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Molecular conversations with soluble adenylyl cyclase:A journey of serendipity
No full textAdenylyl cyclases are enzymes that produce cAMP. In contrast to the more well-known transmembrane adenylyl cyclases, soluble adenylyl cyclase (sAC) is found in the cytoplasm and in intracellular organelles. sAC is also not regulated by G-proteins or activated by forskolin; instead, it is regulated by intracellular bicarbonate, calcium, and ATP concentrations. Recent studies have demonstrated the role of sAC-specific cAMP in various tissue-specific and cell autonomous contexts. Despite these unique known properties and functions, not much is known about how cellular sAC protein levels are regulated or maintained. In this thesis, using the H69 cholangiocyte cell line as our model, we set out to investigate how sAC is regulated at the post-translational level and is involved in cholangiocyte-specific functions and physiology, such as cellular apoptosis and ciliogenesis. The observations presented in this thesis imply that sAC could potentially be therapeutically targeted to restore or maintain cholangiocyte physiology in diseases such as primary biliary cholangitis or polycystic liver disease
Young citizens and their parents, peers, and teachers in a changing world:Social contexts of citizenship competences in adolesence
No full textCitizenship knowledge, attitudes, and skills enable adolescents to understand and participate in a pluriform and democratic society. Adolescents today grow up in a complex and uncertain world, facing serious challenges. In different social settings, adolescents share opinions, exchange ideas, practice principles of democracy, and experience what it means to be part of a community. This dissertation aimed to enhance understanding of the associations between adolescents’ citizenship competences and contextual factors. The central research question was: “To what extent are adolescents’ experiences with their parents, peers, and teachers, as well as their concerns about the world’s future, associated with their citizenship competences?”. A quantitative, large-scale, and representative dataset among adolescents in the Netherlands (13-14 years old) was used. The data included a civic knowledge test, a questionnaire on civic attitudes, engagement and skills, and a questionnaire about European issues. By including additional questions about parents and peers, a unique dataset was created that provided deeper insight into adolescents’ citizenship competences in relation to various important social contexts. Three main conclusions are drawn: 1) Adolescents’ citizenship competences are associated with their (interrelated) experiences with their parents, peers, and teachers; 2) Even in times of societal and educational changes, adolescents’ experiences within schools remain important for their citizenship competences; and 3) Civic engagement in adolescence manifests in various ways and is intertwined with individual perspectives on macrosocial issues. Taken together, this dissertation underscores the importance of acknowledging adolescents’ social contexts and their own macrosocial concerns to understand and support their citizenship competences
Novel fluorophores for advancing super-resolution and correlative microscopy
No full textOptical and electronmicroscopy are fundamental imaging techniques in life and material sciences.However, conventional optical microscopy is constrained by the diffractionlimit (~200 nm), preventing visualization of fine subcellular structures.Single-molecule localization microscopy (SMLM) overcomes this limitation byexploiting photoswitchable fluorophores to achieve nanometre-scale resolution.Further expanding SMLM applications and enabling super-resolution correlativelight and electron microscopy (SR-CLEM) require intrinsically blinking andchemically stable fluorophores.This thesis reportsthe development of two classes of such fluorophores—nanographenes and rylenes—anddemonstrates their utility in advanced imaging. Hydrophilic and functionalizednanographenes were synthesized and exhibit environment-independent blinkingunder diverse conditions, enabling SMLM imaging of amyloid fibrils in air,lysosomal dynamics in live cells, and nascent peptide translation in neurons.These studies revealed heterogeneous local translation along axonal branches.To extend SMLM intothe near-infrared (NIR) region, intrinsically blinking rylene derivatives weredeveloped, offering reduced phototoxicity for live-cell SMLM imaging. Theirexceptional chemical stability allowed successful application in SR-CLEM,retaining robust blinking behavior after osmium tetroxide fixation and Epon resinembedding. Both single- and dual-color SR-CLEM were achieved, and theOsO₄-induced quenching mechanism, involving energy/electron transfer and aninner filter effect, was elucidated, providing valuable guidance for the futuredesign of SR-CLEM-compatible fluorophores.Overall, this researchestablishes nanographenes and rylenes as robust, intrinsically blinkingfluorophores for SMLM and SR-CLEM. The mechanistic insights and moleculardesigns presented here advance the development of fluorophores and expand thefrontiers of super-resolution microscopy in the life sciences.</p
Viruses in the brain:Insights into viral neuropathology using stem cell-derived organotypic models
No full textThis thesis explores virus-induced neuropathology using human stem cell-derived organotypic models that mimic the molecular and cellular complexity of the central nervous system (CNS). Chapter 1 introduces the challenges in studying viral neurological disease, emphasizing the limitations of traditional models and the potential of neural organoids as human-relevant systems. Chapter 2 highlights the importance of unified terminology and context-dependent host–virus interactions in understanding neuropathology.Part I focuses on modeling neuropathology caused by human Parechoviruses (HPeV) and Human Immunodeficiency Virus (HIV). Neural organoids were used to show that the neurovirulent HPeV-3, but not HPeV-1, induces strong immune and metabolic disturbances rather than differences in viral replication or tropism. Reanalysis revealed disrupted immunometabolism and glutamate excitotoxicity, implicating host metabolic imbalance in disease severity. Using microglia-containing organoids, HIV infection studies showed that microglia facilitate viral persistence, elevate HIV gene expression, and promote inflammatory amino acid metabolism, highlighting their role as reservoirs contributing to HIV-associated neurocognitive disorders.Part II applies organoid platforms for antiviral testing. Halofuginone Hydrobromide showed broad-spectrum antiviral potential in organoid systems but limited efficacy at clinically relevant concentrations, demonstrating the translational value of organoids for assessing both efficacy and toxicity.Together, these studies establish human iPSC-derived neural organoids as powerful models for studying viral infection, immune–metabolic crosstalk, and therapeutic interventions. Their multicellular architecture and human relevance position them as essential tools for mechanistic discovery, antiviral screening, and the advancement of precision medicine in neurovirology
From crisis to cure:Allogeneic stem cell transplantation for adults with sickle cell disease
No full textSickle cell disease (SCD) is a group of inherited hemoglobinopathies, associated with chronic hemolytic anemia, recurrent vaso-occlusive pain episodes, and progressive organ damage. To date, allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative treatment for patients with SCD. Historically, HSCT was used in children with severe SCD and an available matched sibling donor, applying myeloablative conditioning regimens. More recently, non-myeloablative conditioning and haploidentical HSCT protocols have been developed, rendering HSCT a feasible treatment option for many more patients, including adult patients with SCD. In the Netherlands, the first non-myeloablative transplantation program for adult patients with SCD was implemented in 2018 at the Amsterdam UMC. The studies presented in part I of this thesis aim to improve the outcomes after non-myeloablative HSCT in adult patients with SCD, with a focus on reducing graft failure rate while balancing the toxicity of the conditioning regimen and the risk of GvHD. In part II of this thesis, three studies are presented which sought to enhance our understanding of the impact of allogeneic HSCT on the patients’ immune system. Last, part III of this thesis focusses on evaluating the effects of HSCT on SCD-related organ (dys)function and health-related quality of life.</p
From darkness to light:Exploring deep brain stimulation for treatment-resistant depression
No full textDeep brain stimulation (DBS) is a promising intervention for treatment-resistant depression (TRD). This thesis explores its neurobiological mechanisms, symptom trajectories, effects on cognitive functioning, and response predictors. Findings from a systematic review of neuroimaging studies indicate that TRD may be a distinct major depressive disorder subtype, characterized by abnormalities in default mode network and occipital lobe functioning. Furthermore, we show that DBS effectively reduces depressive symptoms across all dimensions in TRD, although insomnia symptoms may improve at a slower rate. Additionally, patients with more anxiety symptoms, who typically tend to have worse pharmacological treatment outcomes, may particularly benefit from DBS. Using a meta-analytic approach, we further show that DBS for TRD does not lead to a decline in cognitive functioning. Two neuroimaging studies show that vALIC DBS normalizes amygdala hyporesponsivity and modifies amygdala functional connectivity in TRD. In addition, findings indicate that baseline and changes in reward circuit activity is associated with DBS outcome, although there was no significant effect of vALIC DBS on reward circuit functioning in patients compared to healthy controls. A systematic review and meta-analysis of preoperative predictors found no reliable predictors of response to DBS in TRD. Although further research is necessary, some findings suggests that a less chronic, more treatment-responsive course of depression may be associated with response, as well as hyperactivity in the subcallosal cingulate gyrus. In order to improve and personalize DBS treatment in TRD, future research should focus on personalizing DBS targets, identifying response predictors, and enhancing DBS treatment with adjunctive therapies
Tissue-specific interactions between <i>Xanthomonas campestris</i> pv. <i>campestris</i> and its host plant
No full textThe work in this thesis focused on the interaction between the bacterial plant pathogen Xanthomonas campestris pv. campestris (Xcc) and the host plant Arabidopsis thaliana. As this pathogen displays an intricate infection process with multiple distinct phases, efforts were made to identify plant resistance mechanisms in the early phase of infection when the bacteria enter the plant hydathodes, which are organs involved in water homeostasis that are located at the leaf margins. An intracellular immune receptor was identified that confers resistance against Xcc early in hydathodes, but not in later stages of infection. To track progression of the bacteria through the plant, bioluminescence was applied to genetically modify the bacteria to emit light. Next, a high-throughput imaging method was developed to follow infection events Arabidopsis rosettes non-invasively over time. This method yielded insights in the infection process and allowed for phenotypic screening of large plant populations. Finally, a bacterial virulence factor was identified that contributed to the vascular phase of the bacteria, when they colonize the plant xylem vessels and spread systemically through the plant. Taken together, the findings in this thesis yielded insights on the tissue-specific interactions between Xcc and its host plant
Pathways of entrepreneurial urban governance:Spatial dynamics and community politics in Istanbul's regeneration
No full textWhat happens when urban governance adopts state-driven entrepreneurialism? Istanbul—a city metamorphosed into a canvas with its towering megaprojects—tells a profound tale of power, policy failures, and post-populist adaptations. Through the lens of Istanbul's transformation, the dissertation focuses on socio-spatial dynamics and community politics of entrepreneurial urban governance. While this governance model promises economic growth and innovation, this study reveals a fundamental tension: even as it generates new forms of social capital and community engagement, it simultaneously intensifies socio-spatial inequalities and marginalizes resistance and contestation, especially through state-led interventions. Highlighting Istanbul’s large-scale regeneration as a case to understand the broader phenomena of non-Western entrepreneurial governance, this dissertation contributes more diverse perspectives to urban governance scholarship. The outcomes demonstrate how state-driven entrepreneurial strategies are not fixed in one mode but fluctuate depending on scenarios shaped by resistance, negotiations, or multi-level interactions among urban actors. These governance mechanisms move back and forth between contrasting approaches—from top-down planning to self-organization and to post-populist politics.This dissertation argues that authoritarian entrepreneurial governance paradoxically creates conditions for local innovation and resistance. Local actors leverage state-designed tools and frameworks to challenge the system itself, either by re-politicizing depoliticized governance frameworks or by shaping community politics through market-driven imperatives. Urban residents display varieties of ‘entrepreneurial citizenship’, institutionalizing self-organization or adopting post-populist responses that imitate entrepreneurial practices of the state and property developers. This demonstrates how entrepreneurial governance, even in authoritarian contexts, can emerge as a platform for negotiated urban governance
A transnational social contract:How a plurality of actors shape the rights of Indian low-wage labor emigrants along the India-Gulf Cooperation Council migration corridor
No full textMany low-wage employed migrant workers worldwide face precarious jobs, unsafe conditions, and poor living situations. The India-Gulf Cooperation Countries (GCC) corridor exemplifies this: India sends the most migrants globally, and approximately half of all Indian migrants stay in the GCC region, where most work in so-called unskilled job categories. Migrant-origin states such as India potentially deploy a variety of policy tools to protect and enforce their citizens’ labor and human rights abroad. However, despite the norm of supporting and providing rights to their nationals abroad, this is not an obligation states have. This dissertation shows that the rights Indian emigrants receive are informed by notions of deservingness and membership negotiated and shaped by a plurality of local, subnational, national, trans- and international state and non-state actors.Drawing on document analysis, observations, and interviews with actors involved in the transnational policy process of emigration and emigrant policymaking in the GCC region and India, the dissertation finds that the Indian state differentiates its policies along labels of high and low-skilled migration and that differentiated access to social protection and other citizenry rights also results from varying subnational incorporation of emigrants and practices of CSOs in the origin and destination context which support emigrants in procuring rights
Een kwestie van uitvoering:De gemeente Amsterdam als instrument van de Duitse repressie 1940-1945
No full textTijdens de Duitse bezetting van Nederland is de gemeente Amsterdam betrokken geweest bij de onderdrukking, uitsluiting en vervolging van haar eigen burgers. Zo zijn Joodse Amsterdammers door het Bevolkingsregister geregistreerd, door het Bureau voor Sociale Zaken naar werkkampen gestuurd en door de Gemeentepolitie, het Trambedrijf en de Gemeentelijke Gezondheidsdienst naar de deportatiecentra en -treinen vervoerd. Dit roept vragen op naar de verantwoordelijkheid en motieven van de toenmalige bestuurders. De keuzes die destijds door de burgemeester, wethouders en hoofden van gemeentelijke diensten zijn gemaakt worden in dit onderzoek geanalyseerd, met elkaar vergeleken en in een bredere context geplaatst. Waarschijnlijk hebben meerdere factoren een rol gespeeld in de vergaande medewerking van ‘gewone’ Amsterdamse gemeentelijke functionarissen aan de Duitse repressie. Hoewel die functionarissen na de oorlog diverse formele rechtvaardigingen voor hun samenwerking met de vijand hebben gegeven, is de uitkomst van dit onderzoek dat de houding van Nederlandse bestuurders en ambtenaren bovenal bepaald lijkt te zijn geweest door de vrees voor Duits geweld en het besef van eigen machteloosheid. De geschiedenis van het Amsterdamse gemeentelijke apparaat tijdens de Duitse bezetting kan geïnterpreteerd worden als een geschiedenis van menselijke en ambtelijke tekortkomingen. Tegelijkertijd mag echter niet uit het oog verloren worden dat dit apparaat te maken kreeg met een bezetter die over de nodige dwangmiddelen beschikte waarmee hij zijn wil kon trachten door te drijven