ObjectiveTo assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.BackgroundMigraine has been linked to IBD and celiac... Show moreObjectiveTo assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease.BackgroundMigraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition.MethodsLinkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed.ResultsMigraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99–1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99–1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96–1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79–1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00–1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92–0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02–1.29, p = 0.025). However, the results were not significant after multiple testing correction.ConclusionsWe found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes. Show less
Shalgunov, V.; Broek, S.L. van den; Andersen, I.V.; Raval, N.R.; Schäfer, G.; Barz, M.; ... ; Battisti, U.M. 2024
Brain pretargeted nuclear imaging for the diagnosis of various neurodegenerative diseases is a quickly developing field. The tetrazine ligation is currently the most explored approach to achieve... Show moreBrain pretargeted nuclear imaging for the diagnosis of various neurodegenerative diseases is a quickly developing field. The tetrazine ligation is currently the most explored approach to achieve this goal due to its remarkable properties. In this work, we evaluated the performance of F-537-Tetrazine, previously developed by Biogen, and N-(3-[18F]fluoro-5-(1,2,4,5-tetrazin-3-yl)benzyl)propan-1-amine, previously developed in our group, thereby allowing for the direct comparison of these two imaging probes. The evaluation included synthesis, radiolabeling and a comparison of the physicochemical properties of the compounds. Furthermore, their performance was evaluated by in vitro and in vivo pretargeting models. This study indicated that N-(3-[18F] fluoro-5-(1,2,4,5-tetrazin-3-yl)benzyl)propan-1-amine might be more suited for brain pretargeted imaging. Show less
Previous studies have demonstrated the common occurrence of constituency focus in parliamentary questions, which is most often attributed to electoral incentives. If an electoral system makes use... Show morePrevious studies have demonstrated the common occurrence of constituency focus in parliamentary questions, which is most often attributed to electoral incentives. If an electoral system makes use of a single nationwide district, however, these district-oriented electoral incentives do not apply. MPs may still substantively represent a geographical region, because they are motivated to stand up for a specific region for other reasons. This article explores the extent to which Dutch MPs pay attention in parliamentary questions and debates to specific regions. We find that those with stronger ties to a region, and especially MPs who reside in a region, are more likely to mention it in parliamentary questions and speeches. In addition, we find that this effect is stronger for provinces where regional attachment among residents is relatively stronger. Show less
Baca, M.; Popović, D.; Agadzhanyan, A.K.; Baca, K.; Conard, N.J.; Fewlass, H.; ... ; Nadachowski, A. 2024
The narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of... Show moreThe narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of the collared lemming and common vole have revealed dynamic population histories shaped by climatic fluctuations. To investigate the extent to which species with similar adaptations share common evolutionary histories, we generated a dataset comprised the mitochondrial genomes of 139 ancient and 6 modern narrow-headed voles from several sites across Europe and northwestern Asia covering approximately the last 100 thousand years (kyr). We inferred Bayesian time-aware phylogenies using 11 radiocarbon-dated samples to calibrate the molecular clock. Divergence of the main mtDNA lineages across the three species occurred during marine isotope stages (MIS) 7 and MIS 5, suggesting a common response of species adapted to open habitat during interglacials. We identified several time-structured mtDNA lineages in European narrow-headed vole, suggesting lineage turnover. The timing of some of these turnovers was synchronous across the three species, allowing us to identify the main drivers of the Late Pleistocene dynamics of steppe- and cold-adapted species. Show less
This thesis contains several investigations into the contribution of complement proteins, especially C1q, in several human diseases. Additionally, human autoantibodies against C1q (anti-C1q) are... Show moreThis thesis contains several investigations into the contribution of complement proteins, especially C1q, in several human diseases. Additionally, human autoantibodies against C1q (anti-C1q) are studied, cloned and characterized in order to further the understanding of their role in autoimmune disease. 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
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
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 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
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
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
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
Manumission is the release from slavery, and therefore, a transition from the most extreme form of subjugation into another position and status in society. Some historians have defined manumission... Show moreManumission is the release from slavery, and therefore, a transition from the most extreme form of subjugation into another position and status in society. Some historians have defined manumission as a formal act, often understood as a gift that severed the bond between slave and master. More recently researchers have emphasized that it was a lengthy process that involved pre-existing dependencies and resulted in new hierarchies. This article takes a fresh look at the process and tries to gain a fuller understanding of manumission by examining it from the position of the manumitted and their social relations. Taking into consideration a wide range of documentary sources from colonial, notarial and Dutch governmental archives, we reconstruct the dependencies that were created in the process of manumission. The dependencies that evolved during manumission processes were related to family and other kinship ties, but also had an urban, communal, religious, economic and institutional logic. Manumission was not only an act at a specific moment, but also a process, and it was not a bilateral, but a multilateral one. With the instrument of manumission and within the limits set by economic reality and the colonial government, the manumittees tried to make meaningful life choices that transformed slave society profoundly. We find that they created complex dependencies across boundaries of status and racial categorization. Show less
