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A needle in a haystack:Antigen-specific CD4T cell responses in physiological and pathological contexts
No full textThis doctoral thesis investigates antigen-specific CD4 T cell responses and their role in adaptive immunity under both physiological and pathological conditions. The work examines these responses during natural SARS-CoV-2 infection, following vaccination, and under immunosuppressive therapies, while addressing challenges in monitoring low-frequent T cells.Immune correlates of sustained antibody responses following mild SARS-CoV-2 infection were investigated. Individuals with long-lasting antibodies showed distinct memory B cell profiles, stronger B-T cell interactions, and improved antibody quality, suggesting enhanced germinal center activity. We then assessed how immunosuppressive treatments affect vaccine-induced immunity. Methotrexate therapy led to delayed antibody responses and reduced spike-specific CD4 T cells, indicating impaired T-B cell cooperation. Conversely, patients receiving B cell-depleting therapy failed to produce antibodies but exhibited strong activation of memory CD4 and CD8 T cells, revealing altered immune dynamics in the absence of B cells.To improve detection of antigen-specific T cells, activation-induced marker (AIM) assays were optimized, demonstrating that multi-marker strategies enhance sensitivity and phenotyping accuracy. Additionally, novel high-valent peptide–MHC class II multimers were developed, enabling direct detection of antigen-specific CD4 T cells with high sensitivity and specificity. Combining these multimers with single-cell transcriptomics, we characterized how B cell depletion reshapes de novo CD4 T cell differentiation, uncovering distinct activation profiles and transcriptional programs in spike-specific CD4 T cells
Lifting the corporate veil: The responsibility of international organizations and their member states
No full textThis thesis aims to contribute to closing the responsibility gap in international law, which is characterized by a lack of remedies against international organizations and their member states. International courts and tribunals typically do not have jurisdiction to adjudicate claims against international organizations, which also enjoy far-reaching immunity before domestic courts. Member states are not held responsible for the acts of an international organization due to its separate international legal personality. Part I on ‘The Corporate Veil’ discusses the relationship between international organizations, their member states and third parties based on the concept of the corporate veil. In their internal relations with their member states, international organizations are agents of their members, which grant the organization autonomy through a constitutional framework. In their external relations with third parties, those internal relations are cloaked by a corporate veil, and the principal-agent relationship may be reversed. Part II applies the concept of the corporate veil to the determination of ‘Wrongfulness’ in the law of international responsibility. Based on the mutual agency relationships between international organizations and their members, it examines different rules and principles, as elaborated by the pertinent codification projects, that relate to situations of lifting and piercing the corporate veil of an international organization. Part III on ‘Responsibility’ considers the procedural and substantive remedies available to injured parties. The recognition that international organizations and their members regularly incur shared responsibility, based on their mutual agency relationships, is an important factor in understanding and increasing the remedial avenues for injured parties
CEO influence on strategic decisions and firm outcomes:A behavioral perspective
No full textFirms today operate in an increasingly complex environment shaped by digital transformation, artificial intelligence, globalization, resource constraints, and geopolitical and trade instability. The strategic value of investing in corporate social responsibility (CSR), sustainable development goals (SDGs), or firm growth is often ambiguous and contested. Drawing on Upper Echelons Theory, this dissertation investigates how CEOs’ personal attributes and life experiences influence these strategic decisions and firm outcomes.The first study introduces CEO masculinity-femininity, finding in S&P 100 panel data that predominantly feminine CEOs lead firms to higher levels of CSR. Firm risk and institutional ownership attenuate this relationship. The second study uses original survey data to investigate how CEO political orientation, social class background, and openness to change values influence SDG contribution preferences. Progressive and lower- or upper-class CEOs prioritize social and environmental SDGs, whereas conservative and middle-class CEOs emphasize economic goals. Openness to change weakens the effect of social class background. The third study examines in S&P 100 panel data how CEO marriage and parenthood affect firm growth. Marriage is positively associated with growth, while parenthood is negatively associated, with high firm risk dampening marriage’s positive effect.Collectively, these studies show how personal and often overlooked CEO attributes and experiences shape strategic decisions and firm outcomes, thereby contributing to the literature on upper echelons, CEO effects, and strategic leadership. These findings offer practical insights and encourage a broader perspective on CEO selection, development, and incentive design to improve alignment between CEOs and organizational strategic goals
Advancements in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy
No full textChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare heterogeneous autoimmune neuropathy that generally responds well to treatment. The treatment of CIDP can be divided into two distinct phases, each with its own treatment objectives. The first phase is induction therapy, which aims to achieve improvement in disability, remission as well as limit residual deficits. The second phase consists of maintenance therapy and is initiated when patients exhibit ongoing disease activity despite induction treatment. The goal of maintenance treatment is to preserve the improvement achieved during induction and to prevent deterioration (‘relapse’). Part 1 of this thesis outlines the currently available (first-line) treatment options with immunoglobulins (Ig) and corticosteroids. Part 2 discusses a novel treatment strategy consisting of the combination of intravenous immunoglobulin (IVIg) and intravenous methylprednisolone (IVMP). In the general discussion, the findings of this thesis are placed into context, and a perspective is offered on the future direction of treatment for CIDP
Challenging the HIV DNA integration dogma:Integration-independent HIV replication to escape from integrase inhibitors
No full textLike other retroviruses, human immunodeficiency virus (HIV) has an RNA genome that is converted into a linear DNA molecule upon infecting host cells. This viral DNA is then integrated into the host’s cellular DNA by the viral integrase and subsequently used for the production of new virus particles. Integrase inhibitors, such as dolutegravir (DTG), effectively block DNA integration and inhibit virus replication, and are therefore widely used in antiretroviral therapy. HIV typically escapes the effects of inhibitors by acquiring mutations in the gene encoding the targeted protein. Accordingly, mutations in the viral integrase have been linked to resistance to DTG. However, this thesis describes an alternative mechanism of DTG resistance involving mutations in the viral 3’-polypurine tract (3’PPT), an RNA sequence element that serves as a primer for the regular reverse transcription of HIV RNA into DNA. These mutations inactivate the 3’PPT element, leading to the production of circular, rather than linear, HIV DNA. This circular HIV DNA does not integrate into the host genome but still allows the production of new virus particles. As a result, the virus can replicate in the presence of integrase inhibitors, thereby reducing the effectiveness of these antivirals. Moreover, this integration-independent replication pathway challenges the prevailing dogma that integration is an essential step in retrovirus replication
Navigating housing beyond arrival:The trajectories of EU labour migrants in the Netherlands
No full textThe housing difficulties faced by EU labour migrants in the Netherlands have consistently drawn concern, particularly regarding their reliance on intermediaries such as employment agencies. Current understanding of labour migrants housing conditions presents a uniform and static understanding, dismissing how housing struggles can accumulate, diverge, or recede over time. This dissertation provides a more fine-grained and dynamic perspective on housing struggles using a longitudinal mixed-method approach. It shows how labour migrants’ housing trajectories can be progressive, stable, and at times even profitable, but also non-linear, messy, and persistently precarious. Crucially, these conditions are shaped not only by individual strategies, but also by the need to navigate an infrastructure built towards employment and temporariness yet rarely makes room for migrant housing stability
<i>De novo</i> acquisition of antimicrobial resistance in six bacterial species from the food chain
No full textAntimicrobial resistance evolves through diverse genetic routes, yet often yields similar phenotypic outcomes. Using experimental evolution across six bacterial species and multiple antibiotics, we show that resistance arises through distinct, species-specific trajectories with limited mutational convergence. We further demonstrate that regulatory mutations and copy number variations can accelerate resistance evolution but are frequently reversible when selection is removed. Analysis of collateral sensitivity and cross-resistance networks across evolved populations reveals little conservation between species, underscoring the context dependence of resistance pathways. Overall, our findings highlight the diversity, reversibility, and evolutionary instability of genetic changes underlying antimicrobial resistance, offering principles that may guide strategies to slow resistance emergence in clinical and veterinary settings
Neurocognitive outcomes and neural mechanisms in children with traumatic brain injury:Towards personalized prognosis
No full textTraumatic brain injury (TBI) is the leading cause of disability in children and young adults worldwide, with highly heterogeneous outcomes affecting daily life, including neurocognitive, behavioral, and academic functioning. This thesis aims to improve the assessment and understanding of neurocognitive outcomes and underlying neural mechanisms in children with TBI, and to move towards personalized prognosis.In Part I, comprehensive computerized neurocognitive assessments revealed that even after mild TBI, children are at risk for long-term deficits in domains such as information processing stability, and longitudinal school performance data revealed deficits in technical reading up to two years post-injury. Network analysis showed that mild to severe TBI disrupts the global organization of the neurocognitive network, which was related to intelligence and behavioral outcomes. Furthermore, cluster analysis identified distinct subgroups with diverging neurocognitive outcome profiles, highlighting the heterogeneity of TBI sequelae.Part II investigated neural mechanisms of impairment using advanced neuroimaging techniques, including quantitative EEG and resting-state fMRI. The findings showed widespread disruptions in brain network dynamics and organization following TBI, which were associated with neurocognitive and behavioral outcomes, and provided additional information beyond conventional clinical characteristics.Part III systematically reviewed and proposes prediction models for neurocognitive outcome, integrating demographic, premorbid, clinical, and neuroimaging data. Findings underscore the limited predictive value of injury-related characteristics alone and emphasize the need for multimodal, machine learning-based approaches to achieve individualized prognosis.Overall, this thesis contributes to a better understanding of the complex interplay between injury, neurocognitive functioning, and daily life outcomes in children with TBI, and highlights the importance of early identification and tailored follow-up to optimize recovery and development
Charting vascular development:Junctional landscapes guiding endothelial migration and signaling routes to capillary malformations
No full textThis thesis dissects how endothelial cells build, remodel, and sometimes corrupt the vascular network, linking vascular morphogenesis to human vascular disease. First, it interrogates asymmetric adherens junctions (AAJs), an adhesive molecular structure that forms at leader-follower interfaces in migrating endothelial collectives. Using live fluorescence imaging, focused ion beam scanning electron microscopy, proteomics and we uncover the ultrastructural landscape of AAJs. Secondly, we use live imaging of endothelial migration in the developing zebrafish common cardinal vein to establish the functional relevance of AAJs in vivo. We describe AAJs as highly curved, engulfed membrane folds packed with the adhesion molecule VE-cadherin, and a substantial number of membrane curvature sensing BAR proteins, endocytic and cytoskeletal regulators. Systematic tracking of AAJ lifecycles shows that sequential BAR protein recruitment sculpts junctional membranes, controls VE-cadherin trafficking, and tunes junction plasticity. We discover that AAJ internalization emerges as a key bottleneck for maintaining collective migration in vitro and in vivo. The second arm of the thesis confronts GNAQ-driven capillary malformations, including Sturge-Weber Syndrome, by combining patient-derived endothelial cultures, CRISPR engineered cells, and SILAC-based phosphoproteomics. These approaches reveal that the GNAQ p.R183Q mutation rewires calcineurin NFATC and PTEN signaling, offering molecular hypotheses for aberrant endothelial behavior and pinpointing candidate targets for pathway-specific intervention. Together, the two objectives establish AAJs as transient spatially restricted adhesive platforms that steer vascular morphogenesis, while mapping pathogenic signaling circuits in GNAQ-mutant endothelium. As such, this thesis delivers foundational insights into how junctional dynamics and G protein signaling shape vascular form and function, opening new conceptual and therapeutic avenues in cardiovascular medicine
Negotiating the future of AI:How societal stakeholders shape imaginaries of artificial intelligence in Germany, the US, and China
No full textThis dissertation examines how societal stakeholders negotiate the future of artificial intelligence (AI) by co-constructing AI imaginaries, as dominant, discursively produced visions of desirable and undesirable technological, social, economic, and political futures. Drawing on the Science and Technology Studies concept of sociotechnical imaginaries, and integrating insights from media and platform studies, the research conceptualises AI imaginaries as processual, contested, and power-laden outcomes of interactions among societal stakeholders. These imaginaries not only express stakeholder interests but shape AI development, regulation, funding, and public perception.Drawing on longitudinal social media analysis, cross-national comparison between the United States, Germany, and China, and over 40 semi-structured interviews with AI stakeholders, the dissertation addresses three core questions: which stakeholders constitute the contemporary AI environment and how they are interconnected; how AI imaginaries are relationally negotiated among stakeholders; and how platform corporations shape AI imaginaries both as influential actors and as infrastructures of public discourse. The analysis reveals significant power asymmetries in the negotiation of AI futures and substantial national differences in dominant imaginaries. A key finding is the central role of platform corporations, which emerge as multifaceted stakeholders occupying overlapping roles across industry, governance, academia, and media. By simultaneously participating in and enabling public discourse, platforms mediate and entangle AI imaginaries in line with economic and political agendas. Conceptually, the dissertation advances sociotechnical imaginary research by introducing new analytical frameworks for studying AI and platform imaginaries. It further urges close attention to the communicative and political negotiations through which AI futures are imagined and stabilised