This thesis is about the role of elites in Ethiopia's nation-building process, 1960-2020. The study aims to answer questions regarding the formation, manoeuvering and circulation of elites. Using a... Show moreThis thesis is about the role of elites in Ethiopia's nation-building process, 1960-2020. The study aims to answer questions regarding the formation, manoeuvering and circulation of elites. Using a combination of theoretical notions on elite circulation and elite bargaining as conceptual framework, the research employed mixed methods, including in-depth interviews and document analysis. The trajectory of Ethiopian state formation is analyzed, highlighting elites' evolving nature and characteristics across different regimes. From the imperial regime via the Derg and EPRDF regimes to today’s PP rule, changes in power structures, ideologies, and socioeconomic dynamics have influenced elite composition and behaviour. Various dimensions and instruments of nation-building like economic integration, cultural integration, political centralization, and the establishment of effective state institutions are discussed. It is concluded that successive governments struggled to effectively utilize these instruments. It resulted in fragmentation, polarization, and authoritarianism, as key challenges were not met, including the failure to establish a compelling ideology and unifying national symbols, to provide overall public goods, to further civil society, or develop overarching language and education policies. The study proposes recommendations to address these challenges to nation-building, including elite reconfiguration, fostering consensus among ruling elites and stakeholders, and reducing the dominance of politicized ethno-elites. Show less
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
Offer, K.; Mischkowski, D.; Rahwan, Z.; Engel, C. 2024
Why do people punish experienced unfairness if it induces costs for both the punisher and punished person(s) without any direct material benefits for the punisher? Economic theories of fairness... Show moreWhy do people punish experienced unfairness if it induces costs for both the punisher and punished person(s) without any direct material benefits for the punisher? Economic theories of fairness propose that punishers experience disutility from disadvantageous inequality and punish in order to establish equality in outcomes. We tested these theories in a modified Ultimatum Game (N = 1370) by examining whether people avoid the urge to reject unfair offers, and thereby punish the proposer, by deliberately blinding themselves to unfairness. We found that 53% of participants deliberately ignored whether they had received an unfair offer. Among these participants, only 6% of offers were rejected. As expected, participants who actively sought information rejected significantly more unfair offers (39%). Averaging these rejection rates to 21%, no significant difference to the rejection rate by participants who were directly informed about unfairness was found, contrary to our hypothesis. We interpret these findings as evidence for sorting behavior: People who punish experienced unfairness seek information about it, while those who do not punish deliberately ignore it. Show less
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
Visualizing the internal structure is a crucial step in acquiring knowledge about the origin, state, and composition of cultural heritage artifacts. Among the most powerful techniques for exposing... Show moreVisualizing the internal structure is a crucial step in acquiring knowledge about the origin, state, and composition of cultural heritage artifacts. Among the most powerful techniques for exposing the interior of cultural heritage objects is computed tomography (CT), a technique that computationally forms a 3D image using hundreds of radiographs acquired in a full circular range. The diversity in materials, shapes and sizes of cultural heritage objects poses a challenge for the broad application of this technique, since each scan needs to be tailored to the object. Moreover, the lack of affordable and versatile CT equipment in museums, combined with the challenge of transporting precious collection objects, currently keeps this technique out of reach for most cultural heritage applications. In this thesis, we explore how CT imaging can be further integrated in cultural heritage applications by 1) integrating expert feedback into the data acquisition process, 2) tailoring acquisition methods to obtain specific information, 3) developing a low-cost method to use in-house X-ray facilities for 3D CT imaging and 4) providing tools to interactively visualise and inspect the CT data. Show less
The research presented in this thesis concerns one of the most important questions in software engineering of our time: how can we make sure that software is free from memory safety bugs? Memory... Show moreThe research presented in this thesis concerns one of the most important questions in software engineering of our time: how can we make sure that software is free from memory safety bugs? Memory safety bugs are the major cause of common vulnerabilities and exposures, and their presence threatens the stability and security of our digital world. This question is so important that it has escalated to the highest level. In a recent White House press release (February 26, 2024), the National Cyber Director of the United States of America calls on the academic community to help solve this hard problem: “addressing [this challenge] is imperative to ensuring we can secure our digital ecosystem long-term and protect the security of our Nation.” The accompanying technical report advises on the use of memory safe programming languages, and prominently mentions formal methods as one way to achieve the highly desired freedom from bugs, including memory safety bugs.In this thesis, formal methods are studied that are used to analyze software for its correctness, where correctness means that software satisfies its specification and incorrectness means the presence of a bug. The focus is on separation logic, a formal method designed as a scalable technique in ensuring freedom from memory safety bugs. Nowadays, separation logic is a well-established field of research: it has been widely studied academically in the past twenty years, and is successfully applied on an industry-wide scale to ensure memory safety. For example, separation logic is the technique used to prove, with mathematical certainty, that memory safe programming languages (such as Rust and Go) indeed live up to the promise that “they offer a way to eliminate, not just mitigate, entire bug classes.”In two parts, this thesis presents important scientific contributions that fill a gap in the academic literature. The first part contains the missing completeness theorem for separation logic, that is on par with the fundamental result by Goedel for first-order logic. Completeness is important for any formal method as it shows that the formal method can be adequately used for demonstrating every validity. The second part finally introduces dynamic separation logic that gives an alternative way to analyze memory safety problems, such that now it is possible to prove elementary specifications without needing extra logical techniques. This is important because it ensures ‘backwards compatibility’ with automated reasoning techniques that are optimized for first-order logic. Show less
The use of opioid is increasing in the Netherlands, which is reflected in an increase in complications associated with the use, such as hospital admission and death due to opioid poisoning. In... Show moreThe use of opioid is increasing in the Netherlands, which is reflected in an increase in complications associated with the use, such as hospital admission and death due to opioid poisoning. In addition to these direct hazards of opioid use, patients also face the risk of unplanned ICU admission and all-cause mortality. Dependent on socio-demographic characteristics and co-morbidities the risk of theseoutcomes may vary, but is unique to the general population of the Netherlands when compared to other countries. 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
The endocannabinoid receptors CB1R and CB2R are involved in a plethora of processes, and consequently are involved in many pathological conditions. Their wide distribution makes the CBRs both an... Show moreThe endocannabinoid receptors CB1R and CB2R are involved in a plethora of processes, and consequently are involved in many pathological conditions. Their wide distribution makes the CBRs both an interesting therapeutic target and hard to study. Additional chemical tools are required to study and understand the function and mechanism of CB1R and CB2R. This thesis describes the development of several such tools to improve our insight in the (pathological) roles of the receptors in order to develop novel and improved therapeutics. First evaluation of three dimensional ligand-CB2R complexes made and analysed with Cryo-EM are described. Hotspots that potentially generate selectivity between CB1R and CB2R are evaluated with point-mutations in vitro. Consequently describes the development of the first tools, two-step bifunctional probes based on LEI-121 and LEI 102, is described. As two-step probes are not compatible with every assay, the toolbox is expanded with a one-step fluorescent probe. Briefly touching upon CB1R, ligands were designed with negatively charged phosphonium groups that are potentially selective for mtCB1R. Show less
The global trade of plastic waste has raised environmental concerns, especially regarding pollution in waste-importing countries. However, the overall environmental contribution remains unclear due... Show moreThe global trade of plastic waste has raised environmental concerns, especially regarding pollution in waste-importing countries. However, the overall environmental contribution remains unclear due to uncertain treatment shares between handling plastic waste abroad and domestically. Here, we conduct a life cycle assessment of global plastic waste trade in 2022 across 18 countries and six plastic waste types, alongside three “nontrade” counterfactual scenarios. By considering the required cycling rate, which balances importers’ costs and recycling revenues, we find that the trade resulted in lower environmental impacts than treating domestically with the average treatment mix. The trade scenario alone reduced climate change impact by 2.85 million tonnes of CO2 equivalent and mitigated damages to ecosystem quality, human health, and resource availability by 12 species-years, 6200 disability-adjusted life years (DALYs), and 1.4 billion United States dollars (USD in 2013), respectively. These results underscore the significance of recognizing plastic waste trade as a pivotal factor in regulating global secondary plastic production when formulating a global plastics treaty. Show less
Throughout the history of computer science, a major challenge has been how to assert that software is free of bugs and works as intended. Software bugs can lead to serious negative impacts on any... Show moreThroughout the history of computer science, a major challenge has been how to assert that software is free of bugs and works as intended. Software bugs can lead to serious negative impacts on any software system. Throughout the main body of the thesis, we implemented a series of studies on exploring ways to apply formal methods systematically for the verification of complex object-oriented libraries such as the Java Collection Framework. We start with specifying and verifying methods in the java.util.LinkedList class, but we encounter challenges with methods that take an interface type as a parameter. To address this, we proposed to use histories as method calls and returns to completely determine the concrete state of any implementation and thus can be seen as a way to reason about the interface. The executable history-based (EHB) approach embeds histories and attributes directly as Java objects. This approach could be seamlessly integrated in the KeY theorem prover itself. However, the EHB approach still has its limitations, particularly when it comes to reasoning about the heap and properties of user-defined attributes.To mitigate this, we introduce the logical history-based (LHB) approach, which models histories as an external abstract data type with functions. Building on the LHB approach, we have developed a history-based refinement theory for reasoning about hierarchy in object-oriented programs. Show less
A group of bacterial proteases, the Pro-Pro endopeptidases (PPEPs), pos-sess the unique ability to hydrolyze proline-proline bonds in proteins. Sincea protease’s function is largely determined by... Show moreA group of bacterial proteases, the Pro-Pro endopeptidases (PPEPs), pos-sess the unique ability to hydrolyze proline-proline bonds in proteins. Sincea protease’s function is largely determined by its substrate specificity,methods that can extensively characterize substrate specificity are valuabletools for protease research. Previously, we achieved an in-depth characteri-zation of PPEP prime-side specificity. However, PPEP specificity is alsodetermined by the non-prime-side residues in the substrate. To gain a morecomplete insight into the determinants of PPEP specificity, we character-ized the non-prime- and prime-side specificity of various PPEPs using acombination of synthetic combinatorial peptide libraries and mass spec-trometry. With this approach, we deepened our understanding of the P3-P30 specificities of PPEP-1 and PPEP-2, while identifying the endogenoussubstrate of PPEP-2 as the most optimal substrate in our library data. Fur-thermore, by employing the library approach, we investigated the alteredspecificity of mutants of PPEP-1 and PPEP-2. Additionally, we character-ized a novel PPEP from Anoxybacillus tepidamans, which we termed PPEP-4. Based on structural comparisons, we hypothesized that PPEP-4 displaysa PPEP-1-like prime-side specificity, which was substantiated by the experi-mental data. Intriguingly, another putative PPEP from Clostridioides diffi-cile, CD1597, did not display Pro-Pro endoproteolytic activity.Collectively, we characterized PPEP specificity in detail using our robustpeptide library method and, together with additional structural informa-tion, provide more insight into the intricate mechanisms that govern prote-ase specificity. 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
