application of the United Nations Convention on the Rights of the Child, 1989 (‘the CRC’) by domestic courts, in the light of the formal domestic rules which govern the... Show moreThis thesis explores the application of the United Nations Convention on the Rights of the Child, 1989 (‘the CRC’) by domestic courts, in the light of the formal domestic rules which govern the relationship between international treaties and domestic law. The focus is on three legal systems – Australia, France and South Africa – purposefully selected to represent three different reception models: dualist, monist and hybrid respectively. The thesis demonstrates that the formal rules of reception are only a starting point for the courts, but do not always explain why, how and with what consequences the courts have given effect to the CRC. The courts have applied the CRC creatively, building on the strengths of their respective systems and sometimes compensating for potential vulnerabilities in the domestic reception framework. The thesis calls for, inter alia, a recognition of the complex position of the courts at the intersection between domestic and international law; and for a closer exploration of the added value of the Convention in relation to other legal instruments. It also encourages a dialogue between the CRC Committee and the courts in relation to the interpretation of the CRC. Show less
Growth hormone profiles are pulsatile and highly variable between individuals, limiting the implementation of mathematical models to quantify an individual's secretion.In this thesis, five key... Show moreGrowth hormone profiles are pulsatile and highly variable between individuals, limiting the implementation of mathematical models to quantify an individual's secretion.In this thesis, five key topics regarding the quantification of growth hormone (GH) in literature and the application in (future) clinical trials were addressed consecutively:1. The current standards in reporting clinical trial outcomes in acromegaly patients were assessed and recommendations for future reporting were provided 2. A new deconvolution-informed population pharmacodynamic model wasdeveloped and validated for the quantification of drug effects on pulsatile profiles 3. Population pharmacokinetic/pharmacodynamic models were developed to better understand the clinical pharmacological properties of BIM23B065 to support decision making and future clinical trial design 4. A population model for GH secretion based on physiological information,including a GHRH pulse generator, was developed based on data from differentexperiments to be used for the simulation of pulsatile GH profiles in healthy controls, active acromegaly patients and acromegaly patient after surgery. 5. The impact of different sampling protocols, ranging from a single sample to a 24h GH profile, on the study power and classification of responders in GH research were quantified and implementation of the research methodology in new scenarios was stimulated. Show less
This thesis gives insight into the patient group that survived an OHCA and gives directions to the development, evaluation and implementation of integrated rehabilitation treated programs, with the... Show moreThis thesis gives insight into the patient group that survived an OHCA and gives directions to the development, evaluation and implementation of integrated rehabilitation treated programs, with the ultimated goal being that all surviors and their spouses regain optimal quality of life and autonomy. Our studies showed that survivors of an OHCA attending a rehabilitation program may experience cognitive problems. A first attempt of identifying cognitive problems with a set of cognitive screening instruments in patients who attend a (cardiac) rehabilitation program appeared to be feasible, although the screening needs further refinement. The finding that cognitive impairments have a negative effect on exercise capacity is important to take into account while further optimising the best rehabilitation program. Finally, the rehabilitation program should not only focus on the patient but also on the spouse or the caregiver. By developing a core outcome set for rehabilitation the effectivenss of cognitive rehabilitation in OHCA patients and their relatives can be better evaluated. Show less
This thesis focuses on the political decision-making culture of the Netherlands in the second half of the twentieth century. The dominant view of this culture has been one of compromise cooperation... Show moreThis thesis focuses on the political decision-making culture of the Netherlands in the second half of the twentieth century. The dominant view of this culture has been one of compromise cooperation and consensus. This view is strongly influenced by Lijphart’s 1968 book Politics of Accommodation. Since then, the extent to which this culture of consensus politics may have changed at the elite level is being debated. This study contributes to this debate by studying the parliamentary debates about some of the major socio-economic (social security) and ethico-religious issues (cremation, abortion and euthanasia). These debates have been characterized by studying the informal rules of the political game. Two sets of rules, corresponding to the dichotomy between consensus and majoritarian democracy, were used. An important observation is that the studied issues are difficult to position within the dichotomy of consensus and majoritarian politics. Only a few cases can be included, while most cases do not fall into either category or have characteristics of both. This leads to the main conclusion that the political elites primarily act on the basis of their own political interests, and less with regard to higher normative notions that underlie the concept of consensus politics. Show less
The main subject of this thesis is the design and synthesis of paramagnetic molecules for protein studies with NMR and EPR spectroscopy. With the development of paraNMR and DEER experiments,... Show moreThe main subject of this thesis is the design and synthesis of paramagnetic molecules for protein studies with NMR and EPR spectroscopy. With the development of paraNMR and DEER experiments, synthetic paramagnetic centers are becoming popular. About half of the current paramagnetic probes were described in the past five years, reflecting this popularity. Several of them improved the stability and rigidity of the probes, mainly by introducing novel attachment groups forming thioether and triazole linkers.1–3 Such linkages help to extend the application of the probes to in-cell measurements.4,5 Some small probes were designed for 3d-block metal ions as well, but these probes show low metal ion binding affinity.6,7 The research described in this thesis contributed to the development of paramagnetic probes. Hereafter, the properties of these new probes are discussed, and some general conclusions and prospects are given. Show less
