The replication of all positive-stranded RNA viruses of eukaryotes is thought to take place at cytoplasmic membranous replication organelles. One of the most prominent types of viral ROs induced by... Show moreThe replication of all positive-stranded RNA viruses of eukaryotes is thought to take place at cytoplasmic membranous replication organelles. One of the most prominent types of viral ROs induced by a number of these viruses, including coronaviruses and arteriviruses, are double-membrane vesicles (DMVs) that contain viral double-stranded RNA. This thesis discusses the formation of these replication organelles by arteri- and coronaviruses and provides new insights in the viral proteins involved. The ultrastructure of the replication organelles was unravelled using both electron microscopy and tomography. Furthermore, this research described in this thesis also shows that the innate immune system in infected cells can prevent the formation of the membrane structures. Show less
This thesis consists of two subjects, that are both a consequence of radiation pressure. In optomechanics, light is used to influence the motion of a trampoline resonator. It is possible to slow... Show moreThis thesis consists of two subjects, that are both a consequence of radiation pressure. In optomechanics, light is used to influence the motion of a trampoline resonator. It is possible to slow down this motion, cooling it from room temperature to an effective temperature of several milllikelvins, The other subject is how superconductivity influences the Casimir force between a niobium-titanium-nitride plate and a gold microsphere. This has been investigated both theoretically and experimentally. Show less
The dissertation describes TEM experiments on heterogeneous catalysts. Starting with characterization of (Ni/Co)MoS2 on Alumina and the effect of oxidation, and sequential resulfidation. After that... Show moreThe dissertation describes TEM experiments on heterogeneous catalysts. Starting with characterization of (Ni/Co)MoS2 on Alumina and the effect of oxidation, and sequential resulfidation. After that, Co-based catalysts are used for high-resolution (S)TEM/EDX caracterization studies, and in situ catalysis experiments. Show less
We investigate how radiation pressure can be used to influence the mechanical motion of a micro-mirror suspended from springs. This trampoline resonator is part of an optical Fabry-Perot cavity. By... Show moreWe investigate how radiation pressure can be used to influence the mechanical motion of a micro-mirror suspended from springs. This trampoline resonator is part of an optical Fabry-Perot cavity. By tuning the laser frequency with respect to the optical resonance, we are able to optically cool the mechanical motion of the resonator. When combining this optical cooling with cryogenic cooling techniques, we are able to bring the mechanical resonator close to the quantum mechanical ground state. This is a requirement for future experiments to investigate the fundamentals of quantum mechanics. Show less
Imagined Voices deals with a form of composition, music with on-screen text, in which the dynamic between sound, words and visuals is explored. The research explores the ideas around these 'music... Show moreImagined Voices deals with a form of composition, music with on-screen text, in which the dynamic between sound, words and visuals is explored. The research explores the ideas around these 'music-text-films', and attempts to explain how meaning is constructed in the interplay between the different layers of media. Issues that initially arose out of the research, were directly related to the question of 'voice': Who is narrating? And where is the voice located? These questions became more pertinent after noticing a phenomenon occurring during performances of these works: that when we read text synchronised to music, we become very aware of an inner voice silently reading along. This effect of hearing one's own voice in the music, was a discovery that had many consequences for the ways in which the ideas about listening and the role of multimedia could function within music. In the creative work of the research, that has resulted in over thirty works of 'music-text-film' the media are set up to highlight ways of listening that puts emphasis on the role of the listener/spectator. A state of limbo is created between the narrative voice of the text and the implied voice of the music, due to the absence of a conventional focal point to pin it on - an actor or a singer. The thesis suggests that because of this vacancy and the way the projected word takes the place of the sung or spoken voice, the inner voice of the audience becomes activated. This then becomes a vital immersive dimension in the performance, as the inner voices of the audience find their place within the fabric of the music. Show less
This dissertation investigates the life of Judean deportees in Babylonia in the sixth and fifth centuries BCE. The results from the study of Judeans are placed in the wider context of... Show moreThis dissertation investigates the life of Judean deportees in Babylonia in the sixth and fifth centuries BCE. The results from the study of Judeans are placed in the wider context of Babylonian society and are evaluated by using a group of Neirabian deportees as a point of comparison. The sources of this study consist of 289 clay tablets written in Akkadian cuneiform, such as promissory notes, leases, receipts, and lists. The dissertation shows that there was considerable diversity in the deportees’ socio-economic status and integration into Babylonian society. The majority of deportees were settled in the countryside and integrated into the land-for-service system, which was aimed at increasing agricultural output and providing the state with labour, soldiers, and tax income. In addition, foreign professionals were employed in cities, and the worlds of commerce and royal administration were open to some deportees. A relatively small number of deportees were donated to Babylonian temples. The Babylonian practice of settling deportees in ethnically homogenous rural communities supported the survival of their culture and traditions in the countryside. Adoption of Babylonian names and culture was faster among those Judeans who lived in cities and were in regular contact with the native population. Show less
The phenotype and functionality that CD8+ T cells acquire upon encountering their cognate antigen depend on many factors that are controlled by the nature of the pathogen The acquired... Show moreThe phenotype and functionality that CD8+ T cells acquire upon encountering their cognate antigen depend on many factors that are controlled by the nature of the pathogen The acquired phenotypical and functional characteristics determine the potential of the CD8+ T cells to form bona fide memory populations that are able to expand upon secondary challenge. We investigated factors that control CD8+ T cell differentiation. We have shown that the height of the viral dose greatly impacts the immunological outcome by affecting the magnitude of the response and the phenotype and function of the (memory) CD8+ T cells that are induced. The acquired phenotype and functions determine the capacity to expand upon re-encounter with the same pathogen and we have shown that the IL-2 producing capacity of CD8+ T cells functions as a crucial determinant of CD8+ T cell expansion potential. Although we addressed only a small fraction of all variables involved in the induction and maintenance of antigen-specific T cell populations our observations and insights gathered by others already provide a basis for rational immunotherapeutic treatment design, however, for fine-tuning of therapy-induced immune responses aspects about e.g. the timing and cooperating signals still need to be understood in more detail. Show less
The current thesis explores the evidence base of new techniques in minimally invasive surgery. For this purpose the main objectives of this thesis are: • To present a multidisciplinary... Show moreThe current thesis explores the evidence base of new techniques in minimally invasive surgery. For this purpose the main objectives of this thesis are: • To present a multidisciplinary evidence based guideline for MIS including the main topics in laparoscopic surgery; • To identify the evidence of three new minimally invasive techniques: trocar types for laparoscopy, LESS-hysterectomy and hysteroscopic sterilization; • To evaluate the course of introduction of a new minimally invasive technique (robot-assisted surgery) and the status of the evidence; • To assess whether recent RCTs serve the clinical needs of the MIS approach. Providing the answers to these questions, this thesis provides insight in the evidence of MIS and its limitations. Therewith, it provides guidance to optimize research and evidence based implementation of MIS towards better minimally invasive surgical care. Show less
Of all the mass in our Universe, 80% is thought to consist of a hypothetical and invisible substance called dark matter (DM). So far, all observations of DM are based on its gravitational... Show moreOf all the mass in our Universe, 80% is thought to consist of a hypothetical and invisible substance called dark matter (DM). So far, all observations of DM are based on its gravitational interaction, either through the dynamics of normal (baryonic) matter or through the deflection of light. The latter approach, called ‘gravitational lensing’, is a unique way to probe the distribution of DM without making any assumptions on its dynamical state, and on scales larger than the extent of baryons. Using weak gravitational lensing with the Kilo-Degree Survey (KiDS), we first study the relation between galaxies and their dark matter halos on the scale of individual galaxies and galaxy groups. We then attempt to measure the effect of the local and large scale (cosmic web) density distribution on galaxies and halos, and we measure the interplay between galactic and DM structures at the scale of the cosmic web. Finally, we perform the first test of Verlinde’s theory of Emergent Gravity, all with the ultimate goal of gleaning some insight into the possible nature of the elusive ‘missing mass’. Show less
Traditional drug discovery approaches have been hampered by (in vitro) cell-culture models that poorly represent the situation in the human body. Principally, cells grow in the body in a three... Show moreTraditional drug discovery approaches have been hampered by (in vitro) cell-culture models that poorly represent the situation in the human body. Principally, cells grow in the body in a three-dimensional (3D) environment that cannot generally be captured using cell culture methods. For this reason, cell-culture models have been developed where cells grow in a 3D-environment, which allows them to form structures that are more comparable to tissue in the body. However, the full complexity of these advanced cell-culture models can only be fully used for routine drug testing if the cell culture model can be used on a large scale (also termed high-throughput screening or HTS), and if the readout can capture all of the biological complexity reflected by the 3D-cultured cells (high-content screening or HCS). Due to these technological limitations, 3D cellular models are not yet routinely applied in drug and drug-target discovery. This thesis describes the development of fully-scalable 3D cell-culture screening platforms in the context of cancer and polycystic kidney disease. Show less
Producing the local: Javanese performance on Indonesian television explores how television represents Javaneseness, as a factor designed to catch and keep the attention of its putative... Show moreProducing the local: Javanese performance on Indonesian television explores how television represents Javaneseness, as a factor designed to catch and keep the attention of its putative audiences. Central is the question of how people make use of national, regional, local, public and private television in Indonesia – each in their own way and with their own goals – to represent the local and, in particular, how they construct images of Javaneseness through the production and dissemination of performance. Performance in Javanese has been used by the Indonesian television industry to achieve various purposes: to entertain and inform its audiences, to represent the local/the regional, to preserve and nurture the traditional and to build national culture, for persuasive (commercial or propaganda) aims, as a counter-voice of diversification towards global or Jakartan influences, and to express multiculturalism. These issues have been put into the framework of discursive practices about local, national and global cultures in the electronic audiovisual media in Indonesia. Three main themes structure the study: representing tradition, localizing persuasion and mediating the local. Above all, this dissertation is a plea for a more thorough study of the role of proximity in the production, dissemination and reception of local television programmes. Show less
Neonatal brachial plexus palsy (NBPP) is a nerve injury to the brachial plexus which controls arm-movements. This thesis describes the impact of this injury on the lives of patients in terms... Show moreNeonatal brachial plexus palsy (NBPP) is a nerve injury to the brachial plexus which controls arm-movements. This thesis describes the impact of this injury on the lives of patients in terms of quality of life, participation, healthcare use and treatment outcomes. Findings in this thesis have led to important insights into the care for patients with NBPP and their families. It turns out that there is considerable information need in these patients, that NBPP has impact on families of very young patients and adult patients perceive influence of NBPP on their study and career choices. This thesis also showed that when describing outcomes of shoulder surgery (tendon-transfers) it is important to take into account treatment history because outcomes differ for children with a surgical treatment history. This may help to manage patients’ outcome expectations. A recommendation in this thesis is to develop and investigate a standardized paramedic treatment protocol for the different life-phases of NBPP patients because this is not available yet. Hereby, a more strict follow-up is very important. Furthermore, better information should be developed in order to provide NBPP patients with the information they need throughout their lifespan. Findings in this thesis can be used for this. Show less
Maritime archaeologists, historians and heritage managers have struggled to position maritime and underwater cultural heritage (MUCH) in the sub-Saharan African heritage context. Management of... Show moreMaritime archaeologists, historians and heritage managers have struggled to position maritime and underwater cultural heritage (MUCH) in the sub-Saharan African heritage context. Management of MUCH resources, based on Western legal systems, has focused almost exclusively on shipwreck sites. Management strategies have been implemented to stop treasure hunting and limit the damage caused by salvage activities. The application of internationally accepted MUCH management practices has, however, failed to engage the publics of many African nations. This has meant that the application of regulatory strategies has been a challenging task which has ultimately failed to successfully manage MUCH resources or engage sub-Saharan communities. This research proposes, applies and assesses alternative management and engagement models at several southern-African case study sites, and contributes towards establishing a new approach to MUCH. The approach examines the context in which the heritage resource exists, including the socio-political and economic environments, as well as the available mechanisms in place, and available, for research and management. It considers the scope of MUCH in a regional context and seeks to establish some preliminary guidelines for management strategies built on local relevance and buy-in. Finally, it offers a management approach that is beneficial to both professional practitioners and community leaders. Show less
The aim of this research is to develop a 'flowchart' for the application of international law in the national legal order by the Dutch judiciary in civil cases. Both national law - especially... Show moreThe aim of this research is to develop a 'flowchart' for the application of international law in the national legal order by the Dutch judiciary in civil cases. Both national law - especially the articles 93 and 94 of the Dutch Constitution - and international rules for the interpretation and application of international legal sources are thereby taken into account. In order to analyse the different ways of application and interpretation, four casestudies are conducted. Based on (a comparision between) the results of these casestudies, some suggestions are given for the national application of international law. Show less
Transfusion of red blood cells (RBCs) causes exposure to foreign antigens and, consequently, may induce alloimmunization. This research focused on identifying clinical determinants of RBC... Show moreTransfusion of red blood cells (RBCs) causes exposure to foreign antigens and, consequently, may induce alloimmunization. This research focused on identifying clinical determinants of RBC alloimmunization, eventually aiming to prevent alloimmunization by pre-emptively select extended matched blood for the predicted responder patient. Both RBC antigen intrinsic characteristics and patient-related factors were studied. Regarding antigen immunogenicity, K was confirmed to be the most potent antigen, followed by E, Cw, e, Jka and c. Of importance, anti-Jka is known to easily induce complement-mediated hemolysis. Inflammation due to severe bacterial and viral infections was associated to increased RBC alloimmunization incidences. Remarkably, although in line with murine models, Gram-negative bacteremia coincided with a twofold reduction of alloimmunization risk. In a non-hemoglobinopathy population, alloimmunization post-splenectomy was a highly unlikely event. Consequently, the Caucasian splenectomized patient does not benefit from RBC products matched beyond ABO/RhD. Patients with acute (either myeloid of lymphoblastic) leukemia, mature lymphomas, myelodysplastic syndrome, or patients post-autologous or -allogeneic stem cell transplantation demonstrated strongly reduced incidences of RBC alloimmunization, primarily explained by the intense immunosuppressive nature of treatments. Consequently, matching for the MDS population deserves renewed focus and should be based on the cumulative transfusion burden rather than on the diagnosis itself. Show less
The main goal of the research described in this thesis was the development of new photoactivated chemotherapy (PACT) ruthenium(II) complexes bearing a non-toxic photolabile ligand. We first... Show moreThe main goal of the research described in this thesis was the development of new photoactivated chemotherapy (PACT) ruthenium(II) complexes bearing a non-toxic photolabile ligand. We first investigated whether non-toxic ligands such as L-proline, 2-(methylthio)methylpyridine (mtmp), or 3-(methylthio)propylamine (mtpa), once coordinated to ruthenium(II) complexes, could be photosubstituted upon visible light irradiation. The lipophilicity, and in some cases the strain of the ruthenium(II) complexes, were systematically varied and the effects of such variations on the cytotoxicity of the complexes in the dark and under light irradiation were studied. In the second part, the best ligand candidates (i.e. mtmp and mtpa) were coordinated to cyclometalated ruthenium complexes of the type [Ru(bpy)(phpy)(S,N)]PF6 (bpy = 2,2’-bipyridine and phpy = 2-phenylpyridine), to shift the absorption of the complex to the red region of the spectrum. The photosubstitution properties of these cyclometallated complexes were investigated in detail. The most promising ruthenium complexes were tested in cancer cell monolayers under hypoxic conditions (1% O2) to investigate their mode of action and distinguish between PACT and PDT. Show less
Drug-target binding kinetics determine the time course of the central event in pharmacotherapy: Drug-target interaction. However, the time course of a drug effect is also influenced by many... Show moreDrug-target binding kinetics determine the time course of the central event in pharmacotherapy: Drug-target interaction. However, the time course of a drug effect is also influenced by many other physiological processes such as the metabolism and excretion of a drug and the transduction of the relevant biological signals. In this study, we investigate when target binding kinetics are determining the time course of drug effect and generate understanding into the relation between the parameter values and the rate-limiting step in the duration of a drug effect. Show less
Cardiovascular diseases are among the most frequent causes of death in the world. The main underlying pathology of cardiovascular diseases is the development of atherosclerosis in the medium and... Show moreCardiovascular diseases are among the most frequent causes of death in the world. The main underlying pathology of cardiovascular diseases is the development of atherosclerosis in the medium and large-sized arteries. The role of several immune cell subsets has been identified in atherosclerosis and it has been established that the immune system contributes to initiation and progression of cardiovascular diseases. Atherosclerosis is thus currently described as a chronic inflammatory disease and both the innate and adaptive immune cells contribute to disease initiation and progression. This suggests that targeting the ongoing inflammatory response may limit atherogenesis. This thesis discusses several therapeutic immune targets to limit atherosclerotic lesion development. The results described show the interplay between lipids and the immune system and a number of anti-inflammatory strategies to reduce atherosclerotic lesion development. The studies show a clear advantage of reducing inflammation in atherosclerotic lesion development. Future (clinical) studies identifying new targets will lead to a better-personalized therapy reducing atherosclerosis. Show less
Planets are formed in disks of gas and dust around young stars. These planet-forming disks undergo several physical and chemical processes that can lead to planetary systems like our own. This... Show morePlanets are formed in disks of gas and dust around young stars. These planet-forming disks undergo several physical and chemical processes that can lead to planetary systems like our own. This thesis uses data of two well known planet-forming disks around TW Hya and HD 163296 taken with the Atacama Large (sub)Milimeter Array (ALMA) and the Herschel Space Telescope to study the spatial distribution of their dust and gas content. In particular, we aim to constrain the spatial distribution of the main oxygen- and nitrogen-bearing species in planet-forming disks and to explore the relationship between their physical features and the formation and chemistry of common molecular species. By analysing water and ammonia emission form the disk around TW Hya, we conclude that the location of oxygen- and nitrogen-bearing volatiles in planet-forming disks are set by grain evolution, in particular radial drift. In addition, we conclude that the spatial location of temperature-sensitive species trace substructures in the temperature profile of protoplanetary disks and therefore (indirectly) the impact of dust evolution process on its morphology. Show less
There is an urgent need for more physiologically relevant cell culture methods to guide compound selection in pre-clinical stages of the drug development pipeline. This thesis describes the... Show moreThere is an urgent need for more physiologically relevant cell culture methods to guide compound selection in pre-clinical stages of the drug development pipeline. This thesis describes the development of the OrganoPlate, a microfluidic platform that enables enhanced physiology in cell culture models by combining 3D cell culture, co-culture and perfusion flow, whilst maintaining ease of use, compatibility and throughput. Phaseguides are capillary pressure barriers that enable microfluidic liquid routing and patterning without the use of membrane or other physical barriers. This technology was further developed to enable complex liquid routing using only a standard pipette Phaseguide technology was implemented for gel patterning in a dedicated 3D cell culture device embedded in a standard 384 wells plate. Each plate contains up to 96 microfluidic networks that enable perfusion culture of extracellular matrix embedded tissues and perfused epithelial or endothelial tubules. The standard dimensions and high quality optical readout allows interrogation of these tissues using high content readers as well as other standard readout equipment. The platform has been used for the culture of a variety of tissue types and disease models by the authors, but has also been adopted by expert and non-expert users across the field. Show less
