Oratie uitgesproken door Prof. dr. E.P.M. (Bart) Joosen bij de aanvaarding van het ambt van hoogleraar Financieel recht aan de Universiteit Leiden op vrijdag 24 mei 2024
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
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
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
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
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
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
This dissertation explores the impact of international cultural heritage law on individuals and local communities, particularly through the lens of cultural heritage law's use of universalising... Show moreThis dissertation explores the impact of international cultural heritage law on individuals and local communities, particularly through the lens of cultural heritage law's use of universalising language such as the ‘cultural heritage of mankind’. It argues that this rhetoric empowers states to prioritise purportedly common interests over local ones, potentially erasing living heritage value in the process. The dissertation places cultural heritage law in the context of broader international legal trends, in particular the tension between the pursuit of common interests through international law and the enduring influence of state sovereignty as a structuring principle of that law. It argues that contemporary cultural heritage law often fails to effectively limit state powers or protect the interests of individuals and local communities. It thus calls for stronger guarantees of participation within cultural heritage law, drawing upon legal standards developed within environmental law and human rights law. The dissertation suggests a rethinking the concept of ‘universal interest’ in heritage law to qualify the operation of state sovereignty and to better accommodate the interests of individuals and local communities, emphasizing their role as central actors and the need to bridge the gap between local and global interests in cultural heritage protection. Show less
In this reflective chapter, we examine the structural biases and empirical challenges underlying human trafficking ‘indicators’ (especially problem, risk and performance indicators) that are... Show moreIn this reflective chapter, we examine the structural biases and empirical challenges underlying human trafficking ‘indicators’ (especially problem, risk and performance indicators) that are routinely used to describe and measure human trafficking, assess risk, identify abuses, evaluate responses, and encourage accountability. While frequently used, such indicators can give an undue illusion of objectivity and reliability when they are neither neutral nor unskewed. In fact, numerous factors affect which elements are privileged as ‘indicators’ and which are obscured. We therefore examine here the selectivity, politics, racialized and gendered concerns that relate to the production and use of human trafficking indicators. Since human trafficking is a complex, highly-contested, and multi-faceted practice, it is not easily reduced to the crude generalizations upon which many indicators rest. We explore how the uncritical use of indicators can both contribute to stereotypical and unachievable ideals of victimhood and engender undue criminalization or withholding of victim support. In doing so, we disentangle some paradoxes around who is deemed ‘vulnerable’, ‘at risk’, ‘worthy of support’ and requiring ‘protection’. We highlight the – routinely overlooked – weak empirical basis and other limitations of many commonplace ‘indicators’ and challenges in building empirically-stronger and more robust indicators. The chapter concludes with overall implications of these critical reflections for policy, interventions, and research. Show less
This thesis explores ancient Egyptian descriptions of sicknesses of the inner body, the concepts used to understand them, and the trends in associated therapeutic applications for healing. It... Show moreThis thesis explores ancient Egyptian descriptions of sicknesses of the inner body, the concepts used to understand them, and the trends in associated therapeutic applications for healing. It concludes that the ancient Egyptian system of understanding recorded in writings—while somewhat obscured as the surviving texts were never intended to be descriptive of ideas—can be compared to other ways of thinking and categorising sickness experiences as found in other written cultures. Especially in terms of how such ideas are constructed and how therapies are associated with such concepts. Similarities can be observed in terms of core concepts and associated therapeutic applications recorded in cuneiform compendia of comparable age from Mesopotamia. Rather than using these observations as evidence of an influence of one culture over another, it is argued that these writings include practices and ideas which can instead be considered common to this region of the world, rather than as exclusive and invariably peculiar either the Egyptian and/or Mesopotamian cultures. Show less
