The origin and evolution of galaxies are closely linked to many different physical phenomena. Among them, the most important one is the environment they reside in. Isolated and cluster member... Show moreThe origin and evolution of galaxies are closely linked to many different physical phenomena. Among them, the most important one is the environment they reside in. Isolated and cluster member galaxies indeed are affected by different forces which affect their evolution. The main concern of this thesis is to understand such forces and how they are related to galaxy evolution. Therefore, this thesis covers various topics including black hole mass calculations, the black hole mass-stellar velocity dispersion relation, the nature of AGN emission in galaxy clusters and field galaxies, a detailed investigation of X-ray and optical galaxy overdensity phenomenon, and the dynamical processes in pre-merging galaxy clusters. Show less
Streptomyces bacteria are a valuable source of natural products, many of which are used in the clinic or in biotechnology. In our search for novel antibiotics we discovered lugdunomycin, a natural... Show moreStreptomyces bacteria are a valuable source of natural products, many of which are used in the clinic or in biotechnology. In our search for novel antibiotics we discovered lugdunomycin, a natural product with a highly complex chemical architecture that is produced by Streptomyces sp. QL37. It is derived from the angucyclines, a well-known class of molecules known for their antibacterial and anticancer activities. Though angucyclines are produced in high quantities under most conditions, lugdunomycin is produced in minimal amounts. This thesis describes novel insights into the transcriptional control of the lugdunomycin biosynthetic gene cluster and into the lugdunomycin biosynthesis pathway. These insights may be applied to improve the yield of lugdunomycin and expand the chemical diversity of angucyclines. Using molecular biology, bioinformatic approaches and omics studies, such as metabolomics and transcriptomics, we have characterized the lugdunomycin biosynthetic gene cluster, the regulatory genes (lugRI–lugRV) required for transcriptional activation of the cluster, and the oxygenase genes (lugOI–lugOV) that play a key role in the different chemical rearrangements of the angucyclines. Furthermore, this thesis contains a detailed review of the regulatory network that controls antibiotic production in Actinobacteria. Show less
The transition to electric vehicles (EVs) reduces vehicle emissions to combat climate change. EVs raise concerns regarding the production of lithium-ion batteries and related emissions; while... Show moreThe transition to electric vehicles (EVs) reduces vehicle emissions to combat climate change. EVs raise concerns regarding the production of lithium-ion batteries and related emissions; while batteries can also provide energy storage services for the electricity system. Here we use the material flow analysis method to quantify the future material demand for lithium-ion batteries and the prospective life cycle assessment method to quantify future emissions of battery production. Further combined with battery technology modelling, future energy storage potential of EV batteries is evaluated. Results show the demand for battery raw materials will increase by a factor of over 15 in the next three decades, which requires a drastic expansion of battery supply chains. The increasing utilization of renewable energy and improved mining technology of raw materials for battery production will result in a 50% decrease in emissions per lithium-ion battery production between 2020-2050. Renewable energy transition contributes largely to this emission reduction, but EV battery storage can provide short-term grid services for complementing variable renewable generation. EV batteries alone could satisfy short-term grid storage demand by as early as 2030. This research reveals environmental challenges and opportunities for EV batteries as well as options to improve EV battery sustainability. Show less
Parkinson's disease is the second most common neurodegenerative disease in the world. One of its symptoms is the loss of dopaminergic neurons in the substantia nigra pars compacta. A number of... Show moreParkinson's disease is the second most common neurodegenerative disease in the world. One of its symptoms is the loss of dopaminergic neurons in the substantia nigra pars compacta. A number of phenotypes, including the aggregation of misfolded proteins, mitochondrial dysfunction, and neuroinflammatory chemicals released by microglia and activated astrocytes, may all play a role in its pathogenesis.Due to the multisystemic nature of Parkinson's disease, novel tools for developing mechanistic models that simulate its pathogenic processes have been proposed. Furthermore, as the amount of information in biological databases grows and the cost of omics experiments decreases, methods for integrating different types of biological data have become essential for increasing the level of detail in mechanistic models of biological systems.Constraint-based modelling is a valuable tool in bioengineering and biomedicine. It is used to estimate the reaction flux in a metabolic network. The constraints represent essential characteristics of a biological system, including connectivity between metabolites and reactions, thermodynamics, maximum and minimum flux rates, and the steady-state.This thesis presents studies and tools for integrating various types of specific information to genome-scale models used in constraint-based modelling. In addition, is presented the iDopaNeuro default models, genome-scale models of a culture of dopaminergic neurons derived from induced pluripotent stem cells. Show less
In this thesis, the monitoring of the immune system in balance and during active responses (by flow cytometry) plays a central role. In chapter 2.1 and 2.2, we investigated the optimal sample... Show moreIn this thesis, the monitoring of the immune system in balance and during active responses (by flow cytometry) plays a central role. In chapter 2.1 and 2.2, we investigated the optimal sample logistics for high-dimensional flow cytometry in clinical trials. In chapter 3.1-3.4, we monitored the longitidinal kinetics of circulating immune cells in humans after vaccination or bacterial challenge against Bordetella pertussis. Lastly, in chapter 4, we investigated the immune system in humans carrying a genetic variant of PLCG2 'p.P522R', which is associated with increased longevity and reduced chance of developing dementia. Show less
In condensed matter systems electron-electron interactions, negligible in everyday metals, can dramatically alter the electronic behavior of the system. Examples of such altered behavior include... Show moreIn condensed matter systems electron-electron interactions, negligible in everyday metals, can dramatically alter the electronic behavior of the system. Examples of such altered behavior include high-temperature superconductivity and modulation of the electron density. A common feature of this correlation driven behavior is the tendency of the spatial electronic structure to vary on the nanometer scale. In this thesis we explore the nanoscale variation of the electronic structure of various correlated electron systems. We use the wave-like oscillations in the electron density of states to probe fundamental properties of the system providing insights into when various experimental probes disagree with each other. Turning our attention to high-temperature superconductors we find that close to the transition between superconductor and metal a granular superconductor emerges, small nanoscale patches of superconductivity interlaces with a metallic matrix. A careful examination of the wave-like oscillations hints at the presence of spatial ordering of the electrons. Finally we study how the presence of strong interactions can alter the way electrons flow through a material such that concepts usually reserved for everyday fluids become relevant. Show less
In this thesis, we consider various (electro)chemical phenomena at surfaces and nanoparticles and their underlying atomistic processes, which we studied using first-principles methods such as... Show moreIn this thesis, we consider various (electro)chemical phenomena at surfaces and nanoparticles and their underlying atomistic processes, which we studied using first-principles methods such as density functional theory. These phenomena range from CO2 reduction to C2 and C3 species, through solvation of adsorbates on various surface features of late transition metals, to the impact of graphene on hydrogen evolution reaction, cathodic corrosion and surface oxidation of Pt. With our thermodynamic and kinetic calculations, we provide explanations for experimental observations by unraveling underlying phenomena, support novel computational methods and techniques, and propose new atomic structures that explain prior findings and provide inroads into future electrocatalytic research. Show less
Quantum annealing belongs to a family of quantum optimization algorithms designed to solve combinatorial optimization problems using programmable quantum hardware. In this thesis, various methods... Show moreQuantum annealing belongs to a family of quantum optimization algorithms designed to solve combinatorial optimization problems using programmable quantum hardware. In this thesis, various methods are developed and tested to understand how to formulate combinatorial optimization problems for quantum annealing. Use of both purely quantum approaches as well as hybrid quantum-classical algorithms are investigated using state-of-the-art quantum hardware. How the developed methods affect the performance of quantum hardware in practice is tested using both real-world and canonical academic problems. Show less
Despite being the object of intense study, embryonic development has been difficult to model due to a number of reasons. First, complex tissues can be comprised of many cell types, of which we... Show moreDespite being the object of intense study, embryonic development has been difficult to model due to a number of reasons. First, complex tissues can be comprised of many cell types, of which we probably only know a subset. Therefore, we first focused on the discovery of cell types by single-cell RNA-sequencing (scRNA-seq). Cell types are routinely identified by clustering scRNA-seq data, however, there was no principled way to determine the right number of clusters. To improve cell type classification, we developed phiclust, a clusterability measure for scRNA-seq. Another challenge in a developing tissue is that many signaling processes and morphogenic events occur simultaneously, which makes it hard to isolate the individual contributions. For this purpose, I looked at stem cell derived in vitro systems, in which a small number of specific cell types can be combined deliberately and studied in isolation. My analysis of different model systems shows that cellular communication causes structural and transcriptional changes in the developing cells. Finally, while tissue organization has been characterized extensively, we lack generative models that can relate specific patterns to the underlying gene regulatory mechanisms. Therefore, I later focused on deep learning-based approaches to infer gene regulatory networks from observed spatial patterns. Show less
In response to the shortage of nursing staff and the so-called refugee crisis in 2015, two residential homes invited first-generation immigrants with a refugee background to participate in a... Show moreIn response to the shortage of nursing staff and the so-called refugee crisis in 2015, two residential homes invited first-generation immigrants with a refugee background to participate in a project for nursing education, orientation and internships. Between 2015 and 2018, a group of ten immigrants started working in a Dutch residential home and a group of seventeen immigrants in the German home. This dissertation investigates the social processes when these newcomers start working with the established staff, as well as the extent to which their mutual interactions and values of good care influence the enactment of geriatric care. Using ethnographic observations (305 hours), in-depth interviews (44) and six focus groups (24), the established care workers and immigrants were followed in both homes. The empirical data shows that institutional constraints, such as staff shortage, the imposition of professional norms, gossip used as a ‘weapon of the weak’, mutual suspicions of indifference, and collective images of ‘us’ versus ‘them’ affected the enactment of geriatric care. Their habitus stimulated them to tinker among each other as well as with different, sometimes conflicting, values of good care. However, both groups shared the feeling of ignorance by management, a pain of not mattering. Show less
Acute cardiovascular clinical events such as myocardial infarction and cerebral stroke represent the major cause of death in Western societies. These pathologies are primarily resulting from... Show moreAcute cardiovascular clinical events such as myocardial infarction and cerebral stroke represent the major cause of death in Western societies. These pathologies are primarily resulting from atherosclerosis, a progressive condition characterized by the accumulation of lipids, immune cells, and fibrous elements in large arteries. The pathogenesis of atherosclerosis involves complex interactions between a wide variety of cells, including monocytes, macrophages, neutrophils, and lymphocytes. It is essential to identify novel targets for therapeutic application in order to reduce the residual atherosclerotic cardiovascular disease risk in current and future patients. Recent studies have suggested that members of the protein arginine methyltransferase (PRMT) family can potentially serve as novel therapeutic targets for atherosclerosis because of their regulatory role in inflammation and metabolism. To validate the contribution of PRMTs in the progression of atherosclerosis, in the studies presented in this thesis we have investigated the effect of inhibition of PRMT functionality on atherosclerosis susceptibility in established atherosclerotic mouse models.To address the role of PRMTs in atherosclerosis, we therefore made use of specific PRMT inhibitors, i.e. TC-E 5003 for PRMT1 inhibition, TP-064 for PRMT4 inhibition, and GSK3326595 for PRMT5 inhibition, that thus far have primarily been applied in vivo in the context of cancer treatment. Show less
This thesis is the result of several studies into the clinical and echocardiographic outcome of both open and hybrid surgical ventricular reconstruction for the treatment of ischemic cardiomyopathy... Show moreThis thesis is the result of several studies into the clinical and echocardiographic outcome of both open and hybrid surgical ventricular reconstruction for the treatment of ischemic cardiomyopathy. Additionally, predictors for a favorable outcome and important associated issues such as management and late outcome of functional mitral regurgitation and the use of LV ejection fraction as a selection criterium for indication for a implantable cardioverter defibrillator for the primary prevention ofventricular arrhythmias after surgical ventricular reconstruction were studied. In chapter 2 the early and late outcome of different types of open left ventricular reconstruction surgery by means of a meta-analysis are presented. Chapter 3 describesthe use of echocardiographic wall motion score index to predict mortality and functional results after surgical ventricular reconstruction for advanced ischemic heart failure. In chapter 4 the management of functional mitral regurgitation during left ventricular reconstruction is presented followed by a landmark analysis into the 10-year outcome of functional mitral regurgitation after left ventricular reconstruction. Chapter 5 discusses the use of the improved LV ejection fraction after SVR as an indication for a implantable cardioverter defibrillator for the primary prevention of ventricular arrhythmias after surgical ventricular reconstruction in heart failure patients. Chapter 6 discusses the early experience with a minimal-invasive hybrid transcatheter surgical ventricular reconstruction technique. First the technique of hybrid transcatheter left ventricular reconstruction is described. Followed by the preliminary results of this technique from 2 cardiac centres in the Netherland. Finally, the multicenter European results of hybrid less invasive reconstruction on clinical, functional and echocardiographic outcome are presented. Show less
Drug induced organ toxicity is the main problem of the drug development and drug usage in the clinic. The liver and kidneys are the most sensitive organs towards drug induced toxicity. The liver... Show moreDrug induced organ toxicity is the main problem of the drug development and drug usage in the clinic. The liver and kidneys are the most sensitive organs towards drug induced toxicity. The liver neutralizes xenobiotic to which human are exposed to while the kidneys remove waste products from the blood. Due to their detoxification function, these organs are continuously exposed to high amount of toxicants leading to potential injury. Investigating the molecular and cellular mechanisms contributing to drug-induced liver injury (DILI) and drug-induced kidney injury (DIKI) will open new avenues that can help in the prediction of induced organ injury caused by drugs as well as other xenobiotics.In this thesis, we mapped the dynamics of cellular stress responses in the liver and kidneys upon the exposure of a set of model compounds in order to gain a more holistic insight in DILI and DIKI. We conducted multiple extensive in vitro and in vivo studies to understand the dynamics of these cellular responses and determined the translation of our findings from in vitro to in vivo. Transcriptomics analysis was central in the research which was complemented with other methodologies, such as reporter cell assay, immunohistochemistry, to unravel the mechanisms of drug-induced organ toxicity in both liver and kidney. Show less
This dissertation takes a technological approach to ceramic production and provides a fine-grained view of the circum-Caribbean region. It discusses the usefulness of the chaîne opératoire... Show moreThis dissertation takes a technological approach to ceramic production and provides a fine-grained view of the circum-Caribbean region. It discusses the usefulness of the chaîne opératoire methodology, together with the community of practice theory, as models to potentially explore questions related to the boundedness and cultural relations of peoples during the precolonial, colonial and postcolonial periods. Each chapter tackles diverse aspects of the manufacturing process, from the procurement of the raw materials to the forming stage and provide different cases of how methodologies need to be tailored to answer specific research questions. Geochemical and petrographic analysis combined with macro and micro-observations of the ceramic materials from different sites in Nicaragua, Haiti, Dominican Republic and Puerto Rico clarify the human-environment interactions and socio-cultural aspects of communities in precolonial times, and during the colonial and postcolonial periods. Show less
Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic repression of the D4Z4 repeat resulting in misexpression of the repeat-encoded DUX4 gene in skeletal muscle. Two... Show moreFacioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic repression of the D4Z4 repeat resulting in misexpression of the repeat-encoded DUX4 gene in skeletal muscle. Two mechanisms are known to drive this D4Z4 epigenetic dysregulation: a contraction of the D4Z4 repeat or mutations in DNMT3B or SMCHD1, both epigenetic regulators of the repeat that are responsible for the establishment or maintenance of the repeat’s epigenetic repressive state in somatic cells. However, the aforementioned (epi)genetic changes lead to FSHD only if the individual also has a disease-permissive D4Z4 allele which allows for stable DUX4 expression in skeletal muscle. This disease permissivity of D4Z4 alleles has been attributed to the presence of a DUX4 polyadenylation signal adjacent to the D4Z4 repeat which is used for transcription termination. Despite knowing the root cause of FSHD, to date, there is no curative therapy available for FSHD and in some cases, the genetic etiology of the disease remains unknown. In this thesis, we identified a new FSHD disease gene called LRIF1 and performed its follow-up functional studies in human somatic cells and mouse embryonic stem cells. In addition, we also pursued a new targeted gene therapy for FSHD by employing CRISPR-based mutagenesis of the DUX4 polyadenylation signal. Show less
The learning of software design is known to be a difficult and challenging task for students. This dissertation studies different didactic approaches for learning software design to improve the way... Show moreThe learning of software design is known to be a difficult and challenging task for students. This dissertation studies different didactic approaches for learning software design to improve the way we teach students software design. The research in the dissertation questions whether we can assess software design skills, what guidance is needed for the improvement of students’ understanding of software design and how to motivate and engage students for learning software design. The research explores the following: an instrument for measuring software design skills based on design principles, the gamification of learning software design, revealing students’ software design strategies, the use of peer-reflection for uncovering the difficulties students have during software design tasks, the use of teaching assistants as bridge between the lecturer and the students, the automation of grading software designs with machine learning, guiding feedback by a pedagogical agent and a workshop for engaging students into the process of software development. The research contributes to the future education of software design. Show less
This thesis examines the normative dimensions of the acts that constitute international crimes. It offers a conceptualisation of the normative dimensions of these acts as processes of construction... Show moreThis thesis examines the normative dimensions of the acts that constitute international crimes. It offers a conceptualisation of the normative dimensions of these acts as processes of construction and meaning making. Using the crimes of attacks on cultural property, pillage, sexual violence and reproductive violence as case studies for analysis, the thesis develops an interdisciplinary methodological approach which centralises the narratives and discourses that emerge around particular crimes as central to how they are given normative content in practice. This analysis reveals a diverse, flexible and dynamic normative picture of these crimes, which demonstrates how their normative meanings are not natural or given, but are instead produced through an ongoing process of meaning making that takes place throughout the legal process in a continuum of cases. Understanding the normative dimensions of the acts that constitute international crimes in these terms not only exposes a diversity of interests that transcends their dominant characterisations as violations of basic security rights, but also uncovers the processes through which their normative foundations are constructed and transformed internally through practice. This thesis ultimately offers a dynamic, pluralist and socially constructed account of wrong in international criminal law, which recognises the relationship between criminal wrong and transformations in the wider social and political order, and contributes to developing a more granular understanding of the nature of the representational work that international criminal justice does in the world. Show less
Dark matter is one of the biggest mysteries of the Universe. Its properties cannot be explained with the known laws of physics and elementary particles. Yet, it is the most abundant form of matter... Show moreDark matter is one of the biggest mysteries of the Universe. Its properties cannot be explained with the known laws of physics and elementary particles. Yet, it is the most abundant form of matter in the Universe.Several dark-matter theories exist, including cold dark matter (CDM), self-interacting dark matter (SIDM), and fuzzy dark matter (FDM). These theories make different predictions for the density profiles of dark-matter haloes (cuspy or cored), depending on the nature (CDM, SIDM, FDM) and properties (self-interaction strength, FDM particle mass) of dark matter. These profiles can be determined from the stellar kinematics of the galaxies hosted by the haloes. Many massive dwarf galaxies show cored profiles. However, baryonic processes such as star formation may also induce cores.In this thesis, I test CDM, SIDM, and FDM using the faintest and most dark matter–dominated galaxies, ultra-faint dwarf galaxies (UFDs), which offer a new perspective on the cusp–core problem. The stellar kinematics of UFDs should not be significantly affected by baryonic processes. I find that UFDs have no detectable cores, implying that the cores of more massive dwarf galaxies are not caused by dark-matter physics. I can also exclude the previously promising particle masses ~10^-22 eV/c^2 for FDM. Show less
Antimicrobial drugs constitute a fundamental part of modern medicine. The global rise in antimicrobial resistance poses a major threat to global health. Optimising antimicrobial treatment... Show moreAntimicrobial drugs constitute a fundamental part of modern medicine. The global rise in antimicrobial resistance poses a major threat to global health. Optimising antimicrobial treatment strategies in patients offers an important direction to address this challenge. In this thesis, we describe how quantitative characterisation of the drug, the pathogen, and the patients, and how these three factors interact, can help to achieve this goal. To this end, we used a combination of state-of-the-art in silico model-based approaches to analyse and integrate experimental data from in vitro models, and clinical data from healthy volunteers and patients. We developed models describing infection site drug exposure, antimicrobial resistance evolution, and host response biomarker dynamics. We explored the impact of infection on pulmonary pharmacokinetics, evolutionary-based treatment strategies, and the utility host response biomarker for treatment monitoring. The work in this thesis builds towards developing novel strategies to optimise antimicrobial treatments and showcases the importance on interdisciplinary collaborations. Show less
