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
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
Malaria continues to wreak havoc in tropical regions, due largely to the lack of an effective vaccine. Vaccine candidates based on whole parasites have shown promising results in malaria-naïve... Show moreMalaria continues to wreak havoc in tropical regions, due largely to the lack of an effective vaccine. Vaccine candidates based on whole parasites have shown promising results in malaria-naïve individuals, but their potency in malaria-exposed individuals is considerably lower. This dissertation described the development of a chemical strategy for boosting such parasites’ potency in pursuit of more efficacious malaria vaccines for use in endemic areas.Chapter 2 outlined the adaptation of a method for chemically modifying microbial cell surfaces.Chapter 3 showed the chemistry underlying this modification system to be stably compatible with in vivo usage.Chapter 4 demonstrated that when the chemical modification system was used to introduce immune-potentiating agents onto bacteria, better immune responses ensued.Chapter 5 tied it all together by using the chemical modification system to potentiate malaria parasites, and showed that doing so markedly improved immune responses in an in vivo immunization model.Chapter 6 summarized these findings in the context of malaria vaccine development and posited next steps forward. Show less
In this dissertation we investigate the emotional and psychiatric effects of glucocorticoids (e.g. cortisol, dexamethasone and prednisone). Glucocorticoids are widely used and their possible... Show moreIn this dissertation we investigate the emotional and psychiatric effects of glucocorticoids (e.g. cortisol, dexamethasone and prednisone). Glucocorticoids are widely used and their possible psychiatric side effects are well known. It is still unclear who is susceptible to side effects and what mechanism is behind this. In this thesis we try to better understand the underlying causes. For example, we use a relatively new static method in this research field, which can analyze changes over time better than the usual methods. In a study, we show that in depressed study participants, changes in certain affect items preceded changes in cortisol levels, while in control participants this was the other way around. Furthermore, we explore a hypothesis that may explain the mechanism of the psychiatric side effects of glucocorticoids. This mechanism is also used for a strategy to prevent the psychiatric side effects. The strategy is based on the fact that synthetic glucocorticoids are very similar to the body's own hormone cortisol, but their binding to the two cortisol receptor proteins and their effects may be different. By achieving a balanced activation of the two cortisol proteins when using glucocorticoids, the psychiatric side effects could possibly be prevented. In summary, this thesis provides further insight into the emotional and psychiatric side effects of glucocorticoids, but the search for a better understanding of the neuropsychiatric side effects remains a pressing concern, which will hopefully benefit patient care in the future. Show less
The lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main SC lipid classes are ceramides (CER), cholesterol and... Show moreThe lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main SC lipid classes are ceramides (CER), cholesterol and free fatty acids. In inflammatory skin diseases, such as atopic dermatitis and psoriasis, the SC lipid composition is altered compared to the healthy SC composition. The studies presented in this thesis focused on the effect of the CER subclass composition on the lipid organization, molecular arrangement and barrier function of the skin. First, the CER compositional changes were examined in the SC of seborrheic dermatitis patients, an inflammatory skin disease. A particular emphasis was paid to the ratio of two important CER subclasses, sphingosine CER (CER NS) and phytosphingosine CER (CER NP), and its correlation to the skin barrier. In the subsequent chapters lipid model systems with a simple CER subclass composition were used to study the influence of the CER NS: CER NP molar ratio on the barrier function and lipid organization. Show less
The dissertation investigates the role of lexical tone in spoken word recognition and production. In particular, it focuses on three groups of speakers: native speakers of Standard Chinese, bi... Show moreThe dissertation investigates the role of lexical tone in spoken word recognition and production. In particular, it focuses on three groups of speakers: native speakers of Standard Chinese, bi-dialectal speakers of Standard Chinese and Xi’an Mandarin, and bilingual speakers of Standard Chinese and English. Through a series of experiments employing the eye-tracking visual world paradigm and the picture-word interference paradigm, four key issues were explored: the role of lexical tone in Mandarin spoken word recognition; tonal interference in bi-dialectal spoken word recognition; the activation of lexical tone in bilingual spoken word production; and the influence of lexical tone on the bilingual mental lexicon. The findings of this dissertation not only showed how Mandarin listeners utilize tonal information during tone word recognition but also revealed dynamic tonal interaction between language systems. Overall, this dissertation contributes to a deeper understanding of lexical access by highlighting the significant role of lexical tone in both monolingual and bilingual contexts, shedding light on the intricate processes involved in spoken word recognition and production across languages. Show less
This thesis has studied several modalities how to increase the organ utilisation rate. The results in this thesis indicate that the acceptance of kidneys with acute kidney injury stage 1 or 2 will... Show moreThis thesis has studied several modalities how to increase the organ utilisation rate. The results in this thesis indicate that the acceptance of kidneys with acute kidney injury stage 1 or 2 will significantly contribute to the donor pool as AKI kidneys have comparable outcomes and should therefore not be discarded. Clinically relevant biomarkers such as cell-free unmethylated-INS DNA, FMN, GSN, IGFBP3 and IGF2R were identified or explored in the first part of this thesis and may, if analysed and/or validated thoroughly, contribute to a better assessment of organ viability supporting the justified decision whether to accept or decline the donor organ.The second part of this thesis describes different aspects of the organ preservation technique of abdominal normothermic regional perfusion (aNRP). This relatively new machine perfusion technique has been shown to be feasible and safe, however, consensus regarding assessment parameters during perfusion, protocols and outcome measurements is still lacking. Despite of an inspiring surgical enthusiasm and keeninterest to accept this modality as a new standard, a randomised clinical trial is still required and entirely ethically justifiable in order to scientifically demonstrate superiority of this method for each individual abdominal organ comparing it to other successful (ex-situ) preservation and perfusion strategies. If aNRP can be shown to obtain better post transplantation outcomes whilst increasing organ utilisation, it may be the least complex and most cost-effective strategy in organ preservation. On the other hand, aNRP will only be used in DCD donors. As such, uncertainty regarding the quality of higher risk organs from DBD donors will still be evaluated ex-situ during cold and/or warm machine perfusion with the potential to repair or even regenerate injured organs and making them ‘transplantable’ again. Show less
Emotions significantly influence our perceptions and interactions with the environment, yet the impact of our emotional states on judging and responding to others remains underexplored. In this... Show moreEmotions significantly influence our perceptions and interactions with the environment, yet the impact of our emotional states on judging and responding to others remains underexplored. In this thesis, I examined how (romantic) attraction influences our attention (Part I), how we judge others’ intentions (Part II), and whether mimicking another facilitates bond formation (Part III). In two empirical chapters, I demonstrate that people have a strong attentional bias towards visual attractiveness and a tendency to indicate interest in establishing a romantic connection to attractive others. In the subsequent empirical chapter, I show that men are more likely to judge women they find attractive as more sexually aroused. Crucially, in a real-life dating study, I show that men who are attracted to another are more likely to assume mutual interest. Further, I introduce a framework suggesting that people align their actions and emotional states with others to foster romantic relationships. The final empirical chapter suggests that mimicking the attraction cues of others enhances bond formation. Overall, this dissertation sheds light on how attractiveness and attraction affect our attention, our social cognition, and the synchronization of actions and emotions, offering insights into the mechanisms underlying romantic connections. Show less
In this thesis, I focused on studying the above- and belowground interactions of J. vulgaris from a plant-soil feedback (hereafter, PSF) perspective. I investigated the temporal variation of... Show moreIn this thesis, I focused on studying the above- and belowground interactions of J. vulgaris from a plant-soil feedback (hereafter, PSF) perspective. I investigated the temporal variation of negative PSF and examined the effects of root-associated bacteria on plant performance and aboveground herbivores. Additionally, I tested the role of PSF in relation to plant population structure and the significance of soil legacy effects in natural conditions. The findings reveal that temporal dynamics in PSF are driven by changes in plant sensitivity and in the soil microbiome. Although bacteria isolated from J. vulgaris roots can negatively affect plant performance, they can also affect aboveground herbivores and other plant species. Consequently, these bacteria may not be suitable for biological control of J. vulgaris. Moreover, I discovered that soil nematodes can mediate plant-plant interactions, but often favoring J. vulgaris. In my field work, I detected soil legacy effects, but seedling recruitment spatial patterns of J. vulgaris were not soil-mediated. The insights gained from studying PSF and above- and belowground interactions have the potential to reshape traditional approaches employed in controlling invasive plants. This thesis emphasizes the importance of transitioning PSF experiments from indoor to outdoor settings considering various influencing factors simultaneously. Show less
Cancer immunotherapies utilizing immune checkpoint blockade (ICB) therapy targeting CTLA-4 and PD-1/PD-L1 relieve tumor-induced immune suppression and induce durable tumor regression. The use of... Show moreCancer immunotherapies utilizing immune checkpoint blockade (ICB) therapy targeting CTLA-4 and PD-1/PD-L1 relieve tumor-induced immune suppression and induce durable tumor regression. The use of ICB therapy have demonstrated remarkable therapeutic efficacy in a proportion of patients with melanoma. However, still a substantial percentage of patients does not respond (durable) to ICB treatment and many questions remain. Therefore, in this thesis, the aim is to improve our understanding of ICB efficacy. We demonstrate the promise of neoadjuvant ICB therapy (approach in which ICB therapy is applied before surgery) and analyze different cohorts of melanoma patients. This results in the identification of several markers that are associated with prognosis, including IFN-y related gene signature score, Batf3 dendritic cell associated gene signature score, tumor mutational burden and systemic LRG1 expression. These markers can potentially be targeted and might facilitate rational combination therapies that can boost the efficacy of ICB therapy. For this purpose, we perform a repurposing compound screen that targets antigen cross-presentation. Togethers, this work increases our understanding of factors that determine ICB therapy efficacy and toxicity, with the goal to identify novel strategies to improve outcome of melanoma patients in a rationale and personal manner. Show less
In this thesis we examined patient readiness for shared decision making (SDM) about treatment. We first assessed associations between patient-related characteristics and the occurrence of SDM.... Show moreIn this thesis we examined patient readiness for shared decision making (SDM) about treatment. We first assessed associations between patient-related characteristics and the occurrence of SDM. Overall, we did not find consistent associations between characteristics such as age or education level, and the extent to which SDM occurred (measured from the perspective of patients, clinicians, or observers). Second, we assessed what patients need to be ready, i.e., enabled and well-equipped, to participate in SDM about treatment. We identified a wide range of skills, cognitions, and emotions. For instance, patients need to be able to understand the relevant information, be able to and dare to express themselves in consultations with clinicians, and experience an adequate amount of time to talk to clinicians and to consider the options. Finally, we developed a questionnaire, the ReadySDM. The aim of the ReadySDM is to retrospectively measure the extent to which patients felt ready for SDM during a treatment decision-making process. The questionnaire has the potential to identify novel insights into patients’ support needs and ways to enhance SDM in daily practice. Show less
This thesis focuses on data found in the field of computational drug discovery. New insight can be obtained by applying machine learning in various ways and in a variety of domains. Two studies... Show moreThis thesis focuses on data found in the field of computational drug discovery. New insight can be obtained by applying machine learning in various ways and in a variety of domains. Two studies delved into the application of proteochemometrics (PCM), a machine learning technique that can be used to find relations in protein-ligand bioactivity data and then predict using a virtual screen whether compounds that had never been tested on a particular protein, or set of proteins. With this, sets of compounds were suggested for experimental validation that were significant in a myriad of ways. Another study investigated the mutational patterns in cancer, applying a large dataset of mutation data and identifying several motifs in G protein-coupled receptors. The thesis also contains the work done on the Papyrus dataset, a large scale bioactivity dataset that focuses on standardising data for computational drug discovery and providing an out-of-the-box set that can be used in a variety of settings. Show less
The sequence-dependence of biomolecular interactions involving nucleic acids and proteins is essential for numerous processes inside the cell. Insights into the underlying molecular mechanisms have... Show moreThe sequence-dependence of biomolecular interactions involving nucleic acids and proteins is essential for numerous processes inside the cell. Insights into the underlying molecular mechanisms have been obtained using various biochemical and biophysical methods on two different levels — bulk and single-molecule. These have complemented each other as single-molecule studies excel in observing multi-state dynamic interactions, but perform only at low throughput; while bulk studies can probe many different sequences simultaneously, but providing limited kinetic information. To unite the strengths of both levels, we developed high-throughput Single-molecule Parallel Analysis for Rapid eXploration of Sequence space (SPARXS), that allows the study of molecular structure, kinetics and interactions for thousands of different sequences simultaneously at the single-molecule level. We, for the first time, combine single-molecule fluorescence with next-generation Illumina sequencing. As a proof of principle we apply SPARXS to study the sequence-dependent kinetics of the four-way DNA Holliday junction, occurring among others during homologous recombination. Using SPARXS we observe the dynamic behavior of 120,000 Holliday junction molecules covering 3750 distinct core sequences, a result unattainable with previous techniques. Overall, the mechanistic insights obtained using SPARXS will give an entirely new view on the relationship between sequence, structure and function. Show less
A strong correlation exists between abdominal aortopathy and atherosclerosis. In thoracic aortopathy however, the prevalence of atherosclerosis and its role in the etiology of thoracic aortopathy... Show moreA strong correlation exists between abdominal aortopathy and atherosclerosis. In thoracic aortopathy however, the prevalence of atherosclerosis and its role in the etiology of thoracic aortopathy remained unknown. This thesis therefore studied the cardiovascular disease burden within this patient group. These results showed that the prevalence of atherosclerosis (i.e. cardiovascular disease burden), in contrast to abdominal aortopathy, is not increased within the thoracic aortopathy population. Show less
In between 1968 and 1973, the Dutch Atlantic was home to four Black Power organizations: the Black Panthers of Curaçao (1968-1970), Antillean Black Power (1969-1970), the Dutch Black Panther... Show moreIn between 1968 and 1973, the Dutch Atlantic was home to four Black Power organizations: the Black Panthers of Curaçao (1968-1970), Antillean Black Power (1969-1970), the Dutch Black Panther Solidarity Committee (1969-1970), and Black Power Suriname / Afro-Sranan (1970-1973). This dissertation asks why and how these organizations aligned with the transnational movement. Based on archival research conducted in Curaçao, Suriname, the United States, and the Netherlands, it argues that they did so because Black Power offered them an alternative path to decolonization. Instead of striving for equal participation in the Kingdom of the Netherlands, as colonial reformists did, or promoting self-reliance, as nationalists did, Black Power activists believed the best way to free themselves from the legacies and realities of colonialism was to join the movement's global network of Black solidarity, cooperation, and unity. Show less
Online behavioral advertising (OBA) is a form of advertising that relies on data about users’ behavior (e.g., clicks, likes, voice commands) and uses artificial intelligence (AI) to place ads that... Show moreOnline behavioral advertising (OBA) is a form of advertising that relies on data about users’ behavior (e.g., clicks, likes, voice commands) and uses artificial intelligence (AI) to place ads that users may be interested in. Ads that AI chooses to display often leave users in awe and concern them about the potential of total surveillance. People using these services have (legitimate) expectations that tech companies or democratic institutions protect their interests. Indeed, the European Union (EU) heavily regulates OBA, requiring, for example, that companies have users’ consent before their surveillance. Yet, these ads monetize most “free” online services and turn companies like Alphabet and Meta into the world’s wealthiest. Therefore, the industry is incentivized to acquire consumers’ consent by any means necessary, often through manipulation. As almost everyone has encountered manipulative “cookie banners” online, many have started to doubt if EU law can effectively protect consumers from the growing power of the tech industry. This thesis builds a framework of manipulation, describes consumer manipulation via OBA, constructs a theory of the harms of this phenomenon, and analyses its boundaries in the EU legal framework. The thesis concludes that the EU framework can effectively safeguard consumers, anticipating that the enforcement of the Digital Services Act (DSA) and the Digital Markets Act (DMA) will put an end to consumer manipulation (and exploitation) via OBA. Show less
This thesis explores North Korea’s influential role in the liberation of Southern Africa. Specifically, it examines the question of how political elites in Southern Africa benefitted from North... Show moreThis thesis explores North Korea’s influential role in the liberation of Southern Africa. Specifically, it examines the question of how political elites in Southern Africa benefitted from North Korean support, from 1960 until 2020. The main argument of this book is that liberation (and not the Cold War) is the leitmotif for African–North Korean relations, as the transition from anticolonial struggles to postcolonial politics is characterised by continuity not change. This approach is based on three assumptions. First, political culture in Southern Africa transcends national boundaries, which is a legacy of the exile dimension of the struggle for liberation. Second, scholarship must shift its lens from states to regimes. Third, the standard periodisation of African history and the Cold War distorts a proper understanding of African–North Korean interactions. Show less
Security is something that people tend to care about. But is it also something that they should care about? To explore this question, this dissertation first develops a new conceptual framework of... Show moreSecurity is something that people tend to care about. But is it also something that they should care about? To explore this question, this dissertation first develops a new conceptual framework of security. Next, it analyses how security relates to some key values for liberal democratic societies. The first of these is well-being. It is argued that there are important ways in which security can contribute to somebody’s well-being – but there are also ways in which security may hamper a person’s flourishing. The second value is freedom. It is shown that in public decision-making freedom and security may come at each other’s cost – yet there are also ways in which the two can work to each other’s benefit. The third value is equality. It is demonstrated that in order for a society to meet the demands of equality it must provide its members with a particular set of securities – while at the same time the pursuit of equality puts another set of securities out of reach. Ultimately, this dissertation finds no reason for considering security to be good for its own sake, but it argues that security can be good for the sake of well-being, freedom, and equality. Show less
Human vocal communication and music perception represent advanced cognitive skills, seemingly innate and universal. These faculties encompass a range of perceptual and cognitive abilities. Cross... Show moreHuman vocal communication and music perception represent advanced cognitive skills, seemingly innate and universal. These faculties encompass a range of perceptual and cognitive abilities. Cross-species research sheds light on the origins of musicality by investigating whether these traits are shared by nonhuman species. Songbirds, notably zebra finches, serve as valuable models due to their complex vocalizations and similarities to humans in auditory perception. My thesis explored zebra finches' sensitivity to spectral and temporal sound features. Chapter 2 examines the influence of song duration and spectral characteristics on song discrimination, while Chapter 3 tests song preferences. Chapter 4 investigates sequential and spectral feature recognition. Chapter 5 focuses on melody recognition. Zebra finches demonstrate perceptual flexibility, adapting focus based on stimulus characteristics. These findings underscore the importance of training conditions and stimulus nature in shaping auditory perception. Overall, my thesis enhances understanding of auditory cognition and cognitive flexibility among songbirds. Show less
