International Migration, Integration and Social Cohesion online publications
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The rheostats of the immune response:Post-transcriptional regulation of gene expression by RNA-binding proteins in adaptive immunity
No full textThe adaptive immune system protectsthe host from pathogens and cancer through the actions of B and T lymphocytes.B cells produce antibodies, while CD4⁺ and CD8⁺ T cells secrete effector molecules,including inflammatory cytokines such as Tumor Necrosis Factor (TNF),Interferon gamma (IFN-g), and Interleukin-2 (IL-2). To perform their functions, T and Bcells differentiate into specialized subsets, a process governed by geneexpression programs that are tightly regulated at both transcriptional andpost-transcriptional levels. RNA-binding proteins (RBPs) are keypost-transcriptional regulators that control gene expression by modulating mRNAsplicing, stability, translation, and localization.This thesis demonstrates that theRBP ZFP36L2 plays a crucial role in limiting IFN-g production duringprolonged T cell activation. ZFP36L2 binds AU-rich elements in the 3’UTR of IfngmRNA, promoting its degradation and thereby reducing IFN-g output. Incontrast, its paralog ZFP36L1 acts earlier during T cell activation, andcombined deletion of ZFP36L1 and ZFP36L2 induces superior cytokine productionin T cells. We further show that ZFP36L1 and ZFP36L2 cooperate to control cellcycle progression and survival in resting T cells. Furthermore, transcriptomicprofiling reveals that RBPs are highly expressed in T and B cells and undergodynamic changes during differentiation. Lastly, we performed a CRISPR-Cas9screen in primary human T cells to identify RBPs that modulate T cellactivation.Together, the contents of thisthesis underscore the central role of RBPs in T and B cell biology and highlightseveral RBPs as potential targets for modulating T cell function fortherapeutic purposes
Human spermatogonial stem cells:Growing hope for infertile male childhood cancer survivors
No full textThis dissertation focuses on male survivors of childhood cancer, who can become infertile due to the gonadotoxic effects of cancer treatments. Whereas adolescent and adult men can cryopreserve sperm prior to treatment as a method of fertility preservation, this option is not available to pre-pubertal patients due to the absence of spermatogenesis in the pre-pubertal testis. However, these patients are offered the option to collect and cryopreserve a testicular biopsy, harboring the spermatogonial stem cells (SSCs), which are present from birth onwards. In case of infertility in later life, the biopsy can be used to retrieve testicular cells including these SSCs, culture them to increase their numbers and autotransplant them into the healthy testis to restore spermatogenesis in the adult cancer survivor. However, this treatment is not clinically available yet, although good results have been obtained in animal models. The research described in this work aimed to review knowledge gaps in the field; optimize the culture of SSCs to reduce the previously observed hindering overgrowth of somatic testicular cells; investigate ways to facilitate clinical implementation of the culture by using xenofree, scaled-up methods; and uncover perspectives of cancer survivors on the potential future use of this technique. We found that growth of somatic cells could be limited by a combination of adaptations to the culture temperature, culture surface and medium components including growth factors. Additionally, patient perspectives revealed the necessity of a focus on reproductive autonomy during the course of their treatment, fertility consultations and future therapy
Stronger together:Stabilizing the interactions between HCV E1 and E2 for vaccines
No full textHepatitis C virus (HCV) infection places a major burden on global health, affects 50 million people and causes 250,000 yearly deaths. Yet, there is no HCV vaccine available. The only target for neutralizing antibodies against HCV is the E1E2 glycoprotein on the virion surface. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. Furthermore, standardized tools to study immune responses and vaccine effectiveness are needed to help in vaccine development. This thesis explores both the design of vaccines against HCV and the tools needed to evaluate the immune responses. The first section focuses on refining in vitro methodologies to study antibody responses against HCV and on the study of a family of broadly neutralizing antibody (bNAbs) that targets an antigenic region that overlaps with the receptor binding site of HCV and that has been the focus of many vaccine strategies. The second part of the thesis is then focused on antigen design, where different design strategies are explored and protein engineering strategies culminate in the design of a stabilized soluble E1E2 that does not require dimerization domains to resemble the native E1E2. The set of stabilizing mutations is applied to different strains of HCV and even to a synthetic sequence generated from the consensus sequences of 10 major subtypes of HCV, which results in an antigenically superior immunogen. The results of this thesis are a milestone for HCV vaccine design and provide the foundations for the next generation of vaccines against HCV
Enhancing consistency between climate and energy law and policy in fossil fuel-rich LDCs:A case study of Uganda
Full text linkThe central research question of this thesis focuses on how Uganda and similar fossil fuel-rich LDCs can improve consistency in implementing climate and energy laws and policies in the context of the global climate change legal regime. The study highlights a literature gap, particularly the lack of emphasis on the climate change implications of energy laws in fossil fuel-rich LDCs. Existing research mainly discusses the resource curse and development, without adequately discussing the intersection with climate policy. Further, implication for climate change action of energy laws and policies that co-exist with climate change legislation and policies in fossil fuel-rich LDCs is not addressed. The thesis contributes findings, recommendations and identifies areas for future research that could benefit both policy makers in fossil fuel-rich LDCs and North-South international law scholars
Transient spectroscopy of color centers in semiconductors and their application
Full text linkThis thesis investigates color centers in wide-bandgap semiconductors, which are crucial for quantum technologies. A transient absorption (TA) spectroscopy setup, spanning 400-2300 nm with nanosecond resolution, was developed for the investigation of their intricate electronic structures and dynamics over pump-probe delays reaching milliseconds and even seconds. The present study focused on the investigation of nitrogen-vacancy (NV) centers in diamond and silicon vacancy (VSi) centers in 4H-SiC. For NV centers, numerous previously unknown electronic states were discovered in both negatively and neutrally charged states (NV- and NV0, respectively), and their inter-charge conversion was documented. This also included the first direct observation of tunneling-mediated charge conversion. A magnetometer operating at room temperature, employing the NV-singlet absorption, has been demonstrated. This magnetometer demonstrated a noteworthy achievement, achieving a sensitivity of 18pT/√Hz, thereby eliminating the requirement for optical cavities. Subsequently, the photoexcitation dynamics of VSi centers were reported, and the initial transition energies between their spin-doublet electronic states were identified. These findings significantly advance our understanding of color centers, with direct implications for quantum sensors, providing a foundation for future research in wide-bandgap materials.</p
Exploring proteolytic strategies to improve huntingtin clearance in cell models for Huntington's disease
No full textHuntington’s disease (HD) is a neurodegenerative disorder, caused by an expanded polyglutamine (polyQ) tract close to the N-terminus of the mutant huntingtin protein (mHTT). The primary goal of this thesis was to explore proteolytic strategies to improve mHTT clearance, as a therapeutic strategy to delay the onset of the disease. To study how proteasome complexes are altered in HD we used murine models of HD. In addition, cellular models for HD were used to modify (proteasomal) degradation to determine the effect on mHTT turnover. This thesis contributes to a better understanding of how changes in the proteostasis machinery affect the degradation of polyQ fragments and ultimately mHTT levels. While we found that PA28αβ and IDE upregulation improves the degradation of polyQ fragments, the opposite effect (decreased turnover) was observed on polyQ containing mHTT fragments. This suggests that not the polyQ stretch itself, but rather the (misfolded) protein context hinders the degradation of mHTT. Moreover, as observed with PA28αβ and IDE, an increase in mHTT aggregation was detected, despite no direct effect on the turnover of soluble mHTT levels was seen. This indicates that protein aggregation is not only driven by the total levels of an aggregation-prone protein, but is also (directly or indirectly) influenced by other factors, such as chaperone function. Finally, the regulation of the different pathways is tightly connected, and a defect in one system, leads to the upregulation of a compensatory pathway. Which was observed after RPN10 silencing
Coding cognition:Representing and communicating information in perceptual and memory systems
Full text linkThe mammalian brain uses neural networks to perform various impressive cognitive computations. In this thesis, I explore the neural code neural networks use to perform such computations. In chapter 2, we investigate the correlations of spiking activity of entire populations in the freely moving rat between- and within 4 cortical areas: visual cortex, whisker fields of the somatosensory cortex, perirhinal cortex, and the CA1 region of the hippocampus. In chapter 3, we investigate if, besides spikes, the phase-of-firing relative to the theta oscillations of the Local Field Potentials provides a means for the representation of audiovisual information. In chapter 4, we address the contemporary problem of non-sensory related signals in behavioral electrophysiology, and test if a forced delay in a behavioral tasks provides us with a method to isolate sensory related activity from behavior related activity. Lastly, in chapter 5, I summarize the information and discuss the implications for the theoretical model as laid out by Pennartz (2009, 2015)
Preterm birth prevention:Cervical length assessment and long-term follow-up
Full text linkAls een kind voor 37 weken zwangerschapsduur geboren wordt, kan dit nadelige gevolgen hebben op de korte én lange termijn. Het voorkomen van een vroeggeboorte is daarom belangrijk. Dit proefschrift richt zich op (1) hoe kan de voorspelling van een spontane vroeggeboorte verbeterd worden met behulp van een meting van de cervix (baarmoedermond) en (2) wat zijn de lange termijn gevolgen van interventies die worden ingezet om een vroeggeboorte te voorkomen?Op basis van dit proefschrift concludeerden wij dat er aanzienlijke verschillen bestaan, zowel tussen als binnen landen voor de methode van meten van de cervixlengte. Een gestandaardiseerde meting van de cervixlengte zal de identificatie van vrouwen met een verhoogd risico op een vroeggeboorte verbeteren. Tevens toonden wij aan dat de afname van de cervixlengte over de tijd potentieel bijdragend is aan de voorspelling van een vroeggeboorte. Er moet overwogen worden om de afkapwaarde voor een korte cervix per populatie aan te passen.Veel gebruikte interventies in de zwangerschap zijn progesteron en laag gedoseerde aspirine. Wij concludeerden dat het gebruik van deze middelen veilig lijkt voor het kind op de lange termijn. Dit ondersteunt een bredere indicatiestelling ter preventie van een vroeggeboorte. Vervolgonderzoek moet uitwijzen of meer vrouwen baat hebben bij deze eventuele interventies
From tissue to clinical practice and back again:A translational approach to adrenoleukodystrophy
Full text linkX-linked adrenoleukodystrophy (ALD) is the most common genetic white matter disease of the central nervous system. It is characterized by a quickly progressive leukodystrophy in the brains of a large proportion of affected boys and men, and as a more slowly progressive myeloneuropathy in the spinal cords of all adult men and most women. While the clinical and biochemical features of ALD have been well documented, its underlying pathophysiology and the reasons for variability between patients remain poorly understood. This thesis investigates the pathology of ALD and, through a translational approach, seeks to link disease mechanisms to clinical manifestations. Part I examines the pathology of ALD: chapter 2 presents a literature review and proposes a working model for its disease mechanisms, while chapter 3 applies quantitative MRI techniques to non-invasively assess tissue-level changes. Part II focuses on the clinical spectrum of ALD, relating it to lipidomics (chapter 4), movement analysis (chapter 5), and established conventional outcome measures in trials (chapter 6). Part III places the clinical impact of ALD in a broader societal context by exploring the perspectives of affected individuals on its inclusion in the Dutch newborn screening program
At the crossroads of epilepsy and Alzheimer's disease:Investigating the role of LRP1 in the cerebral vasculature
Full text linkThere is increasing evidence that people with epilepsy have an increased risk of developing Alzheimer’s disease (AD). Epilepsy is also relatively more common in people with AD. Epileptiform activity may even accelerate the progression of AD. Therefore, managing epileptiform activity is crucial. However, a significant proportion of patients do not achieve seizure freedom following anti-seizure medications. Understanding underlying neurobiological mechanisms is essential for developing of new therapies. Accumulation of amyloid beta (Aβ) in the brain, a neuropathological hallmark of AD, has been observed in (a subset of) patients with epilepsy. In this thesis, we investigated the role of low-density lipoprotein receptor-related protein 1 (LRP1), a multifunctional transmembrane receptor involved in many physiological processes, including the clearance of brain Aβ via the blood-brain barrier (BBB). LRP1 expression in brain capillaries diminishes during aging and in AD. In this thesis, we show that LRP1 is downregulated at the BBB in both experimental epilepsy and patients with epilepsy. Furthermore, inducible knockout of brain endothelial LRP1 in transgenic mice leads to epileptiform activity and cognitive dysfunction associated with gliosis rather than brain Aβ accumulation or the increase of its soluble form. Future research should focus on therapeutic strategies aimed at preventing or restoring the loss of brain endothelial LRP1, potentially reducing epilepsy and cognitive decline