UvA-DARE
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Water and ion dynamics at interfaces
No full textThis thesis explores the ultrafast dynamics of interfacial water using time-resolved vibrational sum-frequency generation (TR-vSFG) spectroscopy, with a focus on triggering and monitoring transient electric fields at the air-water and water-water interfaces.First, the effect of temperature on the vibrational lifetimes of hydrogen-bonded and free OD stretching modes in D2O is studied. The results show that the hydrogen-bonded OD stretching mode relaxes independently of temperature, while the free OD relaxes faster at higher temperatures. These results highlight the similarity between the interfacial and bulk relaxation dynamics of the hydrogen-bonded OD stretching mode. Additionally, we show that intramolecular energy transfer dominates the reorientation relaxation mechanism for free OD.Next, TR-vSFG is used as a contactless T-jump method to study electric double layer (EDL) dynamics at the air-DCl/water interface. The interfacial hydrated proton population is found to be thermally modulated, and the EDL rearrangement occurs within tens to hundreds of picoseconds. Simulations combined with analytical modeling using a modified Poisson-Nernst-Planck equation confirm that electrostatic interactions govern these dynamics. This aligns with the Debye-Falkenhagen theory, even at high ion concentrations.Finally, we investigate the electrolyte's electrical response to the IR-induced shock wave following the T-jump. The measured TR-vSFG signal reveals interference between two SFG signals generated at the air-water and traveling water-water interface, respectively. Strong chemical specificity is observed, and its causes are discussed.These findings deepen our understanding of ultrafast aqueous interfacial phenomena and offer pathways for tuning interfacial ionic behavior relevant to technologies such as electrochemical capacitors and ion-based transistors
Exploring the therapeutic potential of immune checkpoint modulation in preclinical models of inflammatory diseases
No full textAtherosclerosis, a lipid-driven inflammatory disease of large arteries, is a leading cause of cardiovascular disease. While lipid-lowering therapies are effective, some patients retain a residual inflammatory risk, highlighting the need for alternative anti-inflammatory treatments. This thesis investigates the therapeutic potential of immune checkpoint modulation in preclinical models of inflammatory diseases.The first part examines the role of immune checkpoints in T cell-mediated inflammation. It begins by exploring E3 ubiquitin ligases as intracellular immune checkpoints, focusing on the E3 ubiquitin ligase CBL-B. We demonstrate that CBL-B deletion reduces atherosclerosis in mice while promoting T cell activation and T cell plaque infiltration. Next, we identify a novel binding partner for the immune checkpoint CD40L, RACK1, and reveal its role in Th1 cell stabilization. A systematic review and meta-analysis follow, showing that cancer-targeted immune checkpoint inhibitors can accelerate atherosclerosis. Finally, we explore the hypothesis that statins may enhance the efficacy of these immune checkpoint inhibitors.The second part evaluates CD40-TRAF6-targeted therapy, which has shown promise in atherosclerotic mice. Extending this research, we investigate its effects in atherosclerotic pigs, providing an initial analysis, and in secondary haemophagocytic lymphohistiocytosis (sHLH), an acute hyperinflammatory condition. A literature review highlights the roke of immune checkpoints in sHLH, and a pilot study implicates CD40 in the inflammatory response.Overall, this thesis advances understanding of immune checkpoints and highlights their potential as therapeutic targets in inflammatory diseases
Advancing hyperthermia treatment through treatment planning and small animal research
No full textHyperthermia, the heating of tumours to 40–43 °C for one hour, is an established sensitiser to radiotherapy and chemotherapy, effective in several cancers such as melanoma, sarcoma, bladder, recurrent breast, cervix, and rectum. New applications include pancreatic cancer and combinations with immunotherapy. Wider adoption, especially for deep-seated tumours, requires consistent clinical protocols, yet current progress is hindered by variability across institutes and insufficient translational models.This thesis addresses hyperthermia treatment consistency through two main aims: improving the accuracy of hyperthermia treatment planning (HTP) for deep-seated tumours, and enabling clinically representative small-animal studies. In Chapter 2, uncertainty in tissue properties and perfusion was systematically evaluated using a Polynomial Chaos Expansion (PCE) methodology. Results showed that electrical conductivity and perfusion strongly affect predicted temperatures, with variations of up to 9 °C in pancreatic cases. In Chapter 3, robust stochastic optimisation strategies were developed to mitigate these uncertainties, reducing hotspots while maintaining effective tumour heating, thus improving treatment reliability and reducing operator adjustments.Chapters 4, 5, and 6 focus on translational research with the ALBA micro8, a novel miniature phased-array system for mice. Simulations and phantom experiments demonstrated its ability to achieve precise and robust heating of deep-seated tumours under realistic conditions, with high spatial accuracy and tolerance to physiological variations. Dedicated bioheat models for mice further enhanced preclinical HTP accuracy. This system provides a reliable platform for studying hyperthermia’s biological and immunological effects in tumour models.Overall, the research strengthens the foundation for standardised, reproducible hyperthermia delivery, facilitating multi-centre trials and broader clinical implementation. Standardisation and improved consistency will support wider adoption and reimbursement, ultimately advancing oncological care
The technopolitics of cybersecurity:Sociotechnical configurations, epistemic devices, and the production of knowledge
No full textThis thesis critically examines how cybersecurity knowledge is produced and the political implications thereof. Dominant approaches tend to frame cybersecurity as a technical or strategic tool to defend powerful states and corporations. This enacts a universalised conception of danger that legitimises pervasive surveillance, anticipatory intervention, and hierarchical authority. Such framings risk neglecting the mundane, everyday practices and unintended consequences of cybersecurity technologies that shape how insecurity is imagined and governed. At the intersection of Critical Security Studies (CSS) and Science and Technology Studies (STS), this thesis develops a conceptual vocabulary for analysing cybersecurity as sociotechnical configurations in which humans and technologies are co-produced. Empirically, it demonstrates how cybersecurity infrastructures and practices – from standardisation processes to intrusion detection systems – create imaginaries of omniscience that privilege Western, state-centric interests while marginalising alternative epistemologies and lived experiences. By studying how knowledge about threats and risks is constructed through computational ordering and automation, the thesis shows how irregularities are increasingly suspicioned as dangers, producing new categories of insecurity. Ultimately, it argues that cybersecurity is not merely reactive but a technopolitical project that reproduces asymmetries of power, erodes democratic oversight, and transforms everyday security practices into instruments of algorithmic governance. By resisting closures that cast the world as inherently insecure, this research contributes to a broader critical project that reasserts the political stakes of cybersecurity and opens space for democratic contestation and alternative futures
At the crossroads of epilepsy and Alzheimer's disease:Investigating the role of LRP1 in the cerebral vasculature
No full textThere 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
Rare treatment, real barriers:A critical appraisal of cholic acid treatment
No full textThe thesis Rare Treatment, Real Barriers: A Critical Appraisal of Cholic Acid Treatment, explores the pharmaceutical, regulatory, and clinical dimensions of cholic acid (CA) therapy for patients with rare bile acid synthesis disorders (BASDs). While CA is an authorized orphan drug in the EU and US, its evidence base is limited and access in the Netherlands has been unavailable. To address this gap, the Amsterdam UMC developed a pharmacy-compounded CA formulation to enable both patient care and clinical research.The work demonstrates how pharmacists can bridge the gap between unavailable commercial medicines and patient needs by developing safe, high-quality compounded formulations under Good Manufacturing Practice (GMP) conditions. The thesis evaluates the analytical quality of CA as an active pharmaceutical ingredient, validates the compounded formulation, and confirms its stability and safety. A prospective clinical study further assesses long-term biochemical and clinical effects in patients with AMACR and 3β-HSD deficiency, showing biochemical improvement and good tolerability.Beyond its clinical findings, the thesis highlights the broader role of pharmacy compounding as an instrument of pharmaceutical innovation, access, and personalized medicine. It underscores the societal and ethical responsibility of pharmacists to ensure continuity of care when industrial supply fails or becomes unaffordable.By integrating pharmaceutical science, clinical research, and policy analysis, this work illustrates how the pharmacist’s expertise remains essential in safeguarding access to effective treatment for patients with rare diseases.<br/
Preterm birth prevention:Cervical length assessment and long-term follow-up
No full textAls 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
Foreign investment screening in the European Union:The state of exception in investment law
No full textThis thesis argues that the institutionalisation of security as a dominant paradigm under the FDI Screening Regulation constitutes a state of exception in EU investment law. Against the backdrop of successive crises, investment regulation has shifted from a paradigm of liberalisation to one defined by security. Drawing on the theories of Carl Schmitt, Giorgio Agamben, and Achille Mbembe, the thesis identifies three defining features of this state of exception: the tension between the security exception and the rule of law, the friend-enemy paradigm, and the conflation of security and economic interests.The European framework for investment screening is characterised by an open-ended scope of application, indeterminate screening criteria, broad discretion, a lack of transparency, and limited judicial review. These characteristics blur the boundary between law and politics and subtly erode the rule of law. Investment screening law, policy, and decision practice are furthermore shaped by a friend-enemy paradigm that frames foreign investors as trusted allies or security threats. The thesis demonstrates that investment screening pursues a wide range of security, economic and geopolitical interests. To resolve the state of exception in EU investment law, the framework should be reformed through the specification of clear, objective, and non-discriminatory screening criteria
Risk factors and implications of anaesthesia induced hypotension
No full textThis thesis studied haemodynamic perturbation in the perioperative and intensive care settings. The aims of the chapters were to: · Evaluate the implications of the use of different thresholds of hypotension in perioperative haemodynamic research. (Chapter 2) · Provide an overview of the echocardiographic changes in cardiac function due to general anaesthesia and intermittent positive pressure ventilation. (Chapter 3) · Determine the modifiable risk factors in anaesthesia induction for post-induction hypotension. (Chapter 4) · Explore whether time of day of anaesthesia induction affects the incidence of haemodynamic instability. (Chapter 5) · Compile the literature on biological sex as a risk factor of post-induction and intra-operative hypotension. (Chapter 6) · Investigate the performance of a hypotension-prediction algorithm in spontaneously breathing patients without ventilatory support in the post-operative and intensive care settings. (Chapter 7) · Chapter 9 discusses the implications of the aforementioned research and the avenues for future research that remain.</p
The molecular orchestra of early placenta development:Key determinants of maternal-fetal health
No full textThis dissertation investigates the molecular mechanisms underlying healthy and pathological early human placenta development. The placenta is essential for fetal growth and survival, mediating nutrient and gas exchange, hormone production, and immune protection. Disruptions in its formation can lead to complications such as preeclampsia and fetal growth restriction. These complications originate early in pregnancy, during the period when in healthy conditions trophoblast cells differentiate and establish the maternal–fetal interface. Using human trophoblast stem cells, trophoblast organoids, and first-trimester placental and decidual tissue, this work explores both fetal and maternal factors regulating trophoblast differentiation and invasion. The findings reveal that reduced fetal activity of the transcriptional coactivator EP300 impairs the formation of both syncytiotrophoblasts and extravillous trophoblasts, identifying EP300 as a key regulator of trophoblast lineage development. In addition, maternal excess of the pro-inflammatory cytokines IFN-α and TNF-α inhibit trophoblast invasion without affecting differentiation, offering insight into how maternal autoimmune conditions may predispose to placental dysfunction. Together, these results emphasize the need for balanced molecular signaling between fetal and maternal components to support normal placentation. Additional studies showed no adverse effects of the maternal immune response to COVID-19 mRNA vaccination on trophoblast development, reinforcing vaccine safety in pregnancy. Furthermore, analyses of alternative RNA splicing during trophoblast differentiation, and optimized methods for deriving patient-specific trophoblast stem cells, provide new hypotheses and tools for investigating regulatory pathways and disease mechanisms. Overall, this thesis highlights the intricate coordination required for placental development and its critical role in ensuring healthy pregnancy outcomes