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
Inaugural Lecture by Prof.dr. Florian A. Schneider on the acceptance of his position as professor Modern China at Leiden University on Monday 6 May 2024
Inaugural Lecture by Prof.dr. Nadine N.W. Akkerman on the acceptance of her position as professor of Early Modern Literature & Culture at Leiden University on Friday 3 May 2024
Oratie uitgesproken door Prof.dr. Nadine N.W. Akkerman bij de aanvaarding van het ambt van hoogleraar Vroegmoderne Literatuur en Cultuur aan de Universiteit Leiden op vrijdag 3 mei 2024
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
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
Smit, V.; Mol, J. de; Bernabé Kleijn, M.N.A.B.; Depuydt, M.A.C.; Winther, M.P.J. de, Bot, I.; Kuiper, J.; Foks, A.C. 2024
Atherosclerosis, the main underlying pathology of cardiovascular disease, is a chronic inflammatory disease characterized by lipid accumulation and immune cell responses in the vascular wall,... Show moreAtherosclerosis, the main underlying pathology of cardiovascular disease, is a chronic inflammatory disease characterized by lipid accumulation and immune cell responses in the vascular wall, resulting in plaque formation. It is well-known that atherosclerosis prevalence and manifestation vary by sex. However, sexual dimorphism in the immune landscape of atherosclerotic plaques has up to date not been studied at high-resolution. In this study, we investigated sex-specific differences in atherosclerosis development and the immunological landscape of aortas at single-cell level in aged Ldlr-/- mice.We compared plaque morphology between aged male and female chow diet-fed Ldlr-/- mice (22 months old) with histological analysis. Using single-cell RNA-sequencing and flow cytometry on CD45+ immune cells from aortas of aged Ldlr-/- mice, we explored the immune landscape in the atherosclerotic environment in males and females.We show that plaque volume is comparable in aged male and female mice, and that plaques in aged female mice contain more collagen and cholesterol crystals, but less necrotic core and macrophage content compared to males. We reveal increased immune cell infiltration in female aortas and found that expression of pro-atherogenic markers and inflammatory signaling pathways was enriched in plaque immune cells of female mice. Particularly, female aortas show enhanced activation of B cells (Egr1, Cd83, Cd180), including age-associated B cells, in addition to an increased M1/M2 macrophage ratio, where Il1b+ M1-like macrophages display a more pro-inflammatory phenotype (Nlrp3, Cxcl2, Mmp9) compared to males. In contrast, increased numbers of age-associated Gzmk+CD8+ T cells, dendritic cells, and Trem2+ macrophages were observed in male aortas.Altogether, our findings highlight that sex is a variable that contributes to immunological differences in the atherosclerotic plaque environment in mice and provide valuable insights for further preclinical studies into the impact of sex on the pathophysiology of atherosclerosis. Show less
