International Migration, Integration and Social Cohesion online publications
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Navigating progestrone-driven gene regulatory networks in the mammary gland
Get PDFThe genome contains all the information required for organismal development and homeostasis, but gene expression must be tightly regulated in time and space. Enhancers (non-coding DNA elements) play a central role in this regulation by binding transcription factors and facilitating 3D chromatin interactions with target genes. This thesis explores how the steroid hormone progesterone, via its receptor (PR), controls gene expression through enhancer activity, with a focus on the mammary gland.First, we developed new molecular tools to visualize PR signaling at the single-cell level and optimized conditions for robust detection. Next, we used these tools to perform a detailed analysis of the enhancer landscape of Wnt4, a key PR target gene in mammary tissue. We identified a shared 3D enhancer hub that consists of both PR as well as GRHL2 bound enhancers that regulates Wnt4 in both mouse and human mammary tissues via a two-step model. Furthermore, we identified Wnt4 enhancers in the mous kidney and lung and compared them to the enhancers identified in the mammary gland. We found that these enhancers were not conserved between tissues, sugessting tissue-specific regulation of Wnt4.</p
From self to others:Neural and social perspectives on cue-triggered decision-making
Get PDFPredictable, reward-related cues in the environment play a crucial role in guiding behavior and shaping decision-making. Through a series of experiments, this dissertation investigates the role of the motor cortex in cue-triggered decision-making and examines whether the influence of environmental cues on behavior can be transmitted through observation or vicarious reward.Chapter 1 reviews key theories and findings on environmental cues, the Pavlovian-to-Instrumental Transfer (PIT) paradigm, mirror neuron systems, vicarious transfer and reward, and the use of transcranial magnetic stimulation (TMS) and motor-evoked potentials (MEPs).Chapter 2 employs an extended PIT task combined with single-pulse TMS to examine motor cortex activation during cue-triggered decision-making. Results confirm the behavioral influence of cues but indicate that the motor cortex is not directly involved in this process.Chapter 3 summarizes EEG findings from the PIT task and proposes methodological refinements for MEP collection to more accurately capture cue-related motor activity.Chapter 4 implements these refinements, recording MEPs closer to cue onset, replicating earlier behavioral effects, and finding no evidence of direct motor cortex involvement.Chapter 5 introduces a vicarious PIT paradigm, demonstrating that cue-driven behavioral influences can extend to observers through mere observation.Chapter 6 shows that PIT effects persist for rewards delivered to others, remaining insensitive to outcome devaluation but potentially modulated by reward intensity.Chapter 7 synthesizes these findings, highlighting the limited role of the motor cortex in cue-triggered decision-making and the potential for environmental cues to shape behavior socially and vicariously. Limitations and future research directions are also discussed.<br/
Pathogenic mechanisms and therapeutic target discovery in chronic immune-mediated inflammatory diseases:Insights into the role of the lymphatic system and drug repurposing strategies
No full textThe aim of this thesis was to unravel pathogenetic mechanisms and identify novel therapeutic strategies in immune-mediated inflammatory diseases (IMIDs), with a focus on the lymphatic system in inflammatory bowel disease (IBD) and on transcriptomics-driven drug repurposing across IMIDs.In the first part of this thesis, we investigated the role of lymphoid structures in IBD pathogenesis, treatment response, and immunogenicity to biologics. We showed that mesenteric lymph nodes and lymphatic vessels actively shape immune priming, antigen presentation, and lymphocyte trafficking. Using cytometry-based profiling, we found that anti-drug antibody formation against anti-TNF therapies was associated with elevated B-cell and dendritic cell frequencies within lymph nodes. Furthermore, we demonstrated that sphingosine-1-phosphate receptor (S1PR) modulators, such as etrasimod, profoundly alter T-cell migration, highlighting lymphocyte trafficking as a tractable therapeutic axis in IBD.In the second part, we applied transcriptome-guided drug repurposing pipelines to identify novel therapeutic candidates. In systemic lupus erythematosus, we uncovered compounds, which could potentially restore monocyte-derived pathologic gene signatures, including heat shock protein-90 and inflammasome inhibitors. In individuals at risk for rheumatoid arthritis, we identified agents targeting the PI3K kinase and matrix metalloproteinase-9 pathways that could reverse preclinical synovial signatures, thus offering preventive potential. In Crohn’s disease–associated intestinal fibrosis, we discovered that dual blockade of PI3K and histone deacetylases synergistically attenuated fibroblast activation, proposing a new anti-fibrotic strategy.We conclude that the lymphatic system function is a central determinant of IBD pathogenesis and treatment outcomes, while omics-based drug repurposing provides promising, cost-efficient avenues for precision therapy across IMIDs. These insights pave the way for mechanism-driven interventions to improve outcomes in autoimmunity
Writing the Muslim life in Russia, 1880s-1920s:Islamic education and the formation of the autobiographical genre
No full textThis dissertation examines autobiographies (Turkic: tärjemä-i hälem) of Russian Muslims written from the 1880s to the 1920s. The authors, representing different generations and political views, from reformists and secularists to conservatives and isolationists, shared a common cultural and social background: all were men of letters educated in madrasas with similar curricula and social norms. And their student experiences are key themes in most autobiographies. The emphasis on education was not only based on personal stories. I argue that autobiography became a prominent way for educated Muslim men to discuss and express both individual and collective Muslim identities during the late 19th and early 20th centuries. Education emerged as a crucial theme in public discourse, allowing those involved to assert leadership roles by highlighting their educational roles. Broadly, the focus on education as shaping individual and community life was heavily influenced by development and progress discourses, introduced through Ottoman and Russian translations and European intermediaries. Just as an educated person can improve their circumstances through effort, entire communities and nations can achieve a notable position globally if they value education and are led by virtuous, dedicated individuals. This work explores how these Muslim figures narrated their paths toward Muslim leadership.<br/
Personalising treatment and targets in IBD
No full textInflammatoire darmziekten (IBD) zijn chronische ontstekingsziekten van de darm. De precieze oorzaak is onbekend. Klachten die vaak voorkomen zijn buikpijn, diarree, bloed bij de ontlasting en een plotselinge, onhoudbare aandrang voor ontlasting. IBD kan niet worden genezen. De behandeling is erop gericht de ontsteking te onderdrukken, maar dat lukt niet altijd. In dit proefschrift hebben we onderzocht of meer persoonlijke aanpak van zowel de behandeling als de behandeldoelen kan zorgen voor betere uitkomsten voor patiënten.In het eerste deel keken we naar het personaliseren van de behandeling. Uit eerder onderzoek bleek dat patiënten met een ernstige aanval van colitis ulcerosa mogelijk een hogere dosering van het medicijn infliximab nodig hebben, maar dat de optimale dosis verschilt per persoon. Wij hebben daarom in deze patiënten onderzocht of een persoonlijke dosis infliximab (afgestemd op de concentratie infliximab in het bloed) beter werkt dan de standaarddosis. We vonden dat een persoonlijke dosering mogelijk beter werkt en net zo veilig is als de standaarddosering. De persoonlijke dosis heeft daarom waarschijnlijk een beter risico/baten profiel.In het tweede deel richtten we ons op behandeldoelen. Voor veel patiënten is kwaliteit van leven een van de belangrijkste doelen. Bestaande vragenlijsten om dit te meten zijn echter vooral gemaakt door artsen, die kwaliteit van leven anders beoordelen dan patiënten zelf. Ook zijn de vragenlijsten vooral ontwikkeld in westerse landen en leggen ze nadruk op wat patiënten niet meer kunnen. Wij hebben daarom samen met patiënten wereldwijd een nieuwe vragenlijst ontwikkeld. Deze meet in hoeverre mensen met IBD een normaal leven kunnen leiden. De vragenlijst is getest in vier talen (Nederlands, Engels, Spaans en Hindi) en bleek goed en betrouwbaar te werken.Door behandeling en behandeldoelen te personaliseren, hopen we dat patiënten met IBD in de toekomst vaker een normaal leven kunnen leiden
Precision medicine in acute respiratory distress syndrome
No full textAcute Respiratory Distress Syndrome (ARDS) is a severe form of respiratory failure that affects about 10% of intensive care unit patients worldwide and continues to have a high mortality rate. Despite decades of research, effective therapies remain limited, largely due to the biological and clinical heterogeneity within ARDS. This thesis explores ways to overcome this through subphenotyping, a precision medicine approach that identifies distinct and meaningful patient subgroups. The research focuses on three key mechanistic and clinically measurable domains: imaging, respiration, and inflammation. In the imaging domain, the thesis examines whether subgroups differing in lung recruitability can be identified, distinguishing between recruitable and non-recruitable subphenotypes with distinct physiological profiles. The prognostic value of radiographic edema scores in mechanically ventilated patients is also evaluated. In the respiratory domain, previously defined low-power and high-power subphenotypes were applied early in the disease course to assess their potential for guiding personalized ventilatory strategies and evaluating responses to immunomodulatory therapy. In the inflammatory domain, established Hypoinflammatory and Hyperinflammatory subphenotypes are examined in relation to responses to tocilizumab, an immunomodulatory drug. Additionally, the role of nucleosomes as biomarkers of immune activation and organ injury is explored. Together, this thesis demonstrates that clinically relevant ARDS subphenotypes can be identified using multivariate, longitudinal, and complex data. The findings provide exploratory evidence that these subphenotypes may help tailor interventions and improve patient outcomes. The next critical steps are prospective validation of these classifications and evaluation of targeted therapies in clinical trials to bring subphenotyping closer to routine clinical application
Diplomatic propaganda in the Dutch Republic and France, 1609-1674
Get PDFThis dissertation investigates the practices and theories of printed propaganda among seventeenth-century Dutch and French diplomats. It argues that early modern diplomats had more developed and explicit understandings of propaganda than has so far been assumed. The dissertation shows that these diplomats drew from contemporary political philosophy and theories of mind to formulate their publication strategies, and demonstrates how this knowledge was put into practice using a series of case studies. The first two chapters investigate two major diplomatic crises between the Dutch Republic and France to understand how French diplomats evaluated the political effects of pamphleteering within these conflicts. The third and fourth chapters focus on the role of embassy secretaries in coordinating international pamphleteering campaigns in early modern Europe and transferring knowledge about past campaigns within diplomatic circles. The fifth chapter investigates how diplomats understood the psychological effects of propaganda, focusing in particular on contemporary notions of the soul, the animal spirits, and the faculties of reason and will. It argues that subtle differences within diplomats’ understanding of these faculties influenced their views on the desirability and feasibility of particular approaches to propaganda. The dissertation argues the use of and need for a sustained dialogue between studies on early modern public politics and propaganda studies
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
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
Sweet talking:The impact of bacterial glycan diversity on immune sensing
Get PDFAntibiotic resistance is a growing global health crisis, with mortality rates projected to rise significantly. Opportunistic pathogens Staphylococcus aureus and Streptococcus pyogenes are major contributors to skin and soft tissue infections, yet effective vaccines remain unavailable. This thesis investigates how bacterial surface glycans interact with the human immune system at barrier sites, focusing on Langerhans cells (LCs), immune sentinels in the skin. Understanding local host defenses may indicate why some individuals develop infections while others remain asymptomatic, and inform new therapeutic strategies.In S. aureus, wall teichoic acids (WTAs) are glycopolymers involved in colonization and immune evasion. Analysis of over 25,000 genomes, which revealed diversity in WTA glycosyltransferases (TarS, TarM, TarP), affecting glycan structures and immune detection. Specific glycosylation patterns may exacerbate inflammation in atopic dermatitis by activating LCs and promoting T helper 2 responses. Single-cell and bulk RNA sequencing identified LC subsets enriched in AD skin, with upregulated pathways linked to prostaglandin signaling, IgE receptor expression, and T cell activation.In S. pyogenes, the Group A Carbohydrate (GAC) is a conserved cell wall component essential for virulence. Genetic analysis revealed mutations in the gacA–L gene cluster, that altered cell wall composition and immune clearance. Langerin, a C-type lectin receptor on LCs, bound variably to a collection of S. pyogenes strains, and bacterial genes such as emm and mga were found to affect this binding.Together, these findings highlight the importance of glycan diversity in host–pathogen interactions and provide valuable insights for the development of vaccines and alternative therapies targeting these priority pathogens.</p