Tuberculosis (TB) is associated with 1.5 million deaths annually. There is a need exists to optimize both current as well as novel antibiotic combination treatment strategies to improve the... Show moreTuberculosis (TB) is associated with 1.5 million deaths annually. There is a need exists to optimize both current as well as novel antibiotic combination treatment strategies to improve the effectiveness and safety of treatments against TB. This PhD thesis has described how various quantitative pharmacology modeling approaches can contribute to the further development and optimization of both existing and novel therapies and treatment strategies against TB. Show less
Dental calculus. This small, hard, inconspicuous substance that forms on the teeth of humans and animals contains a surprising amount of information about our lives. During its formation and growth... Show moreDental calculus. This small, hard, inconspicuous substance that forms on the teeth of humans and animals contains a surprising amount of information about our lives. During its formation and growth as a living biofilm, it accumulates a wide variety particles, especially bacteria and food debris.What makes this so interesting to archaeologists is that, when plaque hardens and forms dental calculus, these particles become trapped and well-protected against removal and degradation during hundreds to thousands of years, preserving a picture of past activities.The major problem—one of the major problems, for there are several—one of the many major problems is that this picture was never a complete picture of a lifetime of activities, and that picture fades over time. We know that these problems exist and that they limit our interpretations of past activities. What we need to do is approach these problems at a fundamental level. In my dissertation I introduce a protocol for growing artificial dental calculus. Working with a very controlled model allows me to explore the influence of a wide range of factors that may affect the uptake of particles into dental calculus, and better explain why and how our picture is incomplete. Show less
Space data provide timely and reliable information that enables a wide variety of civil and commercial applications. Thanks to their volume, velocity, variety, and veracity, space big data create... Show moreSpace data provide timely and reliable information that enables a wide variety of civil and commercial applications. Thanks to their volume, velocity, variety, and veracity, space big data create the potential for additional benefits from space data.The benefits of space big data depend on the ways in which data are collected, accessed, used, and disseminated, therefore the laws and data policies that affect them should be studied. This thesis answers the question ‘How could space big data be regulated to address existing legal challenges and enhance their benefits?’. In particular, it identifies the laws and data policies that are relevant to the collection, access, use, and dissemination of space big data, among the legal frameworks that govern activities involving space or data. It also assesses the impact of the relevant laws and data policies, in terms of the limitations they impose on data collection, access, use, and dissemination. From the analysis of the relevant laws and data policies and their impact, the thesis draws the areas where their application encounters difficulties and describes the respective legal challenges. Based on these findings, recommendations are provided for overcoming the legal challenges and enhancing the collection, access, use, and dissemination of data, and by extension, their benefits. Show less
In this dissertation, Dutch secondary school teachers’ attitudes, knowledge, noticing skills and reasoned practices regarding culturally responsive teaching in a multicultural classroom context,... Show moreIn this dissertation, Dutch secondary school teachers’ attitudes, knowledge, noticing skills and reasoned practices regarding culturally responsive teaching in a multicultural classroom context, were examined. These components of culturally responsive teaching were addressed in three explorative, qualitative studies. In the first study, expert teachers’ reasoned practices were examined by in depth interviews. In the second and third study, spherical video-based virtual reality (SV-VR) clips of a multicultural classroom were used to provide teachers an immersive, authentic and comparable experience. The second study focussed on student teachers’ and expert teachers’ noticing through a cultural lens. In the third study, the SV-VR clips were used for deeper reflections in focus groups through which expert teachers’ culturally responsive attitudes, knowledge, noticing skills and reasoned practices were examined. The main results of this dissertation show that expert teachers teaching at Dutch multicultural schools indicate that working on a good interpersonal relationship with students is crucial. Moreover, the importance of adopting a genuinely curious attitude regarding students’ Funds of Knowledge/ Identity is often referred to. Such knowledge is also seen as necessary to notice relevant classroom events. Recommendations are made for teacher education regarding preparing teachers to teach multicultural classes. Show less
Lung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of... Show moreLung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of immunotherapy in 2015, this survival has increased significantly, with the first results showing a survival of even a few years. However, the response rate is relatively low, the treatment is expensive and the (low percentage of) side effects are severe. Therefore a biomarker is needed to predict which patients would benefit of immunotherapy.This thesis is about the search for a new biomarker. With the use of the RNA of platelets, proteins, tumor markers in blood and a an electronic nose for exhaled breath, we tried to find a non-invasive biomarker for the prediction of response on immunotherapy and for the (future) use in clinical practice, some of which are promising. Show less
The fundamental research question in this dissertation is what the image of man - in the broadest sense of the word - entails within the classical and modern enlightenment points of view. This... Show moreThe fundamental research question in this dissertation is what the image of man - in the broadest sense of the word - entails within the classical and modern enlightenment points of view. This overarching question is considered with regard to the notions of man maintained by the ancients and moderns, with regard to their visions of society, and with regard to the worldview these theories entail. We also evaluate which of the two paradigms is the more convincing upon scrutiny. We have answered such questions by distilling the ideas of the classical philosopher Aristotle -and some ontological ideas from his teacher, Plato- on the one hand, and from the modern intellectual giant, Thomas Hobbes, on the other hand. This is premised on the belief that the essential features of the classical and modern idealtype are to be found within their thought and works.In order to answer our central question, we had to look into the values which underly each vision of man. After all, values are the ideas that motivate our actions as individuals and as a community. We found that the classical vision is guided by the value of Virtue/Duty, Hierarchy and the pursuit of Community in a world permeated with objective values, whilst the modern conception embraces Freedom, Equality and Individuality in a world that is set free of objective values. Show less
Cerebral Amyloid Angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly, and affects millions of people worldwide. CAA is caused by the deposition of the... Show moreCerebral Amyloid Angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly, and affects millions of people worldwide. CAA is caused by the deposition of the protein Amyloid-β in the walls of the cerebral and leptomeningeal vessels, which leads to vessel fragility and eventually rupture. CAA has a variable disease course and can present with a spectrum of symptoms. There is currently no cure for CAA, and certain diagnosis during life remains challenging.This thesis has used data from patients with hereditary and non-hereditary (sporadic) CAA to investigate novel clinical and radiological (MRI) markers of CAA, and has used them to formulate a pathophysiologic framework for the temporal ordering of disease processes in CAA. Our results provide new insights in the disease cascade, can aid in diagnosing the disease and have important implications for future clinical trial design, aiding in the identification and timing of candidates for disease-modifying treatments and the choice for the appropriate biomarkers to monitor treatment effect. CAA is a disease with a complex disease cascade and a large variety in disease course, both clinically and radiologically. However, it is just this variety that gives hope for the future: if we find what drives variability in CAA we might find ways for disease modification, prevention and treatment, and identification of in vivo biomarkers with specificity for CAA are a vital part of this search. Show less
Time-series forecasting through modelling sequences of temporally dependent observations has many industrial and scientific applications. While machine learning models have been widely used to... Show moreTime-series forecasting through modelling sequences of temporally dependent observations has many industrial and scientific applications. While machine learning models have been widely used to create time-series forecasting models, creating efficient and performant time-series forecasting models is a complex task for domain users. Automated Machine Learning (AutoML) is a growing field that aims to make the process of creating machine-learning models accessible for non-machine learning experts. This is achieved by optimising machine learning pipelines automatically. Time-series machine-learning pipelines include various specialised pre-processing steps that are not currently supported by existing AutoML systems. This dissertation investigates how AutoML can be extended to time-series data analysis problems such as time-series forecasting. Several challenges arise when developing specialised AutoML systems for time-series forecasting. For instance, advanced machine-learning pipelines that can extract time-series features and select well-suited machine-learning models need to be developed. Also, extra hyperparameters such as the window size, which shows how many historical data points are helpful, need to be optimised by the AutoML system. This dissertation addresses these issues. We provide a comprehensive overview of the AutoML research field, including hyperparameter optimisation techniques, neural architecture search, and existing AutoML systems. Next, we investigate the use of AutoML for short-term forecasting, single-step ahead time-series forecasting, and multi-step time-series forecasting with time-series features. Show less
This thesis contains several investigations into the contribution of complement proteins, especially C1q, in several human diseases. Additionally, human autoantibodies against C1q (anti-C1q) are... Show moreThis thesis contains several investigations into the contribution of complement proteins, especially C1q, in several human diseases. Additionally, human autoantibodies against C1q (anti-C1q) are studied, cloned and characterized in order to further the understanding of their role in autoimmune disease. Show less
The decision for immediate breast reconstruction after mastectomy is a preference-sensitive decision. For preference-sensitive decisions, shared decision making is propagated, but not yet properly... Show moreThe decision for immediate breast reconstruction after mastectomy is a preference-sensitive decision. For preference-sensitive decisions, shared decision making is propagated, but not yet properly implemented. Furthermore, prior studies identified unmet decision support needs in women considering breast reconstruction. With this thesis we aimed to optimally support women in making an informed decision about breast reconstruction. For this purpose, we developed an online patient decision aid (pDA) for breast cancer patients considering immediate breast reconstruction after mastectomy. This thesis describes the development and evaluation of this pDA. In our multicenter randomized controlled trial including 250 participants, we found that women who used the pDA felt better prepared for decision making, than women who received usual care. Other outcomes did not differ between both groups. Show less
In this dissertation, I draw on twelve months of ethnographic fieldwork with Egyptians in Amsterdam to study how the nationalization of our imagination and social-legal and material infrastructures... Show moreIn this dissertation, I draw on twelve months of ethnographic fieldwork with Egyptians in Amsterdam to study how the nationalization of our imagination and social-legal and material infrastructures mediates social life. I describe how, just like the group of people categorized as Egyptian in Amsterdam is diverse, the Dutch state is too, consisting of a a range of images, laws, organizations, and people that embody them. I argue that this Dutch state multiple structures almost all aspects of life, but ultimately cannot define who we are, or what we do. Show less
The parabolic Anderson model (PAM), which is the Cauchy problem for the heat equation with random potential. The PAM is a mathematical model that describes how mass (i.e. matter or energy) flows in... Show moreThe parabolic Anderson model (PAM), which is the Cauchy problem for the heat equation with random potential. The PAM is a mathematical model that describes how mass (i.e. matter or energy) flows in a medium in the presence of a field of sources and sinks.The PAM has been extensively studied on regular lattices and is well understood there. However, the lattice is not always a suitable model and we look for extensions to random graphs. Very little is known for general graphs and the literature is extremely sparse. The present thesis is a contribution to this developing area. Because sparse random graphs can often be approximated by trees, the natural first step is to consider the PAM on a tree. In particular, this thesis is devoted to studying the PAM on random trees. Show less
Nicotinamide adenine dinucleotide (NAD+) is the substrate used for the introduction of the ubiquitous and highly dynamic PTM in which either one or multiple adenosine diphosphate ribose (ADPr)... Show moreNicotinamide adenine dinucleotide (NAD+) is the substrate used for the introduction of the ubiquitous and highly dynamic PTM in which either one or multiple adenosine diphosphate ribose (ADPr) moieties are covalently attached to a nucleophilic side chain of an specific amino acid in the target protein to regulate cellular pathways including adipogenesis, DNA damage repair and gene expression. A significant fraction of the nucleophilic amino acid functionalities, most recently histidine and tyrosine, have been identified as ADPr-acceptor sites. In this thesis, new methodologies have been developed to synthesize peptide fragments carrying an ADPr modification to investigate ADP-ribosylation on histidine. Show less
The research presented in this thesis concerns one of the most important questions in software engineering of our time: how can we make sure that software is free from memory safety bugs? Memory... Show moreThe research presented in this thesis concerns one of the most important questions in software engineering of our time: how can we make sure that software is free from memory safety bugs? Memory safety bugs are the major cause of common vulnerabilities and exposures, and their presence threatens the stability and security of our digital world. This question is so important that it has escalated to the highest level. In a recent White House press release (February 26, 2024), the National Cyber Director of the United States of America calls on the academic community to help solve this hard problem: “addressing [this challenge] is imperative to ensuring we can secure our digital ecosystem long-term and protect the security of our Nation.” The accompanying technical report advises on the use of memory safe programming languages, and prominently mentions formal methods as one way to achieve the highly desired freedom from bugs, including memory safety bugs.In this thesis, formal methods are studied that are used to analyze software for its correctness, where correctness means that software satisfies its specification and incorrectness means the presence of a bug. The focus is on separation logic, a formal method designed as a scalable technique in ensuring freedom from memory safety bugs. Nowadays, separation logic is a well-established field of research: it has been widely studied academically in the past twenty years, and is successfully applied on an industry-wide scale to ensure memory safety. For example, separation logic is the technique used to prove, with mathematical certainty, that memory safe programming languages (such as Rust and Go) indeed live up to the promise that “they offer a way to eliminate, not just mitigate, entire bug classes.”In two parts, this thesis presents important scientific contributions that fill a gap in the academic literature. The first part contains the missing completeness theorem for separation logic, that is on par with the fundamental result by Goedel for first-order logic. Completeness is important for any formal method as it shows that the formal method can be adequately used for demonstrating every validity. The second part finally introduces dynamic separation logic that gives an alternative way to analyze memory safety problems, such that now it is possible to prove elementary specifications without needing extra logical techniques. This is important because it ensures ‘backwards compatibility’ with automated reasoning techniques that are optimized for first-order logic. Show less
The use of opioid is increasing in the Netherlands, which is reflected in an increase in complications associated with the use, such as hospital admission and death due to opioid poisoning. In... Show moreThe use of opioid is increasing in the Netherlands, which is reflected in an increase in complications associated with the use, such as hospital admission and death due to opioid poisoning. In addition to these direct hazards of opioid use, patients also face the risk of unplanned ICU admission and all-cause mortality. Dependent on socio-demographic characteristics and co-morbidities the risk of theseoutcomes may vary, but is unique to the general population of the Netherlands when compared to other countries. Show less
Visualizing the internal structure is a crucial step in acquiring knowledge about the origin, state, and composition of cultural heritage artifacts. Among the most powerful techniques for exposing... Show moreVisualizing the internal structure is a crucial step in acquiring knowledge about the origin, state, and composition of cultural heritage artifacts. Among the most powerful techniques for exposing the interior of cultural heritage objects is computed tomography (CT), a technique that computationally forms a 3D image using hundreds of radiographs acquired in a full circular range. The diversity in materials, shapes and sizes of cultural heritage objects poses a challenge for the broad application of this technique, since each scan needs to be tailored to the object. Moreover, the lack of affordable and versatile CT equipment in museums, combined with the challenge of transporting precious collection objects, currently keeps this technique out of reach for most cultural heritage applications. In this thesis, we explore how CT imaging can be further integrated in cultural heritage applications by 1) integrating expert feedback into the data acquisition process, 2) tailoring acquisition methods to obtain specific information, 3) developing a low-cost method to use in-house X-ray facilities for 3D CT imaging and 4) providing tools to interactively visualise and inspect the CT data. Show less
The endocannabinoid receptors CB1R and CB2R are involved in a plethora of processes, and consequently are involved in many pathological conditions. Their wide distribution makes the CBRs both an... Show moreThe endocannabinoid receptors CB1R and CB2R are involved in a plethora of processes, and consequently are involved in many pathological conditions. Their wide distribution makes the CBRs both an interesting therapeutic target and hard to study. Additional chemical tools are required to study and understand the function and mechanism of CB1R and CB2R. This thesis describes the development of several such tools to improve our insight in the (pathological) roles of the receptors in order to develop novel and improved therapeutics. First evaluation of three dimensional ligand-CB2R complexes made and analysed with Cryo-EM are described. Hotspots that potentially generate selectivity between CB1R and CB2R are evaluated with point-mutations in vitro. Consequently describes the development of the first tools, two-step bifunctional probes based on LEI-121 and LEI 102, is described. As two-step probes are not compatible with every assay, the toolbox is expanded with a one-step fluorescent probe. Briefly touching upon CB1R, ligands were designed with negatively charged phosphonium groups that are potentially selective for mtCB1R. Show less
Diacylglycerol lipases (DAGLα and DAGLβ) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain and peripheral tissues. Selective DAGLβ inhibitors... Show moreDiacylglycerol lipases (DAGLα and DAGLβ) are responsible for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain and peripheral tissues. Selective DAGLβ inhibitors have been proposed as a potential treatment for inflammatory diseases with reduced potential for central nervous system (CNS) mediated side effects, but they are currently lacking. To develop DAGLβ selective inhibitors, a fluorescent biochemical assay was optimized and applied in a high-throughput screening (HTS) for DAGLβ. During the HTS, eight hits classified into four distinct chemotypes were identified. Subsequent structure-activity relationship (SAR) studies, focusing on hit 1 and its modifications, revealed a specific group as the modification hotspot crucial for achieving selectivity towards DAGLβ. Through an extensive SAR investigation, focusing on modifying this group, the first-in-class DAGLβ selective inhibitors, LEI-130 and LEI-131, were discovered. Following their discovery, LEI-130 and LEI-131 underwent comprehensive in vitro and in situ profiling studies. These investigations confirmed that LEI-130 and LEI-131 are selective and noncompetitive inhibitors of DAGLβ, effectively reducing inflammation. Show less
Throughout the history of computer science, a major challenge has been how to assert that software is free of bugs and works as intended. Software bugs can lead to serious negative impacts on any... Show moreThroughout the history of computer science, a major challenge has been how to assert that software is free of bugs and works as intended. Software bugs can lead to serious negative impacts on any software system. Throughout the main body of the thesis, we implemented a series of studies on exploring ways to apply formal methods systematically for the verification of complex object-oriented libraries such as the Java Collection Framework. We start with specifying and verifying methods in the java.util.LinkedList class, but we encounter challenges with methods that take an interface type as a parameter. To address this, we proposed to use histories as method calls and returns to completely determine the concrete state of any implementation and thus can be seen as a way to reason about the interface. The executable history-based (EHB) approach embeds histories and attributes directly as Java objects. This approach could be seamlessly integrated in the KeY theorem prover itself. However, the EHB approach still has its limitations, particularly when it comes to reasoning about the heap and properties of user-defined attributes.To mitigate this, we introduce the logical history-based (LHB) approach, which models histories as an external abstract data type with functions. Building on the LHB approach, we have developed a history-based refinement theory for reasoning about hierarchy in object-oriented programs. Show less
