Prenatal detection of congenital heart defects has been known to decrease mortality and morbidity in children born with such defects. This thesis describes the increase of prenatal detection of two... Show morePrenatal detection of congenital heart defects has been known to decrease mortality and morbidity in children born with such defects. This thesis describes the increase of prenatal detection of two outflow-tract anomalies, by adding an additional mandatory plane to the national screening program. The second part of this thesis, studies the development of the fetal brain in children affected by congenital heart defects. These children are known to have worse neurodevelopmental outcome than their healthy counterparts. There is some evidence describing a prenatal origin of the delay in neurodevelopment. In the studies that were described in part two of this thesis, we have used a deep-learning algorithm that can assess the maturation (or development) of the fetal brain. We have found small delays in brain maturation as compared to healthy control fetuses. The clinical significance of these outcomes however, remains unclear. A multifactorial cause of brain damage in children with CHD is much more likely. Whatever the exact cause of the long-term neurodevelopmental delay in children with congenital heart defects is, the correlation is undeniable. And thus, expecting parents must be informed of this matter. Show less
For each living organism health is ensured by correct functioning of its cells. Cells therefore have elaborate methods for regulation of their proteins. In this thesis we examine a set of highly... Show moreFor each living organism health is ensured by correct functioning of its cells. Cells therefore have elaborate methods for regulation of their proteins. In this thesis we examine a set of highly conserved proteins: microtubules (MTs), which are either in a growing or a shrinking phase, together with the MTs' end-binding proteins mal3, tea2 and tip1. Using total internal reflection fluorescence microscopy we grow these proteins in custom-made, patterned flow chambers. We also examine the influence of force on MTs by letting them grow against obstacles, using the same microscopy technique or optical tweezers.Focusing on the switch from a growing to a shrinking state, a so-called catastrophe, we investigate the trigger of a catastrophe. For this we create distributions of the length of MT growth phases and fit them with several functions. All of the functions describe reactions involving several steps. We find that MTs need two steps until a catastrophe, a process which is sped up by the end-binding proteins as well as by force. Besides, we also present another model for MT catastrophe in which noisy growth together with a specific state of the microtubule tip are capable to explain a lot of the published MT data. Show less
This dissertation is about intra-EU workers and labour law related (bogus) constructions under which they work in the Netherlands and other EU member states.Through the following two main research... Show moreThis dissertation is about intra-EU workers and labour law related (bogus) constructions under which they work in the Netherlands and other EU member states.Through the following two main research questions this situation is outlined and analysed.1. To what extent do intra-EU workers in the Netherlands work under labour law related (bogus) constructions that (financially) disadvantage them?2. What are the perceptions of intra-EU workers regarding the use of labour law related (bogus) constructions and their working conditions and circumstances under which they work in the Netherlands and other EU member states?In each chapter of this thesis, these questions are elaborated into more specific research questions.In this research both legal and empirical research that fits within the Empirical Legal Studies (ELS) framework is conducted. Through this combination of research methods it was viable to link the collected empirical (interview) data to the legal data based on literature and case law research. Hence, the theory (law in books) was tested against facts and observations (law in action). Moreover, by establishing this link the present research adds a new and valuable dimension to current academic legal and social scientific research. Show less
The aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of... Show moreThe aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of vulvar and HPV-driven diseases.Firstly, this thesis focuses on the recognition and validation of imaging-based biomarkers for recognition of diseases of the skin and external genitalia. Clinical studies were performed using 3D photography, dermatoscopy optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) on vulvar HSIL, lichen sclerosus, cutaneous warts and anogenital warts. These techniques were subsequently implemented in a clinical trial in which a novel small molecule was tested for safety and exploratory efficacy for the treatment of cutaneous warts.Furthermore, this thesis explores sequencing-based biomarkers for vulvar disease, facilitating insight into the aetiology of vulvar diseases and identifying potential new therapeutic targets. The currently available literature on the vulvar microbiome composition was investigated and expanded in an observational study characterising the vulvar microbiome composition of healthy volunteers, vulvar HSIL patients and lichen sclerosus patients. Lastly, a perspective on recent developments in the field of premalignant vulvar disease is provided, with recommendations for future applications of the biomarkers studied in this thesis. Show less
While immune checkpoint blockade (ICB) (CTLA4/ PD1) therapy has resulted in durable responses in patients with advanced stage cutaneous melanoma, some patients do not benefit from this, due to... Show moreWhile immune checkpoint blockade (ICB) (CTLA4/ PD1) therapy has resulted in durable responses in patients with advanced stage cutaneous melanoma, some patients do not benefit from this, due to resistance mechanisms. This thesis aims to improve response of a subset of melanoma patients to immunotherapy. Firstly, mouse melanoma tumor models are developed that closely resemble some of the resistance mechanisms occurring in patient tumors, which are useful for research. Thereafter, a prognostic biomarker is used to identify the subset of melanoma patients that are unlikely to benefit from ICB therapy. It is then evaluated whether this subset of patients would benefit from combining histone deacetylase inhibitor with ICB. Despite encouraging pre-clinical results showing enhanced anti-tumor immune responses using this combination, this did not result in improved responses in the clinic. Furthermore, this thesis focuses on an immune cell subset, namely regulatory T cells (Tregs), which are known to suppress anti-tumor immune responses. Thus, their presence in the tumor microenvironment (TME) is detrimental to tumor cell killing. This thesis provides an increased understanding of the metabolic adaptation of Tregs to conditions in the TME and propose that targeting these adaptations might overcome the suppression by Tregs and enhance responses to immunotherapy. Show less
There is a need for alternative methods to replace, reduce and refine (3R) animal experimentation. Combining experimental data from high-throughput in vitro studies with in silico modeling is a... Show moreThere is a need for alternative methods to replace, reduce and refine (3R) animal experimentation. Combining experimental data from high-throughput in vitro studies with in silico modeling is a promising approach to unravel the effect of chemicals on living cells and to gain a better understanding of the processes leading to adverse effects. Exposure to chemicals can activate various stress response pathways that limit the amount of cellular damage, help cells to recover or orchestrate irreversible cell fates such as apoptosis. In this thesis, we use experimental data and current knowledge on stress pathway activation and cell fate to create different types of computational models. With these models, we mathematically describe intracellular protein signaling cascades activated upon exposure to various compounds and their link to cell fate. In this way, we integrate molecular-level biological processes to cell-level phenomena such as cell cycle progression, senescence and necrosis, and generate new hypotheses about the mechanisms underlying adversity. Show less
The radio sky harbours both galactic and extragalactic sources of arcminute- to degree-scale emission of various physical origins. To discover extragalactic diffuse emission in the Cosmic Web... Show moreThe radio sky harbours both galactic and extragalactic sources of arcminute- to degree-scale emission of various physical origins. To discover extragalactic diffuse emission in the Cosmic Web beyond galaxy clusters, one must image low–surface brightness structures amidst a sea of brighter compact fore- and background sources. Angularly separating the faint from the bright radio sky requires high-quality ionospheric calibration. This thesis introduces new advances in and investigations into ionospheric calibration, the degree-scale Milky Way foreground, and two sources of megaparsec-scale emission in cosmic filaments: giant galactic outflows and cosmological structure formation shocks. Giant galactic outflows (or ‘giant radio galaxies’) are generated by the jets of active supermassive black holes, and transport relativistic leptons, entrained atomic nuclei, heat, and magnetic fields from the centres of galaxies to their outskirts and beyond. These outflows embody the most energetic pathway by which galaxies respond to the Cosmic Web around them. Structure formation shocks around filaments are a generic, but still elusive, prediction of cosmological simulations and trace the gravitational flow of matter from proto-voids to filaments. Both phenomena inform on the strength, topology, and origin of magnetic fields in the Cosmic Web. Show less
Scholars have contended that the challenge for translators of poems lies in achieving equal fidelity between form and content. Most of the time, a decision must be made to prioritize either form or... Show moreScholars have contended that the challenge for translators of poems lies in achieving equal fidelity between form and content. Most of the time, a decision must be made to prioritize either form or content in the translation process. This research delves into the impact on readers when poems are translated, focusing exclusively on either form or content. It explores how the humor in children's poems, translated from English into Filipino, is preserved. Furthermore, it examines the influence of culture and gender on the appreciation of humor. Despite extensive studies on children's humor development, little is known about the interplay of culture and gender in children's responses to humor in translated literature. The poetry reading sessions conducted with children uncover interesting findings about preferred language for reading and humor perception, as well mode of input and perceived humor in the text. The sessions also provide insights into children's perspectives on children's literature and the role of discussion and comprehensibility on humor response. Other aspects that the study explores are the definition of children's literature and its link to the concept of childhood, current trends in translated literature in the Philippines, theories of humor, and humor within the realm of children's literature. Show less
The different kinds of cultural perspectives on health and disease of the participants are related to their knowledge, beliefs, values and practices manifested in various forms of lifestyle in... Show moreThe different kinds of cultural perspectives on health and disease of the participants are related to their knowledge, beliefs, values and practices manifested in various forms of lifestyle in Indonesia. The cultural diversity of the population is also related to differences in health behaviour. Nursing as a profession has to be able to encourage clients and patients, particularly with Cardiovascular Diseases (CVD) to obtain holistic nursing in an effort to meet all client needs, regardless of their ethno-cultural background and their diverse beliefs and values about health and healing. Every effort to improve cultural competency among nursing practitioners who fully work with diverse patients from the numerous ethno-cultural groups in Indonesia is a challenge. One important step which can be taken is to learn and understand the Sundanese people as the dominant cultural group in West Java. The situation certainly requires a deepening of understanding of social behaviour and public health in terms of how to use traditional institutions such as kearifan kesehatan lokal, as well as indigenous knowledge of jamu and ubar kampung in dealing with health care of the elderly with CVD. Show less
CrO2, a half-metal ferromagnet, has shown great promise for superconducting spintronics applications for nearly two decades. Josephson junctions consisting of superconducting (S) contacts on... Show moreCrO2, a half-metal ferromagnet, has shown great promise for superconducting spintronics applications for nearly two decades. Josephson junctions consisting of superconducting (S) contacts on ferromagnetic (F) structures of CrO2, have been shown to sustain remarkably high supercurrents over hundreds of nanometers. However, advancements in this area have been hindered by the metastable nature of CrO2 at ambient conditions. This results in a poorly controlled S-F interface transparency, which is critical for generation of spin triplets. This thesis explores the potential, challenges and possible solutions to overcome the issues with CrO2 devices. Show less
In a typical glycosylation reaction, a donor is activated to form a (variety of) electrophilic species which can react with a nucleophilic acceptor, following a reaction mechanism having both SN1... Show moreIn a typical glycosylation reaction, a donor is activated to form a (variety of) electrophilic species which can react with a nucleophilic acceptor, following a reaction mechanism having both SN1 and SN2 character. On the SN1-side of the spectrum oxocarbenium ions partake in the mechanism while covalent intermediates act as the product forming intermediates on the SN2-side. The result of a glycosylation reaction is influenced by the properties of both donor and acceptor and can be affected by external factors as well. Because the challenges in carbohydrate synthesis are typically solved for a specific synthetic problem, a general understanding of what effect changing a single variable has on the mechanistic pathway, and thus the (stereochemical) outcome is not available. This in turn means that synthesis of glycosidic bonds typically requires a considerable amount of optimisation at the expense of a significant amount of time and resources. The goal of this thesis is to systematically investigate how changes in stereochemistry and protecting group patterns on the donor and acceptor affect the mechanism and outcome of glycosylation reactions, to enable a more rational design of synthesis routes. Show less
This thesis is divided into three parts. The first part of this thesis describes the epidemiology of infections with Clostridioides difficile, meticillin-resistant Staphylococcus aureus and... Show moreThis thesis is divided into three parts. The first part of this thesis describes the epidemiology of infections with Clostridioides difficile, meticillin-resistant Staphylococcus aureus and colistin-resistant Enterobacterales. An important treatment strategy for recurrent C. difficile infections is restoring the disturbed gut microbiota by faecal microbiota transplantation (FMT). The second part discusses the risk of transmission of pathogenic and/or multidrug-resistant bacteria via FMT and procedures to prevent this. Apart from recurrent C. difficile infections, several new potential indications of FMT are being explored. In the third part of this thesis, FMT is explored as a potential new treatment strategy for several neurological disorders, with a main focus on Parkinson’s disease. Show less
To generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims... Show moreTo generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims to contribute to the knowledge on SUMO regulated oncogenesis, understanding the consequences of abolishment of SUMO signaling and exploiting the potential of SUMO E1 inhibitors. To this end, we describe SUMO as a potential biomarker for cancer aggressiveness and increase our understanding on SUMO’s role in cell cycle progression. We exploited the potential of SUMO E1 inhibition by combining with hypomethylating compound 5-Aza-2’ deoxycytidine, leading to increased cytostatic efficacy. Furthermore, we repurposed the SUMO E1 inhibitor TAK981 and hypomethylating drug 5-Aza-2’ deoxycytidine to improve engineered TCR (eTCR) T cell therapy and broaden our understanding of its immunomodulatory potential. Show less
This thesis discusses several questions regarding the double ramification cycle as a Chow class on the moduli space of stable n-pointed genus g curves using tools from so-called logarithmic... Show moreThis thesis discusses several questions regarding the double ramification cycle as a Chow class on the moduli space of stable n-pointed genus g curves using tools from so-called logarithmic geometry. It contains two extracts from articles; the first of these defines the universal double ramification cycle on the Picard stack of n-pointed genus g curves with a line bundle of fixed degree, which is a way to also include the generalisations that are called twisted double ramification cycles. The second article introduces the logarithmic double ramification cycle in the logarithmic Chow ring. The logarithmic double ramification cycle is proven to be ‘logarithmically tautological’ and it helps us prove that the double-double ramification cycle (or the good definition for ‘intersecting double ramification cycles’) is tautological – that is, these classes lie in a subring generated by ‘computable and known’ classes. The second chapter of the thesis explains and illustrates piecewise-polynomial functions, which are key to describing the forementioned ‘logarithmically tautological’, and how these functions relate to classical divisors which we use to describe tautological rings. Show less
What we collectively call “stress” is how we experience our body’s reaction to a stressor. This response is aimed to deal with the current stressor and to prepare for recurrences in the future. The... Show moreWhat we collectively call “stress” is how we experience our body’s reaction to a stressor. This response is aimed to deal with the current stressor and to prepare for recurrences in the future. The stress response is for an important part dependent on glucocorticoid hormones. By and large, the acute response to glucocorticoids is beneficial, but chronic exposure often becomes maladaptive. To improve prevention and treatment of disorders we can develop due to stress, it is important to better understand the effects and working mechanisms of glucocorticoids. While we already possess extensive knowledge regarding glucocorticoids and glucocorticoid receptor signaling, we introduced and studied five “aspects of context”, which we felt address important current misconceptions or gaps of knowledge. Corticosterone was at the center of all the studies we performed, yet the eventual outcome of glucocorticoid receptor activation differed extensively in all experiments. Thus, the context in which corticosterone exerts its effects matters, and it is to researcher to be aware of this when designing new studies and interpreting available data. Whilst our research merely addressed some specific processes, the lessons learned from these experiments can be applied much broader to the biology of glucocorticoid signaling and other nuclear family members. Show less
Atherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as non-alcoholic fatty liver disease) are a result of lipid... Show moreAtherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction-associated steatotic liver disease (MASLD; previously known as non-alcoholic fatty liver disease) are a result of lipid accumulation in the vascular wall and liver, respectively. In the body, lipids are transported between organs within lipoproteins, and thus disordered lipoprotein metabolism is closely associated with ASCVD and MASLD development. Active brown adipose tissue (BAT) combusts lipids to produce heat, and BAT activation is therefore considered a potential strategy to improve lipoprotein metabolism. In this thesis, I describe a new method of monitoring lipoprotein metabolism and BAT activity by PET-CT scan. To this end, a newly developed 18F-labeled lipid tracer was incorporated in optimized lipoprotein-like particles, and appeared to outperform 18F-deoxyglucose in tracing activated BAT. The results presented in this thesis also further confirm the usefulness of the APOE*3-Leiden.CETP mouse model for studying therapeutic interventions to improve lipoprotein metabolism. Using this translational model, I demonstrated that exercise at the end of the active phase and combined glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide receptor agonism, a strategy for treating diabetes and obesity in the clinic, are promising ways to combat both ASCVD and MASLD. Show less
Within the field of astronomy, understanding how galaxies grow and evolve from the Big Bang to the present day is a challenging and complex question. Radio observations - unhindered by dust... Show moreWithin the field of astronomy, understanding how galaxies grow and evolve from the Big Bang to the present day is a challenging and complex question. Radio observations - unhindered by dust attenuation - are a powerful tool in studying the formation of stars and subsequent buildup of galaxies. In this thesis, the distant star formation is studied using radio observations from the VLA COSMOS-XS survey specifically. In Chapter 2, we discuss the details of the sensitive COSMOS-XS survey and present the derived Euclidean-normalized source counts. In Chapter 3, we derive the dust-unbiased star formation rate density out to high redshift and present evidence for a significant underestimation of the star formation rate density based on ultraviolet observations. In Chapter 4, the focus shifts to the ‘optically dark’ population: extremely dust-obscured sources that are invisible even in deep ultraviolet imaging. We identify these sources with the COSMOS-XS survey and use them to quantify their contribution to the total star formation rate density. In Chapter 5, we present new ALMA observations of ‘optically dark’ sources and confirm the cosmic importance of ‘optically dark’ sources at high redshift. Show less
Aspects which advocate the synergy between dance medicine and dance pedagogy with the aim to prevent musculoskeletal injuries in classical ballet and contemporary dancers were investigated.... Show moreAspects which advocate the synergy between dance medicine and dance pedagogy with the aim to prevent musculoskeletal injuries in classical ballet and contemporary dancers were investigated. Specifically, aspects which have not yet been studied before, such as neuromuscular warm-up in dance, motivational climate, or injuries as stressors and their association with physical (repetitive) injury, respectively, in order to provide the basis for future research. Also, the effects of erroneous dance technique were evaluated, while a dual-approach looked into the causes which dancers perceived for their acute and overuse injuries as well as how they rated their ballet masters’ or ballet teachers’ proactive efforts to implement dance medicine into dance practice with the goal of identifying and preventing musculoskeletal injuries in their dancers. An extensive and international survey study provided retrospective data and longitudinal prospective data was collected over 6 years in a university training professional contemporary dancers. Show less
The aim of this research was to develop an effective, generative, and practical approach to enhance students’ structure-property reasoning (SPR). The approach consists of an evaluation instrument... Show moreThe aim of this research was to develop an effective, generative, and practical approach to enhance students’ structure-property reasoning (SPR). The approach consists of an evaluation instrument that assesses the level of structure-property reasoning and a teaching practice to make structure-property reasoning more explicit for students.As base of the approach, the perspective for SPR was used as model for structure-property reasoning. With this model, we aimed to represent the relationship between chemical concepts and the skill of structure-property reasoning.The SPR-instrument combines a sorting task with a mapping task based on the perspective for SPR. The instrument was tested on secondary school students and first-year chemistry students. The results showed that the SPR-instrument can discriminate between these two groups.This teaching practice consists of demonstration experiments with two design principles, namely the Predict-Observe-Explain (POE) approach and the perspective for SPR. The teaching practice was tested on Y-4 pre-university students. The results showed that the teaching practice contributed to the development of structure-property reasoning. The practicality of (re)designed demonstrations appeared to be as high as that of "traditional" demonstrations.The research showed that perspective for SPR (combined or not with POE-demonstrations) could bridge the gap in students’ chemical reasoning. Show less
