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Optimising PROTACs against integral membrane proteins
No full textIntegral membrane proteins (IMPs) play a critical role in the pathophysiology of a range of diseases. Resistance mechanisms to conventional IMP-targeted therapeutics have driven the need for novel modalities. While PROteolysis TArgeting Chimeras (PROTACs) have shown significant potential for degrading cytosolic proteins, their use in the targeted degradation of IMPs remains challenging due to structural complexity and limited accessibility of IMPs. This thesis explored novel approaches to support the development of IMP-targeted PROTACs. First, potential reasons underlying the complexity of targeting IMPs for PROTAC-mediated degradation were discussed. These included the strong IMP-lipid bilayer interaction and poor understanding of the mechanism of degradation. Next, we addressed current limitations in traditional immunoblotting, which has low throughput and lacks spatial resolution. We proposed an immunofluorescence-based protocol, which provides increased accuracy, a qualitative and quantitative insight into degradation efficacy and a critical distinction between cell membrane-localised and intracellular IMP protein pools. To address the underutilisation of the E3 ligase repertoire, we also developed a ligand-independent E3 ligase recruitment system, integrated with an imaging-based assay, to identify putative E3 ligase candidates. Lastly, we integrated machine learning with proteome-profiling to characterise off target effects of androgen receptor-targeted PROTACs. We demonstrated a link between observed mitochondrial toxicity and the respiratory chain complex I and provided an analytical framework for the proteome-guided rational PROTAC development. Overall, the body of work conducted as part of the PhD thesis provides novel insights into more effective drug development for the targeted degradation of IMPs
Toward opportunities for inclusive GP-specialty training:On building bridges over the unspoken undercurrents
No full textMigration has led to rapidly increased diversity in population demographics, necessitating a healthcare system that addresses its population's varied cultural and social needs. Given primary care's central role, these developments require a GP-workforce that reflects and respects this diversity. However, despite this requirement, ethnic minority GP-trainees in the Netherlands seem more at risk of being assessed as underperforming than their majority peers.This dissertation investigates barriers and facilitators faced by these trainees, examining the impact on their professional development and identifying strategies for fostering an inclusive training environment. The research comprises four complementary studies: Quantitative Analysis of Underperformance Assessments: An analysis of 1,700 trainees revealed that those from minority backgrounds are at a significantly higher risk of being labeled as 'underperforming,' even after adjusting for age and gender.Lived Experiences of Minority GP-Trainees during their 'Educational Journey': In-depth interviews with 14 trainees highlighted experienced bias, microaggressions, and a lack of belonging within predominantly 'white' institutions.Coping Strategies of these trainees: Trainees reported various coping mechanisms, including emotional distancing, religious support, and peer networking, which may put them at risk for isolation and hinder professional growth.Intervention Development: Seven interventions were proposed and co-designed with trainees and faculty. These include mandatory DEI training for all stakeholders, DEI ambassadors, and a significant voice for minority trainees in their curriculum. The researchers underscore the need for continuous evaluation and adjustment in GP-specialty training programs to ensure a genuinely inclusive educational environment that reflects the diversity of the broader society.</p
The diverse roles of FoxO6 in the developing and adult mouse brain
No full textFoxO proteins are known to be involved in a wide array of biological processes, including apoptosis, cellular survival, differentiation and stress resistance. Recently, it came to the attention that FoxO6 displays a specific temporal and spatial expression pattern in the brain, implying that FoxO6 plays a role in the central nervous system. In this thesis the aim was to characterize the function of FoxO6 in the developing and adult mouse brain. Using different FoxO6 deficient animal models, we show that embryonic cortical cells are unable to migrate properly to the superficial layers of the cortex during cortical development. We also identified multiple target genes of FoxO6 and show that ectopic expression of one identified factor, Plxna4, was able to restore the hampered migration. Furthermore, we analyzed the effects of FoxO6 deficiency in the postnatal brain which showed phenotypical changes that resemble pathological changes observed in Cortical Malformation Syndromes, suggesting an involvement of FoxO6 in the development of cortical malformations. Next to these changes in cortical migration we observed other changes indicating that FoxO6 has multiple roles in the developing and adult brain. These overall changes are (more) complex and might even be related to each other. In summary, the research performed in this thesis contributes to the general knowledge of the developing cortex and provides novel insights in the role of FoxO6 and its downstream targets in multiple processes related to brain development and functioning
New Insights from Old Programs:The Structure of The First ALGOL 60 System
No full textIt is a commonplace that computer programming is hard, especially when one aims at creating a program that is correct. What kind of methods should be used to reach that goal is the subject of heated debates. Our thesis is a contribution to these discussions: To understand what computer programming is, and how it should be done, we propose to study how it is actually done – that is, to induce elements of method from factual observation. Our thesis takes the form of a detailed analysis, based on a careful reconstruction, of a particular well-crafted computer program: the first ALGOL 60 system, designed and implemented at the Mathematical Center (now CWI) by E. W. Dijkstra and J. A. Zonneveld, with the assistance of S. J. Christen and M. J. H. Römgens, on an Electrologica X1 computer. It is divided into three main chapters. Chapter I presents the two elements of the problem the Mathematical Center team was facing, namely the ALGOL 60 language and the X1 computer. Chapter II discusses the principles of its solution, explains the implementation choices made by the Mathematical Center team, and compares them to other possible choices. Chapter III presents the details of the Mathematical Center ALGOL 60 system, on an ISO C version of that system, reverse engineered from its X1 assembler source. This program is about 3000 lines long, and is composed of 173 subroutines working on 57 global variables. Finally, our conclusion, in the form of 17 theses and 4 hypotheses, indicates some lessons, in particular on computer programming methods, that we believe can be drawn from the analysis of that particular computer program
Developing gut microbiome-derived therapies for obesity, insulin resistance, and type 1 diabetes
No full textIn this thesis, we investigate the role of the gut microbiome in obesity, insulin resistance and type 1 diabetes. In part I, we used the Amsterdam based GUTDM1-cohort, consisting of 500 individuals with type 1 diabetes, to study endocrine and exocrine dysfunction and the effects of food intake on glycaemic control. We disclose that fibre- and carbohydrate intake are independently associated with glycaemic control and that exocrine pancreatic insufficiency is a prevalent condition in type 1 diabetes. Furthermore, we show the persistence of the insulin prohormone proinsulin in longstanding type 1 diabetes, possibly indicating dormant β-cells. In part II, we study the effect of individual gut-microbiome derived components on metabolic health. We show the improvement in glucose metabolism in individuals with metabolic syndrome upon ingestion of 6-bromotryptophan, a gut microbiome-produced metabolite. We present the protocol of the ongoing PIGER-trial, which aims to diminish fructose-derived ethanol via the ingestion of the probiotic strain Desulfovibrio piger. Finally, we show the safety and gut engraftment of EcNΔClbP, a bio-engineered bacterial strain lacking the carcinogenic protein colibactin, hence providing a platform for future probiotic development. Taken together, this thesis provides novel insights in the pathophysiology and management of type 1 diabetes and explores novel gut microbiome-derived therapeutic agents in obesity, related diseases and type 1 diabetes
The role of microbial ecology in the functioning of slow sand filters for drinking water production
No full textSafe drinking water is essential for public health, and biofiltration offers a natural, sustainable approach to its production. However, the biological mechanisms underpinning indoor slow sand filtration (SSF), often the final treatment stage, are not fully understood. This thesis investigates the microbial ecology of these filters, focusing specifically on the "Schmutzdecke" (the biologically active surface layer) to enhance understanding of SSF performance.Using full-scale and laboratory experiments, the research compared total microbial presence (DNA) with metabolically active populations (RNA). The findings highlighted a significant difference: while DNA analysis identified many members, RNA profiling narrowed this down to the specific active groups driving bioactivities. This confirms that monitoring active communities provides deeper insight than presence alone. Additionally, the study revealed that influent water quality affects the Schmutzdecke microbial community, determining whether the SSF acts as a simple polisher or an active modifier.The research showed that a filter’s age alone does not reliably predict its maturity. Instead, biochemical markers, particularly the protein-to-carbohydrate ratio, emerged as a potentially accurate predictor of removal efficiency and stability. Further experiments demonstrated that sand grain size and type influence initial Schmutzdecke formation, while inoculation with mature Schmutzdecke may accelerate ripening. Modelling of Escherichia coli removal indicated that in indoor SSFs, pathogens are removed primarily through physical attachment, enhanced by Schmutzdecke activity, rather than by direct biological predation.In conclusion, this thesis supports a shift towards activity-based monitoring. By integrating biochemical and microbial analyses with multi-scale experiments, it offers new strategies for performance prediction and design optimisation, reinforcing SSF as a resilient technology for modern drinking water treatment
Hepatitis C virus primary and reinfection among MSM in the DAA era:Changes in infections, behaviours and prevention
No full textHepatitis C virus (HCV) is a type of viral hepatitis which is primarily transmitted by blood-to-blood contact. Since 2000, outbreaks of sexually transmitted HCV have been reported among men who have sex with men (MSM) with HIV in high-income countries, including the Netherlands. The introduction of highly effective direct-acting antiviral treatment in 2014 has substantially changed the epidemiology of HCV in this group. This thesis examines recent HCV epidemiology among MSM, explores behavioural changes after HCV clearance, and aims to develop and implement interventions to potentially reduce the risk of HCV reinfection. Chapters 2 and 3 investigate the epidemiology of HCV among MSM without HIV who are not using HIV pre-exposure prophylaxis (PrEP), and among MSM and transgender persons using PrEP in the Netherlands. Chapter 4 validates the HCV-MOSAIC risk score as a tool to support testing for HCV reinfection among MSM with HIV. In chapter 5, we describe changes in HCV-related behaviours before, during and after treatment, comparing the former pegylated interferon regimen with modern DAA-based therapy. Chapter 6 and 7 present different behavioural trajectories following HCV clearance among MSM with HIV and within an international cohort of people with HIV. In chapter 8, we examine the impact of the COVID-19 and mpox outbreaks on behaviours associated with HCV among MSM with a cleared infection. Finally, chapter 9 outlines a study protocol including two interventions – home-based self-sampling for HCV testing and an online behavioural intervention – aimed at reducing behaviours and prevent onward transmission
Surgical site infection in ankle fracture surgery:Risk factors and current management
No full textThis thesis investigates complications and optimization of surgical management in ankle fracture surgery, with a focus on surgical site infections (SSI), timing of fixation, implant selection, and clinically relevant outcome measures.Part I addresses SSI following open reduction and internal fixation (ORIF) of ankle fractures. A large multicenter retrospective study showed an overall SSI incidence of 9.4%, with open fractures identified as the most important independent risk factor. Deep SSI were strongly associated with diabetes mellitus, higher ASA classification, and open fractures. Microbiological analyses demonstrated Staphylococcus aureus as the most common pathogen in both superficial and deep infections, while gram-negative bacteria, particularly Enterobacter cloacae species, were frequently identified in deep SSI and open fractures. These findings support empirical antibiotic treatment targeting both gram-positive and gram-negative microorganisms. A literature review confirmed established risk factors, diagnostic strategies, and treatment options, and highlighted the negative impact of SSI on functional outcome, emphasizing the importance of preventive measures such as timely surgery and appropriate antibiotic prophylaxis.Part II focuses on refining surgical strategies for ankle fractures. In fracture-dislocations, acute ORIF within 48 hours was shown to be safe when soft tissue conditions permitted, without increased rates of SSI or reoperations compared to delayed fixation. Mini-fragment fibular plates demonstrated favorable functional outcomes and low complication and implant removal rates, suggesting clinical and potential cost benefits compared to traditional small-fragment implants. Finally, this thesis established the minimal clinically important difference (MCID) for the AOFAS Ankle-Hindfoot Scale, enabling meaningful interpretation of patient-reported outcomes following ankle fracture surgery
Animating metamaterials with non-reciprocity
No full textComplex material responses can be achieved by engineering the interactions between a material’s internal components and the geometry that organizes them. Yet even the most sophisticated designed materials remain limited compared to the adaptive, far-from-equilibrium behavior observed in living systems. This thesis explores how materials can be endowed with dynamical and autonomous behavior by embedding non-reciprocal interactions—forces that violate action-reaction symmetry—directly into their structure.This thesis explores the interplay between non-reciprocity and nonlinearity in active elastic metamaterials, which leads to emergent behaviors such as unidirectional soliton propagation, self-spontaneous locomotion, and cyclical shape changes. These effects arise not from external programming or centralized control, but from structured internal asymmetries and feedback. First, we uncover new classes of driven-dissipative solitons, including both topological and breathing solitons. Then, we focus on limit cycle dynamics in odd elastic metamaterials that generate robotic functionalities such as locomotion. We demonstrate how their vibrational spectra exhibit active phonon gaps which depend on the material's geometry. Finally, we uncover wave coarsening, a synchronization mechanism for waves mediated by the momentum-conserving nature of non-reciprocal and non-pairwise interactions.Taken together, this thesis offers a framework for designing active solids—materials that respond actively to deformations, mimicking certain aspects of biological autonomy such as locomotion and shape changing. This points toward a new generation of active matter that blurs the line between material and machine, capable of movement, adaptation, and decision-making
Perspective matters in recovery:From fragmented to collaborative care in complex psychosis
No full textPeople with a hard to manage psychosis and complex co-occurring challenges (“complex psychosis”) and their families often go through long and difficult care trajectories in mental healthcare, including admission to long-term inpatient mental health rehabilitation services. Arguably, they face a complicated (personal) recovery process. People with a complex psychosis, families and professionals often hold diverging views on the problem, and what should happen, which complicates their collaboration for recovery. Unfortunately, research on complex psychosis is scarce, due to the very complexity of problems and potential unwillingness and/or inability to consent to research. This thesis explored perspectives that potentially help to improve care for people with a complex psychosis and their families. Part I discusses prerequisites to do research in this hard-to-access group. Part II focuses on preventing cumbersome trajectories, including the role of familial cognitive vulnerability, long-term outcome prediction and hypotheses on ways to care delivery to people with complex psychosis. Part III focuses on the needs people with a complex psychosis, their family and mental health professionals have to effectively collaborate for recovery, based on their personal perspectives. In conclusion, participatory research, early identification of vulnerabilities of those with complex psychosis, and collaborative care that tolerates diverging perspectives, with continuity of those involved, should go together, to prevent fragmentation and foster growth in people with a complex psychosis, their family and professionals