Oratie uitgesproken door Prof. Dr. Hans Ulrich Scherer bij de aanvaarding van het ambt van hoogleraar Reumatologie aan de Universiteit Leiden op vrijdag 21 juni 2024________________________________... Show moreOratie uitgesproken door Prof. Dr. Hans Ulrich Scherer bij de aanvaarding van het ambt van hoogleraar Reumatologie aan de Universiteit Leiden op vrijdag 21 juni 2024____________________________________________________________Text also in German : Über Barrieren und Brücken: Autoimmunerkrankungen auf dem Weg zur Heilung Show less
The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol,... Show moreThe liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesis. Δ24-Dehydrocholesterol reductase (DHCR24) converts desmosterol into cholesterol, and we previously showed that the DHCR24 inhibitor SH42 increases desmosterol to activate LXR and attenuate experimental peritonitis and metabolic dysfunction-associated steatotic liver disease. Here, we aimed to evaluate the effect of SH42 on atherosclerosis development in APOE∗3-Leiden.CETP mice and low-density lipoproteins (LDL) receptor knockout mice, models for lipid- and inflammation-driven atherosclerosis, respectively. In both models, SH42 increased desmosterol without affecting plasma lipids. While reducing liver lipids in APOE∗3-Leiden.CETP mice, and regulating populations of circulating monocytes in LDL receptor knockout mice, SH42 did not attenuate atherosclerosis in either model. Show less
This thesis discusses the prenatal detection and outcome of fetal congenital heart defects. The first part of this thesis focuses to identify determinants for a prenatal diagnosis in fetus with a... Show moreThis thesis discusses the prenatal detection and outcome of fetal congenital heart defects. The first part of this thesis focuses to identify determinants for a prenatal diagnosis in fetus with a structural congenital heart defect. The second part provides evidence on the prognosis of specific congenital heart defects diagnoses in the fetus, as prenatal counseling remains difficult in some cases, due to the fact that little evidence is available on the outcome of congenital heart defects from a fetal perspective. Show less
Actinobacteria are well known for the production of bioactive natural products, many of which have applications in the fields of human, animal and plant health. Subject of this thesis are the... Show moreActinobacteria are well known for the production of bioactive natural products, many of which have applications in the fields of human, animal and plant health. Subject of this thesis are the anthracyclines, glycosylated aromatic polyketides with potent anticancer activity. Despite remarkable efficacy against acute leukaemia and various solid tumours, their application is limited by severe side effects, such as cardiotoxicity, therapy-related tumours and infertility.Recent insights into the mode-of-action of anthracyclines have prompted renewed interest into this important class of anticancer compounds. One of the most promising compounds is N,N-dimethyldoxorubicin, which exerts significantly reduced side effects. To date, DMdoxo has not been isolated from natural sources, but biosynthesis would be an attractive option for scaling up production of this promising compound.For this reason, we aimed to engineer the Doxo biosynthetic pathway in S. peucetius for the production of biosynthetic N,N-dimethylated anthracyclines. The challenges that we encountered instigated the study of anthracycline resistance mechanisms in Streptomyces, and potential applications of detoxified anthracyclines as antibiotics. Finally, to facilitate future screening and strain engineering efforts of Streptomyces producer strains, we developed a workflow for integrated quantitative proteomics and metabolomics from small-scale Streptomyces cultures Show less
In this thesis, we aimed to assess outcomes of local disease activity in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) who received treatment-to-target, and to... Show moreIn this thesis, we aimed to assess outcomes of local disease activity in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) who received treatment-to-target, and to describe long-term clinical and radiographic outcomes in patients with treated-to-target RA. Show less
Languages frequently make use of spatial vocabulary to describe abstract notions. For instance, the spatial preposition by (‘by the house’) can also describe relations in the temporal and causal... Show moreLanguages frequently make use of spatial vocabulary to describe abstract notions. For instance, the spatial preposition by (‘by the house’) can also describe relations in the temporal and causal domain (‘by Monday’; ‘hit by John’). This dissertation shows that when a spatial term is extended into an abstract domain, some of its spatial meaning persists. Speakers rely on a spatial representation of the abstract domain, which they use to reinterpret the spatial term to obtain an abstract meaning. On the basis of Western European languages, the proposal is formalized for causal prepositions (e.g., French ‘de’ and ‘par’ in passives) as well as demonstratives referring to information content (e.g., the use of English ‘that’ to introduce complement clauses). The proposals are further tested in corpus studies using Biblical Hebrew. Data from the Hebrew Bible additionally show that the analysis can be extended to the use of prepositions for describing social relations. This research shows that spatial meaning often persists when grammaticalization takes place. Use of spatial vocabulary in abstract domains is not metaphorical but deeply embedded in cognition, shaping the conceptualization of abstract relations. In this way, the study of language contributes to our understanding of the human mind. Show less
Tracing the evolution of the molecular gas content in galaxies is critical for a complete understanding of galaxy formation and evolution, as it provides the direct fuel for star formation. Studies... Show moreTracing the evolution of the molecular gas content in galaxies is critical for a complete understanding of galaxy formation and evolution, as it provides the direct fuel for star formation. Studies of high-redshift (z>1) molecular gas reservoirs, most commonly traced by carbon monoxide (CO), have seen substantial growth in recent years thanks to state-of the-art sub-millimeter interferometers such as the Jansky Very Large Array or the Atacama Large Millimeter Array. However, these studies have been largely based on detections of the bright mid/high-J transitions of CO (J>=3), which have been shown to give a biased and incomplete view of the total cold molecular gas content in galaxies. This thesis presents an observational study of the cold interstellar medium of massive galaxies in the distant universe. Chapter 2 presents one of the highest—resolution studies of low-J CO in a high—redshift galaxy to-date, allowing us to map its total cold gas reservoir in unprecedented detail. Chapter 3 presents a survey targeting low-J CO emission in high-redshift unobscured quasar hosts, finding direct evidence for high gas fractions but very short depletion times. Chapter 4 introduces first results from the VLA Legacy Library of Molecular Gas at High Redshift project, which significantly expands the number of high-redshift galaxies with cold gas detections. Finally, Chapter 5 shows ALMA observations targeting emission from atomic carbon in a subset of the VLA targets, and demonstrates how this alternative gas tracer complements our view of cold molecular gas reservoirs at high—redshift. Show less
Scientometrics originate from the analysis of scientific publications, the most popular ways for disseminating scientific information within the scientific community. With the increasing use of... Show moreScientometrics originate from the analysis of scientific publications, the most popular ways for disseminating scientific information within the scientific community. With the increasing use of scientometric data in research management and research evaluation, various analyses can be conducted to better understand different aspects of scientific activities. On the one hand, the analysis of scientific publications from the Middle East and North Africa region opens up a range of possibilities to characterize its science systems. Large scale analyses of bibliographic metadata capture the stories of how the scientific workforce is connected, funded and mobile within diverse science systems. On the other hand, scientometric data is also used as a guide to transform the science systems. The main objective of this dissertation is to better understand recent science systems changes in the Middle East and North Africa by examining several of their facets and their recent evolution. Show less
The Dutch reward system in prison (Promoveren en Degraderen) has never been formally evaluated, therewith obscuring its theoretical soundness, application and effects. There are scholarly concerns,... Show moreThe Dutch reward system in prison (Promoveren en Degraderen) has never been formally evaluated, therewith obscuring its theoretical soundness, application and effects. There are scholarly concerns, however, regarding all three of these aspects. Therefore, the current dissertation aims to improve our understanding of reward systems in prisons, by studying the Dutch reward system in prison. Specifically, the soundness of its theoretical assumptions is tested, prior research is mapped, predictors of receiving rewards are identified (e.g. motivation, self-governance ability and behaviour), and the association between rewards and feelings of autonomy is examined.The current dissertation reveals that the theoretical assumptions can only partially be supported by scientific knowledge and that the system is not fully applied as intended. Moreover, the current reward system disadvantages incarcerated individuals low on self-governance ability. Finally, some rewards do increase feelings of autonomy in prison. These results underscore the relevance of promoting intrinsic over extrinsic motivation for compliance, and of adapting the current system to the level of self-governance ability of incarcerated individuals. Policymakers are advised to effectuate such policy changes, and practitioners are advised to look beyond behaviour as the key determinant of who is ‘deserving’ of rewards. Show less
Central to this thesis was the use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model a rare form of mitochondrial cardiomyopathy. To model this disease required the... Show moreCentral to this thesis was the use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model a rare form of mitochondrial cardiomyopathy. To model this disease required the design of new methodologies, improving upon the current limitations of hiPSC-CMs as model systems, notably the variability and the immature state of the resulting cardiomyocytes. The diseases we were interested in manifest soon after birth. At the outset of the studies, it was unclear whether a phenotype would be evident in our standard immature 2D cultures, or whether more complex models would be required to capture more salient features of the condition. Our focus was on the rare mitochondrial disease Combined Oxidative Phosphorylation Deficiency, caused by mutations in the gene alanyl-tRNA synthetase 2. We refined our emerging 3D cardiac microtissue protocol to improve robustness and reproducibility and reduce cost by basing differentiation on small molecules rather than growth factors without altering the functionality of hiPSC-CMs. We also demonstrated that integrating pH and O2 sensors in a micro-physiological chip was possible for the assessment of metabolic parameters under microfluidic flow. The overall goal of this thesis was to provide additional tools that would have utility in studying mitochondrial and other cardiac diseases. Show less
This thesis explores Breaking of Ensemble Equivalence (BEE) in random graph models by examining the spectral properties of adjacency matrices. The goal is to identify spectral characteristics that... Show moreThis thesis explores Breaking of Ensemble Equivalence (BEE) in random graph models by examining the spectral properties of adjacency matrices. The goal is to identify spectral characteristics that differentiate random graph ensembles, enhancing the understanding of complex network structures and behaviors. The research encompasses both theoretical analysis and practical applications, including a chapter on simulations and sampling methods.Chapter 1 introduces basic random graph theory and emphasizes the importance of maximum entropy models in real-world network modeling. It defines BEE and its characterization within statistical mechanics, highlighting the natural differences between canonical and microcanonical ensembles. It then introduces spectral theory of random graphs and why it is utilized to investigate BEE.Chapter 2 proposes a conjecture linking BEE to a gap between the expectations of the largest eigenvalue in the canonical and microcanonical ensembles, proving it for homogeneous graphs.Chapter 3 examines Chung-Lu random graphs, establishing central limit theorems for the largest eigenvalue and its eigenvector.Chapter 4 verifies the conjecture for inhomogeneous graphs, computing the expected largest eigenvalue of the configuration model.Chapter 5 offers numerical evidence through simulations, after a brief introduction to graph sampling. The thesis concludes with a summary of findings and suggestions for future research. Show less
In this thesis, deep learning is studied from a statistical perspective. Convergence rates for the worst case risk bounds of neural network estimators are obtained in the classification, density... Show moreIn this thesis, deep learning is studied from a statistical perspective. Convergence rates for the worst case risk bounds of neural network estimators are obtained in the classification, density estimation and linear regression model. Special attention is given to the role of input dimension since in practice, neural networks have shown promising results for high dimensional input settings. First, the estimation of conditional class probabilities under the cross-entropy loss is studied. A challenge with this loss is that it becomes unbounded near zero. To deal with this, the loss is truncated. Convergence rates are obtained for a neural network estimator under this truncated loss. The second problem considered is density estimation. A two step procedure is proposed. The first step transforms the density estimation problem into a regression problem by constructing response variables using a kernel density estimator on half of the data. In the second step, a neural network is fitted to this constructed data. Convergence rates for this method are obtained using existing approximation results for compositional functions. Finally, forward gradient descent is studied. This is a biologically motivated alternative for gradient descent. Convergence rates are derived for this method in the linear regression model with random design. Show less
All living organisms are made out of cells, which serve as the fundamental units of life. Protein molecules, comprised of amino acids, carry out diverse functions across various cellular... Show moreAll living organisms are made out of cells, which serve as the fundamental units of life. Protein molecules, comprised of amino acids, carry out diverse functions across various cellular compartments. Proteins are tightly controlled in their synthesis, folding, localization and degradation to ensure proper functioning. Dysregulation of protein control mechanisms within the cell can lead to cellular dysfunction, disease or eventually cell death. Post-translational modifications (PTMs) are the addition of a chemical group to an existing protein to regulate its function, localization, stability or interaction. In this thesis we will dive deeper into PTMs SUMO and ubiquitin, with the aim to understand the biochemistry of these proteins in different aspects of cellular function and human pathophysiology. An interesting aspect of the conjugation process lies in its reversibility, which is governed by specific proteases known as SENPs in the case of SUMO. However, only SENP6 and SENP7 have the ability to depolymerize SUMO2/3 chains by an insertion in their conserved catalytic domains. We delve into the promising horizon that lies ahead of a small yet profoundly impactful post-translational modifying protein. Despite its modest size, this protein wields a significant influence on fundamental cellular processes Show less
This thesis had two main focuses. First, it investigated the mechanisms underlying individual differences in brain structure, developmental changes, and function. Second, it examined how enriched... Show moreThis thesis had two main focuses. First, it investigated the mechanisms underlying individual differences in brain structure, developmental changes, and function. Second, it examined how enriched and deprived environments affect brain development from middle childhood to early adolescence (ages 7-14). The study revealed distinct genetic and environmental influences on the developing brain during this period. Genetic contributions largely explained the variations in brain structure and developmental changes, along with location-specific environmental factors. While studies on genetic and environmental influences on brain regions showed both overlapping and unique outcomes, the interplay between these influences is complex. Using MRI and fMRI provided a comprehensive understanding of how individual differences arise. Additionally, the thesis highlighted the distinct effects of specific environmental influences on brain development. An enriched cognitive environment, such as musical ability, was linked to attenuated development, while a deprived environment, exemplified by the COVID-19 pandemic, accelerated development. Notably, the brain showed resilience to adverse effects, particularly in TPJ growth during the pandemic, suggesting adaptive processes during this developmental phase. Future research should explore whether the relationship between environmental effects and brain maturation pace is linked to positive mental health outcomes. Ultimately, identifying interventions to ensure all children thrive throughout their development is crucial. Show less
It is increasingly common for citizens to take initiatives to improve their immediate living environment. While setting up and implementing these initiatives initiators come into contact with the... Show moreIt is increasingly common for citizens to take initiatives to improve their immediate living environment. While setting up and implementing these initiatives initiators come into contact with the government. Governments are often enthusiastic about these plans, but yet it proves far from easy to get get the initiative off the ground. 'The law' is seen as the main bottleneck. In this dissertation several (legal) bottlenecks are researched and recommendations to facilitate initiators are formulated. Show less
If diversity counteracts solidarity, as welfare state scholarship commonly concludes, then how did the expansion of European welfare states in the postwar period coexist with (post)colonial... Show moreIf diversity counteracts solidarity, as welfare state scholarship commonly concludes, then how did the expansion of European welfare states in the postwar period coexist with (post)colonial migrations? Through a historical-interpretivist lens, this dissertation studies the inclusion of migrants from the Caribbean, Algeria, and present-day Indonesia in post-war British, French, and Dutch welfare setates respectively. It documents a variety of inclusions on inequal terms in French and Dutch welfare states. While those who qualified as repatriates received aid under targeted assistance schemes and expedited access to social security, many who had been disadvantaged under colonial legal codes were directed towards paternalistic arms of the welfare state aimed at surveillance and cultural conversion. In the UK, street-level discrimination and restricitonist immigration law marred the promise of equality under the Beveridgean welfare state for Caribbean citizens. These patterns were racialised, but not inevitable. Ideological efforts to construct certain migrants as deserving cultural insiders have important explanatory power. This dissertation improves the theoretical toolkit available to welfare state scholars interested in inclusion, and elucidates the relationship between race and redistribution. Diversity neither caused retrenchment, nor threatened solidarity. Rather, (post)colonial migrations offered contemporaries an opportunity to consciously and manually create it. Show less
The studies described in this thesis provide additional evidence that the current Dutch population-based screening programmes (CSPs) can be further optimized, particularly concerning the... Show moreThe studies described in this thesis provide additional evidence that the current Dutch population-based screening programmes (CSPs) can be further optimized, particularly concerning the participation of potential participants from highly urbanized and low socioeconomic status (SES) neighbourhoods. Our findings suggest that non-participation in the CSPs in these low SES-neighbourhoods is associated with more unfavourable, relatively advanced, tumour outcomes. Given that the decision to participate in a CSP is not solely based on rational decision-making processes, primary care providers could play an important role here. This would primarily involve informing and advising potential participants who are hesitant about participating in CSPs. In this thesis, we describe that both potential participants and general practitioners support the idea that primary care should be more involved in the invitation process of the CSPs. Based on our findings, we therefore recommend implementing a proactive, risk-based invitation strategy from primary care regarding the invitation process of the current CSPs. Show less
This dissertation examines various monitoring mechanisms within the International Humanitarian and Human Rights Law frameworks in order to draw lessons learned from their monitoring functions,... Show moreThis dissertation examines various monitoring mechanisms within the International Humanitarian and Human Rights Law frameworks in order to draw lessons learned from their monitoring functions, approaches and practices and assess whether they can be applied to a future compliance system under the four Geneva Conventions of 1949 and their Additional Protocols. The scope of the enquiry includes the existing compliance system of the Geneva Conventions, the compliance systems of other treaties within the International Humanitarian Law framework, the United Nations human rights monitoring system, and a number of mechanisms that supervise respect for humanitarian norms by States and/or armed non-State actors. The dissertation suggests that a future compliance system under the Geneva Conventions should include thematic reporting, a plenary forum for States Parties and an International Humanitarian Law Committee. The establishment of effective compliance mechanisms that are tailored to the specifics of International Humanitarian Law would support and advance the implementation of the Geneva Conventions by States Parties as well as strengthen the capacity to monitor their implementation from within the International Humanitarian Law framework. Show less
