Approximately 35% of colorectal cancer (CRC) risk is attributed to heritable factors, with 5 to 10% linked to dominant or recessive inherited syndromes. Known high-risk genes like POLE, POLD1,... Show moreApproximately 35% of colorectal cancer (CRC) risk is attributed to heritable factors, with 5 to 10% linked to dominant or recessive inherited syndromes. Known high-risk genes like POLE, POLD1, NTHL1 and APC contribute to a portion of this risk. However, the genetic basis for 20%-30% of inherited CRC remains unclear. This thesis explores the roles of POLE, POLD1, APC and NTHL1 in CRC and polyposis. While screening for pathogenic variants in POLE and POLD1, remarkably POLE L424V variants were found to induce Lynch syndrome-like features due to somatic mismatch repair gene mutations. Biallelic NTHL1 variants predisposing to CRC and polyposis were studied in a collaborative effort, describing a broad tumor spectrum and a high risk of extracolonic cancers associated with NTHL1 deficiency. For monoallelic NTHL1 variant carriers, no significant evidence link was found with increased polyposis or CRC risk, as supported by mutational signature analysis on colorectal tumors. Show less
This thesis mainly focuses on multimodal understanding and Visual Question Answering (VQA) via deep learning methods. For technical contributions, this thesis first focuses on improving multimodal... Show moreThis thesis mainly focuses on multimodal understanding and Visual Question Answering (VQA) via deep learning methods. For technical contributions, this thesis first focuses on improving multimodal fusion schemes via multi-stage vision-language interactions. Then, the thesis seeks to overcome the language bias challenges to build robust VQA models, and also extend the bias problem into the more complex audio-visual-textual question answering tasks. Furthermore, this thesis explores the open-world applicability of VQA algorithms from the aspects of lifelong learning and federated learning, thereby expanding the continuous and distributed training ability. The efficacy of the proposed methods in this thesis is verified by extensive experiments. This thesis also gives an overview of challenges, benchmarks and strategies for robust VQA algorithms. Show less
This thesis describes the synthesis and biochemical evaluation of a variety of cyclophellitol based activity-based probes and inhibitors targeting various endo- and exo-acting retaining... Show moreThis thesis describes the synthesis and biochemical evaluation of a variety of cyclophellitol based activity-based probes and inhibitors targeting various endo- and exo-acting retaining glycosidases. In the last two decades a variety of probes and inhibitors for (hemi)cellulose degrading enzymes have been developed. However, at the onset of the work described in this thesis the focus has been mainly on cellulases, xylanases, xyloglucanases and glycanases. Chapter 2 describes the design and synthesis of a first generation of inhibitors and probes for β-mannanases. The general scaffold is composed of a β-1,4-linked mannobioside featuring either an epoxide or an aziridine warhead. All synthesized probes feature a linker attached to the nonreducing end and are condensed with either biotin or Cy5. Biochemical evaluation in an Aspergillus niger secretome revealed the utility of these compounds but also the limitations. The probes react efficiently with some endo-β-mannanases yet lack reactivity with others. Chapter 3 describes the design and synthesis of a second generation of β-mannanase probes and inhibitors designed to overcome the limitations of the first generation by changing the general scaffold. In this chapter two conceptually distinct ABP scaffolds are presented: a β-1,4-linked mannotriose and a β-1,4-linked manno-gluco configured scaffold. The second generation Cy5 probes are evaluated in Aspergillus niger secretomes and compared to the first generation. Chapter 4 describes studies towards the design and synthesis of inhibitors and ABPS for both α-N-acetylglucosaminidase and α-Nacetylgalactosaminidase. The chapter introduces an orthogonally protected ribose building block as common intermediate from which both mannoseand talose configured cyclohexenes are synthesized. Furthermore it describes a late state stereoselective C-2 inversion with an azide to install a 20 nitrogen atom at C-2. Chapter 5 presents a summary and suggestions forfuture research. Show less
This thesis focuses on important life history traits and their trade-offs using two hexapod models. Particularly, the trade-off between immune defense and embryonic developmental speed is a central... Show moreThis thesis focuses on important life history traits and their trade-offs using two hexapod models. Particularly, the trade-off between immune defense and embryonic developmental speed is a central theme of this study. In short, I study the details of immune defenses during embryonic development of basal hexapods in Chapter 2, the trade-off with developmental speed in Chapter 3, and the genetic basis of developmental speed in Chapter 4, using selection lines of the red flour beetle Tribolium castaneum. I demonstrate that 1) springtail eggs do show an immune response, despite absence of a serosa that provides immune protection to insect eggs; 2) a strong trade-off is present between developmental speed and fecundity in the selection lines of the beetle T. castaneum; and 3) a life-history allele of large effect shortens developmental time in this wild insect population. I suggest that such alleles of large effect play a crucial role when insects have to adapt their developmental speed to current climate change. Show less
A hallmark of the disease axial spondyloarthritis, especially the radiographic form, is the syndesmophyte. This bony proliferation forms on the vertebral edges and grows in the direction of the... Show moreA hallmark of the disease axial spondyloarthritis, especially the radiographic form, is the syndesmophyte. This bony proliferation forms on the vertebral edges and grows in the direction of the adjacent vertebra and, once reaching this, causes rigidity in the spine. This thesis focusses on the syndesmophyte and on, seemingly related, osteoproliferation in the facet joints and aims to understand how these two lesions develop and interact. Show less
In this thesis, we unraveled the immunostimulatory potential of oncolytic reovirus and investigated how these immunostimulatory characteristics could be exploited for effective anticancer... Show moreIn this thesis, we unraveled the immunostimulatory potential of oncolytic reovirus and investigated how these immunostimulatory characteristics could be exploited for effective anticancer immunotherapy. We demonstrated that administration of oncolytic reovirus does not lead to strong oncolytic effects in tumors, but instead unleashes a very potent immune response, including the priming of reovirus-specific CD8 T cells. We showed that these reovirus-specific CD8 T cells can be effectively employed for anticancer immunotherapy, by either bypassing their specificity (with CD3-bsAbs) or by exploiting their specificity (via installing a preinduced pool using SLP vaccination). Besides the induction of reovirus-specific CD8 T cells, reovirus administration also leads to very fast B-cell responses. We demonstrated that the presence of neutralizing antibodies (NAbs) restricts the use of reovirus as an oncolytic agent, but that the reovirus-induced influx of CD8 T cells is retained and the use of reovirus in combination with T-cell-based immunotherapy can still result in potent antitumor responses. Lastly, we showed that blockade of Transforming Growth Factor-β (TGF-β) does not impair reovirus infection and reovirus-induced ISG expression or the reovirus-induced attraction and activation of T cells, but that intrinsic differences between preclinical tumor models can determine if TGF-β blockade is a beneficial addition to combined reovirus and T-cell-based immunotherapy. Show less
The research described in this thesis focused on the use of bioorthogonal antigens to investigate immunological processes in antigen presenting cells. Bioorthogonal antigens are antigenic proteins... Show moreThe research described in this thesis focused on the use of bioorthogonal antigens to investigate immunological processes in antigen presenting cells. Bioorthogonal antigens are antigenic proteins produced through recombinant expression in a methionine auxotrophic E. coli strain. This allows for the replacement of methionine residues with the bioorthogonal non-canonical amino acid, azidohomoalanine (Aha), that resembles methionine. Aha contains an azide group that enables the selective and rapid visualization or enrichment of the antigen after a biological experiment using alkyne-modified fluorophores or alkyne-containing resins, respectively, via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The research involved studying the effects of post-translational modifications (PTMs), antigen complexation and glycosylation of antibodies in immune complexes on the uptake, proteolysis, and T cell activation by dendritic cells (DCs) of Aha-containing antigens. Additionally, a new method was developed to enrich low abundant bioorthogonal antigenic fragments from complex mixtures. This method can be used in future studies to identify processed Aha-containing fragments from immune cells that are preserved for T cell presentation. Show less
Pulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades,... Show morePulmonary embolism (PE) is a serious and sometimes life-threatening condition that refers to a blood clot that occludes the arteries of the lung. Despite all improvements over the past decades, diagnosing PE is still a difficult process due to the non-specific symptoms, which can frequently overlap with symptoms of other cardiopulmonary diseases. Currently recommended diagnostic strategies for suspected acute PE consist of standardized assessment of the clinical pre-test probability (CPTP) using validated clinical decision rules (CDRs) and D-dimer testing. PE is considered safely ruled out in patients with a non-high CPTP and a normal D-dimer test. Imaging tests as computed tomography pulmonary angiography (CTPA) are required in the case of a high CPTP and/or abnormal D-dimer test to confirm the diagnosis. The first part of this thesis describes the challenges of diagnosing PE in general and in specific clinically relevant patient subgroups. Moreover, this part evaluates the diagnostic performance of non-invasive diagnostic strategies for suspected PE in specific relevant patient subgroups. The second part of this thesis focuses on venous thrombotic complications in hospitalized patients with COVID-19. Show less
Following the Big Bang, structure in the Universe started collapsing under the force of gravity. This resulted in the formation of the first stars, galaxies and clusters of galaxies. The majority... Show moreFollowing the Big Bang, structure in the Universe started collapsing under the force of gravity. This resulted in the formation of the first stars, galaxies and clusters of galaxies. The majority of the baryonic mass in a galaxy cluster is part of the hot intracluster medium, which permeates the entire cluster As this medium cools down, it accretes onto the central galaxies where it triggers the formation of new stars. However, it also feeds the central supermassive black hole, creating an active galactic nucleus (AGN) that injects a large amount of energy into the intracluster medium again, resulting in a feedback cycle. This feedback cycle is an essential ingredient in the formation and evolution of galaxies. Using new high-resolution radio observations taken with the LOw Frequency ARray (LOFAR), we study AGN feedback in galaxy clusters in unprecedented detail, gaining insight into both the duty cycle of the AGN as well as the energy budget of the feedback cycle. Show less
Until now the Dutch women’s movement was mostly studied for a short period or in a single aspect, like one organisation. The choice for Leiden, a middle size Dutch town, made it possible to study... Show moreUntil now the Dutch women’s movement was mostly studied for a short period or in a single aspect, like one organisation. The choice for Leiden, a middle size Dutch town, made it possible to study the women’s movement as a whole over a long period of 130 years. This period included the so-called first feminist wave, with women’s suffrage as most prominent issue and the second with the abortion right movement as focus point, including the period in between. I analysed the wave movement that proved to be different for different organisations and showed an extra upheaval, a wave, in the 1930s. I also studied the relation of the women’s movement with – in the beginning - charitable women’s organisations, with other social movements, like the peace movement, and with political parties. The choice for Leiden also made it possible to go deeper into the background of the women (and men) involved in the women’s movement. The University proved to be a constant supplier of women for the women’s movement. Show less
This is the first study to investigate the ecology and conservation management of the white lion (Panthera leo melanochaita). The white lion is a natural colour variant, or leucistic form, of the... Show moreThis is the first study to investigate the ecology and conservation management of the white lion (Panthera leo melanochaita). The white lion is a natural colour variant, or leucistic form, of the southern subspecies of the African lion (Panthera leo melanochaita) that has only ever been recorded in the wild in the Timbavati, Klaserie and Umbabat Private Nature Reserves (Greater Timbavati Region) and the Central Kruger National Park (KNP) – the Greater Kruger Park Region – in South Africa. The frequency of occurrence of white lions in the region was increasing in the 1980s, with 12 recorded sightings in nine different prides in the Timbavati Private Nature Reserve and Central Kruger National Park. From 1994 to 2006, there was an absence of white lions in the wild, the perception being that white lions cannot survive in the wild due to a lack of camouflage preventing them from hunting successfully. In 2006 a non-profit conservation organisation, the Global White Lion Protection Trust, therefore initiated the first reintroduction of white lions to free-roaming conditions within a small fenced wildlife area in the Greater Kruger Park Region. The results of this doctoral study suggest that the reintroduced white lions show natural behaviour, similar to wild tawny lions, in terms of their social interactions, home range and movement patterns, and their hunting success. These findings are supported by historical observations at the Timbavati Private Nature Reserve, and recent observations at Sanbona and Pumba Private Game Reserves. these observations suggest that white lions are capable of surviving in the wild as part of wild tawny prides. Based on these findings it is concluded that the reason for the low survival rate of white lion cubs in the Greater Kruger Park Region was due to anthropogenic activities And not due to lack of competitive capacity of white lions. Between 2006 and 2022 white lion cubs (17) were born in the Greater Kruger Park Region, confirming that the recessive gene is still present in the wild lion population. Although white lions occur within the wild lion population in this region, due to the rarity of white lions (only 13 wild managed lions and 3 wild adult white lions), the anthropogenic activities that affect the wild tawny lion population may have had a more significant impact on wild and managed white lions in that region. Human-lion conflict and trade in lion body parts for traditional and cultural use are two of the anthropogenic activities that have been identified as a major threat to wild lions in South Africa. The long-standing cultural significance of white lions amongst the local Tsonga and Sepedi communities in the Greater Kruger Park Region led white lions to be referred to as a ‘living cultural heritage’. According to the Global White Lion Protection Trust, this cultural belief may help to mitigate human-lion conflict and prevent lion poaching for body parts. The low incidence of lion poaching and human-lion conflict over the past 20 years at the wildlife areas managed by the Global White Lion Protection Trust suggests that a positive attitude of local Tsonga and Sepedi communities towards the conservation of white lions has contributed to the conservation of white lions in the bordering wildlife areas. The present study had a number of limitations, namely: the small size of the prides and small number of prides studied, the restricted size of the fenced wildlife area included in the study and the captive-origin of the white lions studied. The findings of the study are therefore preliminary, but they do indicate that white lions display natural behaviour similar to wild tawny lions, and they can therefore survive in the wild. This finding is supported by historical observations. The implications of the study are therefore expected to advance the existing knowledge of the ecology of the white lion, may contribute to reintroduction techniques and translocation success for white lions. The results of this study may also contribute to the conservation management of white lions in relation to the metapopulation approach for lions in South Africa. The findings suggest the potential role of the white lion in lion conservation in the Greater Kruger Park Region, in terms of their economic, eco-touristic and cultural significance. Show less
The main aim of this dissertation was to provide insight into possible subtle forms of bias in youth socialization by various socializing agents in the Netherlands, and exploring new ways to... Show moreThe main aim of this dissertation was to provide insight into possible subtle forms of bias in youth socialization by various socializing agents in the Netherlands, and exploring new ways to document bias. Additionally, it addresses the importance of using sound statistical methods for calculating effect sizes. Social bias and unequal treatment of people can lead to structural societal inequalities. Findings in research on the sustained existence of bias have been inconsistent. These inconsistencies may obscure the importance of continuous effort to diminish inequalities. By studying subtle messages, this dissertation shows that bias is present in various contexts. Firstly, parents who talked about kissing and dating to their adolescent child subtly endorsed a sexual double standard, for instance by describing girls as sluts and boys as players. Secondly, in written evaluations by teachers on report cards of primary school pupils, positive bias towards White Dutch girls was found. Lastly, prolonged media attention to a child sexual abuse case was found to negatively affect the attitudes of parents towards male babysitters.As bias and discrimination change over time and context, continuous study is necessary. This dissertation demonstrates that using relevant and authentic data is an important tool in unveiling subtle bias. Show less
The history of the Central African Republic (CAR) has been one of persistent violence, despite internal and external attempts to break the cycle of misfortune in the country. A number of factors... Show moreThe history of the Central African Republic (CAR) has been one of persistent violence, despite internal and external attempts to break the cycle of misfortune in the country. A number of factors are cited as determinants or amplifiers to explain this ever-renewed cycle of violence in the country, including a disastrous colonial legacy, poor governance, an abundance of natural resources in an uncontrolled territory, greed for power, the collapse of the state, or a combination of all or some of these non-exhaustive factors. However, over and above these not insignificant factors, we need to reconsider the weight of history and the role of young people as constants in the recurrent conflict in the Central African Republic. To explain the durability of this context of instability inscribed in a continuum, we propose the concept of the political arena, a situation of confrontation built up over the course of history, and within which a large number of young people are growing up with a limited agency. We conclude that young people in the CAR have ultimately become a usable resource, having been exploited in the same way as natural resources since pre-colonial and colonial times. Hence the reproduction and/or continuation of violent and recurrent conflicts in the Central African Republic. Show less
This thesis has demonstrated the use of mobile health devices for up to three months after cardiothoracic surgery. Mobile health devices, as used in this thesis, were found to increase... Show moreThis thesis has demonstrated the use of mobile health devices for up to three months after cardiothoracic surgery. Mobile health devices, as used in this thesis, were found to increase postoperative atrial fibrillation detection, which may also positively impact complications such as ischemic stroke. Moreover, this thesis demonstrated a positive impact of mobile health on both blood pressure and cholesterol level outcomes, which is hypothesized to be related to an increased patient engagement. Potential pitfalls of mobile health are mHealth literacy in both patients and healthcare providers, data integration and data safety. Future researchers are advised to focus on these factors when implementing or improving mobile health interventions. Show less
This thesis deals with the use of sound in interactions in the context of participatory systems and data sonification. We investigate an interactive environment where participants perceive... Show moreThis thesis deals with the use of sound in interactions in the context of participatory systems and data sonification. We investigate an interactive environment where participants perceive information of the data through sound elements. To define the interactive process, we employ the dialogue model, breaking it down into three components: subject, verbal, and adjective. This supports the purpose of having a better understanding of the topics addressed in this thesis: i.e., interaction models, data sonification, interaction & design, and evaluation of data sonification. Moreover, it contributes new findings and perspectives to these topics. Show less
The first part of this thesis evaluates the proportion of germline APC and MUTYH pathogenic variants in colorectal polyposis patients and subsequently identifies the substantial proportion... Show moreThe first part of this thesis evaluates the proportion of germline APC and MUTYH pathogenic variants in colorectal polyposis patients and subsequently identifies the substantial proportion polyposis patients remaining unexplained. Part II of this thesis elucidates the significance of APC mosaicism in these unexplained polyposis patients. Analysis of more than 400 patients resulted in a suggestion for both testing and surveillance guidelines. Moreover, chapter 4 describes the interesting finding of multiple APC mosaicism cases in one family with the family members having distinct mosaic patterns and phenotypes. The last part of this thesis assesses another explanation for the development of colorectal adenomatous polyps, namely the presence of pks+ E. coli and colibactin-associated mutational signatures. In this part we describe the common c.835-8A>G APC splice variant as fitting the mutational signature caused by colibactin, which is produced by pks+ E. coli. Moreover, we examine this mutational signature and fecal pks genes in a random selection of our cohort. Show less
This thesis explores biochemical and genetical changes associated with migraine and cluster headache. This research aims to increase knowledge of the pathophysiology and signaling pathways involved... Show moreThis thesis explores biochemical and genetical changes associated with migraine and cluster headache. This research aims to increase knowledge of the pathophysiology and signaling pathways involved in migraine and cluster headache, thereby identifying new targets for treatment. Uncovering the biological mechanisms on how patients differ from those without disease leads to a better understanding of the pathophysiology of primary headache disorders. The biological systems in our body are related to each other, and are based on the genomic blueprint and lead via epigenetics, transcription and translation to proteins and biomolecules. The first part of the dissertation focuses on the examination of biomolecules in body fluids (blood and cerebrospinal fluid) in migraineurs. Several studies showed that biomolecule concentrations differed between people with and without migraine for lipids, amino acids and metabolites of glucose metabolism. These results indicate a general disruption of the metabolic profile in migraineurs. For other substances, no differences were found. The second part of the thesis looked at the genetic blueprint of various headache disorders. There a genetic difference between people with migraine and people without migraine was found. In addition, a genetic difference between people with and without cluster headache was found. Show less
There is a lack of knowledge regarding the definition, classification and appropriate treatment of malignant lateral lymph nodes in patients with (locally advanced) rectal cancer. This thesis aimed... Show moreThere is a lack of knowledge regarding the definition, classification and appropriate treatment of malignant lateral lymph nodes in patients with (locally advanced) rectal cancer. This thesis aimed to increase this knowledge and improve treatment practices for this population. Show less
Galaxies in the Universe are distributed along the intricate framework of the Cosmic Web. Groups and clusters of galaxies comprise the densest regions in this network, and therefore, are excellent... Show moreGalaxies in the Universe are distributed along the intricate framework of the Cosmic Web. Groups and clusters of galaxies comprise the densest regions in this network, and therefore, are excellent cosmic laboratories to study different aspects of galaxy evolution in extreme environments. In this thesis, we explore a wide range of properties of cluster galaxies and their host systems, such as the spatial distribution of mass in galaxies within clusters, the faint and diffuse stellar halo in groups and clusters, and processes that quench massive galaxies in high-redshift clusters. For this exploration, we develop methods to enable and optimise detailed comparisons of state-of-the-art observations and cosmological hydrodynamic simulations over more than half of the age of the Universe. Through our carefully-designed analyses, we test the validity of the simulations for studying the low-surface-brightness and high-redshift Universe. We also demonstrate how such comparisons can provide novel insights and motivate new tests for understanding galaxy evolution in dense environments. Show less
Transport inspectorates are looking for novel methods to identify dangerous behavior, ultimately to reduce risks associated to the movements of people and goods. We explore a data-driven approach... Show moreTransport inspectorates are looking for novel methods to identify dangerous behavior, ultimately to reduce risks associated to the movements of people and goods. We explore a data-driven approach to arrive at smart inspections of vehicles. Inspections are smart when they are performed (1) accurate, (2) automated, (3) fair, and (4) in an interpretable manner. We leverage tools from the network science and machine learning domain to encode the behavioral aspect of vehicle’s behavior. Tools used in this thesis include community detection, link prediction, and assortativity. We explore their applicability and provide technical methods. In the final chapter, we also discuss the matter of fairness in machine learning. Show less
