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Exploiting human leukocyte antigens for the treatment and diagnosis of gastrointestinal disesaes
No full textThe aim of this thesis was to allocate opportunities to exploit HLA complexes for both diagnosis and rational therapeutic vaccine design for gastrointestinal diseases that currently have dire outcomes. To this end, I have taken a dual approach to:1) Investigate how we can exploit dendritic cells as highly skilled antigen-presenting cells to further refine the design of novel therapeutic vaccines (part I of this thesis)2) Explore the diagnostic and therapeutic value of soluble HLA complexes and their peptide cargo in circulation of patients suffering from gastrointestinal disease (part II of this thesis
Historisch besef en koloniaal verleden:Veranderende interpretaties in het onderwijs
No full textIn 2020 zei David Van Reybrouck in een interview naar aanleiding van zijn boek Revolusi: ‘Ik wist niet dat in grote delen van de Nederlandse samenleving zo weinig historisch besef is. Ik hoop dat mijn boek bijdraagt aan inzicht, en ook leerkrachten bereikt.’ Het is scherpe kritiek op het historisch besef van Nederlanders over het kolonialisme en de onafhankelijkheidsstrijd van Indonesië. Maar wat bedoelt Van Reybrouck precies met historisch besef
International investment law from below:Taking local community rights seriously
Full text linkThis thesis challenges the traditional conception of extractive investment disputes as only affecting states and foreign investors, and instead takes a view of such disputes ‘from below’, centring the interests and experiences of local communities affected by extractive foreign investment projects. Interviews with affected local community members reveal how investment arbitration is more than an elite legal process abstracted from the disputed ground. Instead, the lives of affected communities are bound up in the goings-on of investment tribunals, in the stories that are being told about them, the fight they put their souls into, and the future of their homes. Incorporating a qualitative methodology into the study of investment arbitration brings a human aspect to an epistemic community that tends to uphold traditional black-letter and doctrinal boundaries. Taking a strictly legalistic view of such cases works to obscure the real-world impacts of how the international economic regime is ordered. If the rights and interests of local communities are made visible, we can start conceptualising them as important in the design of investment projects and resolution of disputes, and stop pretending that they do not matter
Microbial safety in gastrointestinal endoscopy:Risk factors, surveillance, and interventions
No full textEndoscopes are essential for the diagnosis and treatment of gastrointestinal conditions but also pose a potential risk of contamination and infection. This thesis examines the frequency, causes, risks, and potential solutions for endoscope contamination, aiming to improve patient safety.International outbreaks have shown that particularly duodenoscopes, used in endoscopic retrograde cholangiopancreatography (ERCP) procedures, can become contaminated and transmit pathogens. This thesis demonstrates that infections from contaminated duodenoscopes also occur outside of outbreak situations. The risk appears low (<0.9%), but these infections are difficult to recognize, necessitating further research.Additionally, the prevalence of multidrug-resistant organisms (MDROs) among ERCP patients was investigated, which is about 11% in the Netherlands. However, the reliability of rectal swabs as a screening method proved to be limited. The presence of MDROs in the duodenum was therefore overestimated, potentially leading to unnecessary preventive measures.The frequency of duodenoscope contamination with oral or gastrointestinal flora ranged from 14% to 48% in retrospective analyses and was 21% in a prospective study. The biopsy and suction channels were the most frequently contaminated. The duration of manual pre-cleaning was found to be important, with manual cleaning times shorter than five minutes significantly increasing the risk of contamination. Interventions such as the introduction of a new endoscope cleaning brush (Endoss Push and Pull) and an automatic water-based cleaning system (Aquatyphoon) reduced contamination frequency.Finally, this thesis shows that culture methods are not always reliable, and contamination of duodenoscopes sometimes goes unnoticed. Biofilm plays a central role in this process. An innovative mass spectrometric method is described as a potential future technique for biofilm detection in endoscopes.<br/
Aftrek van btw op vastgoedgerelateerde kosten
No full textDit onderzoek richt zich op het huidige Europese en Nederlandse positief recht ten aanzien van de aftrek van btw bij transacties met en exploitatie van onroerende zaken. De auteur onderzoekt niet alleen dit positieve recht, maar stelt ook een toetsingskader vast aan de hand waarvan kan worden vastgesteld wat op dit terrein het wenselijk recht is. Dit toetsingskader bestaat enerzijds uit het rechtskarakter van de btw en anderzijds uit de kwaliteit van de wet- en regelgeving.De auteur stelt vast dat het rechtskarakter van de btw dat van een verbruiksbelasting is. Het onderzoek van de auteur naar mogelijke kwaliteitsnormen leidt hem tot een selectie van vier kwaliteitsnormen, te weten: eenvoud, duidelijkheid, doelmatigheid en uitvoerbaarheid.Aan de hand van het onderzoek naar het positief recht en aan de hand van het toetsingskader presenteert de auteur vervolgens aanbevelingen tot wijziging van de huidige wet- en regelgeving.<br/
Neural mechanisms and genetic modulation of associative motor learning
No full textAssociative motor learning is a fundamental mechanism by which organisms adapt their behavior based on experience. Pavlovian eyeblink conditioning is a widely used experimental paradigm to investigate the neural circuits and cellular processes underlying this form of learning. In this thesis, eyeblink conditioning is employed to systematically examine the contribution of specific brain structures, neural circuits, and genetic factors to associative learning. The work is positioned within the broader context of learning and memory research, with particular emphasis on the cerebellum and its interactions with brainstem nuclei and other brain regions, as well as the cellular and molecular mechanisms underlying cerebellar learning, including synaptic plasticity and calcium dependent signaling.Using the tottering mouse model, which carries mutations in the Cacna1a gene encoding voltage gated calcium channels, this thesis demonstrates that intact calcium channel function is essential for cerebellum dependent eyeblink conditioning. Disrupted calcium signaling results in severe impairments in associative motor learning, highlighting the critical role of calcium dependent processes in cerebellar function. In addition, this thesis shows that cerebellar learning is modulated by brain regions beyond the cerebellum. Selective activation of somatostatin positive neurons in the central amygdala enhances strength of conditioned eyeblink responses, providing new insight into the indirect interactions between emotional and motor learning systems. Finally, the neural mechanisms underlying Neurofibromatosis Type 1 are investigated using a genetic mouse model. These experiments reveal that NF1 mutations are associated with altered neural signaling and changes in cerebellum dependent learning outcomes, including enhanced eyeblink conditioning. Taken together, the results of this thesis show that associative motor learning is shaped by distinct genetic and circuit-level manipulations, each exerting specific and sometimes opposing effects on cerebellum-dependent learning. It addresses methodological challenges within the eyeblink conditioning field and emphasizes the need for standardized experimental protocols to improve reproducibility, cross study comparability, and efficient use of animal models.<br/
Neural mechanisms and genetic modulation of associative motor learning
No full textAssociative motor learning is a fundamental mechanism by which organisms adapt their behavior based on experience. Pavlovian eyeblink conditioning is a widely used experimental paradigm to investigate the neural circuits and cellular processes underlying this form of learning. In this thesis, eyeblink conditioning is employed to systematically examine the contribution of specific brain structures, neural circuits, and genetic factors to associative learning. The work is positioned within the broader context of learning and memory research, with particular emphasis on the cerebellum and its interactions with brainstem nuclei and other brain regions, as well as the cellular and molecular mechanisms underlying cerebellar learning, including synaptic plasticity and calcium dependent signaling.Using the tottering mouse model, which carries mutations in the Cacna1a gene encoding voltage gated calcium channels, this thesis demonstrates that intact calcium channel function is essential for cerebellum dependent eyeblink conditioning. Disrupted calcium signaling results in severe impairments in associative motor learning, highlighting the critical role of calcium dependent processes in cerebellar function. In addition, this thesis shows that cerebellar learning is modulated by brain regions beyond the cerebellum. Selective activation of somatostatin positive neurons in the central amygdala enhances strength of conditioned eyeblink responses, providing new insight into the indirect interactions between emotional and motor learning systems. Finally, the neural mechanisms underlying Neurofibromatosis Type 1 are investigated using a genetic mouse model. These experiments reveal that NF1 mutations are associated with altered neural signaling and changes in cerebellum dependent learning outcomes, including enhanced eyeblink conditioning. Taken together, the results of this thesis show that associative motor learning is shaped by distinct genetic and circuit-level manipulations, each exerting specific and sometimes opposing effects on cerebellum-dependent learning. It addresses methodological challenges within the eyeblink conditioning field and emphasizes the need for standardized experimental protocols to improve reproducibility, cross study comparability, and efficient use of animal models.<br/
Mechanisms of USPs, and Sequential Cleavage of Ubiquitin Chains on PCNA by USP1/UAF1
No full textIn every cell in our body, proteins are the tiny molecular machines that carry out all the different functions of the cell, virtually performing every single active process in the human body. A single protein can perform multiple roles within the cell, which needs to be tightly regulated so that we do not develop disease. By attaching ubiquitin to a protein, the cell can change the fate of that protein: switching between pathways or directing it towards degradation. In this thesis, we study the molecular process in which ubiquitin is removed from other proteins in a process called ‘deubiquitination’, with a focus on the mechanisms of deubiquitinating enzymes that belong to the USP family. The results reveal novel insights in the function and regulation of different USPs. Importantly, it shows that individual USPs distinguish themselves in important ways on a molecular level, despite their many similarities. We show that USP1/UAF1 uses a unique ubiquitin-chain cleaving mechanism unlike any other USP. USP48 is revealed to have a C-terminal peptide, party similar to that of other USPs, which distinguishes itself in important way. Finally, we show that the mechanism of catalysis itself, thought to be highly conserved in USPs, actually varies between different USPs and is more complex than we realized. These biochemical and structural studies of this thesis allow us to gain detailed insights into the nuances of proteins, which can guide and aid us in better understanding the cell
Understanding quality of life in China:Cultural influences and measurements challenges when East meets West
No full textThis PhD thesis explores cultural differences in the perception and evaluation of Quality of Life (QoL), with a particular focus on the Chinese context. It explores both Traditional Chinese Medicine (TCM) and Modern Medicine (MM) frameworks to examine how these paradigms conceptualize QoL, where they converge, and how they diverge. The research also investigates the extent to which existing QoL instruments capture what matters most to Chinese populations
Mechanism of DNA daughter strand incision during the initiation of mismatch repair
No full textThis thesis will focus on the early steps of MMR, namely on the function of MutS andMutL during the reaction steps from mismatch recognition to DNA strand incision.Further details regarding the initiation of repair and the mode of communication ofMutS and MutL on DNA are detailed in our review [Chapter 2]