International Migration, Integration and Social Cohesion online publications
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Alveolar host response in acute respiratory distress syndrome
Get PDFThis thesis presents a series of translational studies investigating the alveolar host response in the patients with acute respiratory distress syndrome (ARDS), integrating molecular, cellular, and clinical perspectives. ARDS is a heterogeneous syndrome characterized by acute hypoxemic respiratory failure, high mortality, and limited treatment options. A deeper understanding of localized host responses may support the development of targeted therapies and improved diagnostics.The thesis begins with a comprehensive review of the alveolar immune landscape, highlighting neutrophils and macrophages as dominant cell populations and underscoring the heterogeneity of immune responses across etiologies and disease stages. Building on this foundation, high-dimensional single-cell proteomics was applied to characterize alveolar immune profiles in ARDS patients with different underlying causes. The results revealed pathogen-specific differences in immune activation and maturation, tightly linked to local cytokine profiles and patient outcomes.Subsequent work focused on the fibroproliferative response in COVID-19-related ARDS, demonstrating that early fibroproliferation is associated with increased short-term mortality but does not reliably predict long-term fibrotic sequelae. Another study evaluated the diagnostic utility of exhaled breath metabolites in large patient cohorts. Although metabolite-based algorithms achieved moderate accuracy, they fell short of clinical applicability, reflecting the challenges of translating breathomics into practice.Together, these studies illustrate the compartmentalized and dynamic nature of alveolar host responses in ARDS, encompassing inflammation, immune regulation, and tissue remodeling. They emphasize the importance of functional immune profiling, longitudinal assessment, and integration of molecular and clinical data to advance precision approaches for this complex syndrome
Cardiac autonomous function and large-vessel hemodynamics:Risk factors for hyppertension and CVD
Get PDFIn dit proefschrift hebben we verschillende technische benaderingen gebruikt om veranderingen in arteriële functie en anatomie te kwantificeren. Hierbij hebben we gebruik gemaakt van verschillende invasieve en niet-invasieve meetmethoden waardoor we inzicht verkregen in belangrijke hemodynamische kenmerken die kunnen helpen bij het voorspellen van hypertensie en cardiovasculaire ziekten (CVZ). In het eerste deel hebben we snelle veranderingen in bloeddruk (BD) en hartfrequentie gebruikt om de invloed van het sympathische en parasympatische zenuwstelsel op het risico op het ontwikkelen van hypertensie en CVD te beoordelen, binnen een multi-etnische populatie. Hier zagen we dat de autonome cardiale regulatie bijdraagt aan een verhoogd risico op het ontwikkelen van hypertensie en CVZ. Daarnaast onderzochten we de rol van het autonome zenuwstelsel in specifieke populaties met een verhoogd CVZ-risico, waaronder zoutgevoelige mensen en mensen met hiv die antiretrovirale therapie krijgen. In deze populaties zagen we een dysregulatie van de autonome balans. In het tweede deel van deze thesis gebruikten we invasieve en niet-invasieve metingen om de hemodynamiek in zowel de aorta, als ook de nierarteriën te beoordelen. Hierdoor hebben we onder andere meer inzicht verkregen in de hemodynamiek bij patiënten met een nierarteriestenose. Tevens hebben we gezien dat in een gezonde populatie de hoogte van gereflecteerde polsgolven geassocieerd is met de systolische bloeddruk. Als laatste hebben we kunnen laten zien wat voor dynamische veranderingen er in de aorta optreden in de periode van een enkele hartslag
From shake to shape:<i>In vitro </i>studies on how shear stress regulates erythropoiesis
No full textAlthough red blood cell (RBC) transfusion is one of the most common clinical practice, its dependency on donor blood presents challenges related to supply, storage, and infection risk. Alternatives to blood transfusions are being explored, among which, in-vitro RBC production is one of the most promising. Nevertheless, scaling manufacturing to transfusion-relevant quantities requires dynamic bioreactors that expose cells to mechanical forces like shear-stress. This thesis investigates how shear-stress influences erythroid differentiation to advance both the biological understanding of erythropoiesis and the optimization of large-scale RBC production. Erythroblasts cultured under moderate levels of shear-stress showed accelerated maturation, achieving enucleated CD49d⁻/CD235a⁺ reticulocytes four days earlier than under static conditions. Transcriptomic analyses revealed the downregulation of DNA replication genes and overexpression of cholesterol biosynthesis and uptake pathways, leading to transient membrane lipid remodeling that possibly enhances mechanical resilience. Functional studies identified mechanosensitive channel PIEZO1 and its downstream effector, the Gárdos channel, as active during differentiation, suggesting a feedback mechanism linking membrane lipid composition, ion flux, and cell volume regulation. Moreover, in-vitro RBC differentiation can provide models to study pathological erythropoiesis, as it has been shown in this thesis by the characterization of a novel β-spectrin mutation (SPTBc.6219G>A) associated with hereditary elliptocytosis. In summary, this work elucidates the mechanotransductive responses of erythroid precursors to shear-stress, demonstrating their impact on lipid metabolism, ion channel activity, and differentiation kinetics. These findings provide foundations for optimizing bioprocess parameters in RBC biomanufacturing and for implementing dynamic culture systems as models to investigate both normal and diseased erythropoiesis
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
Levaraging a cloud-based intensive care registry in a lower-middle income country to enable high-quality critical care research
No full textIndia, a lower-middle-income country, has made significant economic progress over the past two decades. As a result, the nation has witnessed major improvements in healthcare infrastructure and resources, particularly in large urban centers. However, a clear and persistent gap remains between advances in clinical service delivery and the corresponding growth in research output. The overarching objective of this thesis was to demonstrate the potential of a cloud-based registry—and its associated infrastructure—to enable high-quality critical care research in the Indian context. Using a scoping review methodology, we identified the barriers to conducting research in low- and lower-middle-income countries. Subsequently, drawing on data from the Indian Registry of IntenSive Care (IRIS), we explored a series of research questions to illustrate the registry’s ability to facilitate high-quality research. Given the limited information available on the influence of baseline patient characteristics on outcomes, our central research theme examined the association between the characteristics: frailty; persistent critical illness; and sex, on clinical outcomes. In the general discussion, we reflect on the implications of our findings in relation to the specific research questions, as well as the barriers mitigated by the registry ecosystem. We also discuss the strengths and limitations of our approach and outline future directions, including integrating electronic medical records and artificial intelligence technologies to enhance data collection and analysis; advancing recommendations for registry-embedded critical care research to democratize research in India; and developing sustainable funding models to ensure the long-term viability of the registry
Paving the way for nucleic acid-based HIV-1 envelope vaccines
No full textHuman immunodeficiency virus type 1 (HIV-1) remains a major global health challenge, with no effective prophylactic vaccine despite decades of dedicated research. The viral envelope glycoprotein (Env) trimer is the sole target of neutralizing antibodies and a central focus for vaccine development. However, its remarkable sequence diversity, inherent instability, and dense glycan shield, among other factors, hinder the induction of broadly neutralizing antibodies (bNAbs). This thesis explores novel strategies to stabilize Env trimers, enhance their antigenic properties, and improve their suitability for RNA- and other nucleic acid-based vaccine platforms.We first investigated natural mechanisms of Env stabilization by introducing destabilizing mutations and identifying compensatory changes that emerged during viral evolution. Building on these and other prior insights, we engineered hyperstable trimers and found that increased stability led to stronger and more consistent neutralizing antibody responses. By selectively masking immunodominant epitopes with glycans, we redirected immune responses toward subdominant epitopes with greater potential to induce bNAbs.We also developed the Triple Tandem Trimer (TTT) platform, which encodes all three protomers of an HIV-1 Env or influenza hemagglutinin (HA) trimer within a single gene, ensuring exclusive trimer expression. TTT immunogens formed native-like trimers, induced diminished non-neutralizing responses, and enabled the design of chimeric trimers that could simplify sequential vaccine regimens by integrating different immunization stages into a single immunogen.Finally, we engineered RNA-delivered, membrane-bound, germline-targeting Env immunogens that potently activated rare bNAb precursors in knock-in mouse models and outperformed soluble counterparts in triggering these targeted responses.Collectively, these approaches advance the design of stable, immunofocused Env immunogens optimized for nucleic acid-based vaccine delivery, and offer promising tools and strategies for the development of an effective HIV-1 vaccine
New insights in eosinophilic gastrointestinal diseases
Get PDFEosinophilic esophagitis (EoE) is a chronic condition driven by type 2 immunity and commonly triggered by dietary antigens. Conventional diagnostic tools (skin prick, serum IgE) lack accuracy. It was demonstrated that ex vivo culturing of esophageal biopsies with food antigens elicited more relevant inflammatory responses than systemic tests. Identified cytokines (IL-5, IL-8, MCP-1, TNF) served as stronger predictors of food triggers.A recently described phenomenon FIRE (Food-induced Immediate Response of the Esophagus) presents with rapid postprandial symptoms. High-resolution manometry showed that allergen exposure caused increased contractile vigor but no major motility abnormalities. This suggests that mechanisms beyond motility changes are responsible. Treatment adherence was suboptimal in approximately 42% of patients with EoE, paralleling other chronic diseases. Younger age (<40) and low necessity beliefs were significant predictors of non-adherence. This underscores the need for enhanced shared decision-making and structured adherence monitoring.A cohort of patients with non-EoE eosinophilic gastrointestinal disorders (EGIDs) was examined. Patients exhibited nonspecific symptoms and frequently normal endoscopy despite mucosal eosinophilia. No evidence of disease extension across sites or layers was observed. Symptom improvement was common, though standardized treatment strategies are lacking.Finally, the role of eosinophils in ulcerative colitis (UC) was investigated. Elevated eosinophil counts correlated with severe disease but were not prognostic in new UC, suggesting a secondary inflammatory role rather than causality
Molecular containers:Macrocycles, cages and photocages
No full textThis thesis explores the design and properties of molecular containers for the controlled storage and release of molecules, focusing on three key classes: supramolecular tubes assembled from macrocycles, porous organic cages, and photocages. The first part investigates supramolecular nanotubes formed from macrocyclic building blocks, where the balance between hydrogen bonding and halogen interactions governs tubular assembly in single crystals. A key insight is the substitution of bromines with iodines, which strengthens halogen bonding and enhances structural integrity. The study then turns to rylene diimide based organic cages, with a focus on reducing their symmetry to increase functional diversity. Using principles of dynamic covalent chemistry and self-sorting, the formation of kinetically trapped cages is examined, revealing how subtle changes in reaction conditions affect stability and selectivity. The kinetic formation of rylene diimide cages is leveraged to identify intermediates formed during cage assembly and to propose a detailed formation mechanism. Two intermediates were successfully isolated, characterized, and evaluated regarding their kinetic stability. Finally, the isolated intermediates were transformed into cages with reduced symmetry, resulting in varying selectivity. Notably, one case demonstrated the clean formation of a heteroleptic cage. Lastly, the thesis explores bodipy-based photocages as light-responsive molecular tools. These enable selective labeling and cleavage of biomolecules upon green light irradiation, offering a method to control charge states in high-vacuum environments. Computational and experimental studies elucidate the photochemical mechanisms, demonstrating the potential of photocages in precision molecular manipulation
Gut microbiota and pneumonia:From health to severe infection
No full textThis thesis investigates the composition and impact of human microbiota throughout the continuum of health to severe pneumonia, in order to decipher the role and targetability of the microbiome in infection susceptibility, severe illness and its recovery. Despite the recent surge in research on the role of gut microbiota in enteric infections, current understanding on the role of microbiota during pneumonia in humans is limited, and no microbiota-targeted therapies have been implemented in everyday management. We hypothesised that the gut microbiota - particularly obligate anaerobic butyrate-producing bacteria - play a protective role against systemic infections in healthy individuals, are distorted during pneumonia and its recovery, safeguard against adverse clinical outcomes in hospitalised patients, and represent a treatable trait. We used general population cohorts, cohorts of hospitalised patients (including during their recovery), and murine models of pneumonia to examine the role of microbiota before, during and following pneumonia. Our findings show that gut and lung microbiota are altered during hospital admission for pneumonia, and correlate with clinical outcomes. Gut microbiota alterations precede hospitalisation and are associated with infection susceptibility, but also remain altered following recovery. Finally, we describe strategies to target gut microbiota to improve outcomes during pneumonia. Overall, this work advances our understanding of the role of gut microbiota in pneumonia, and its potential as preventive and therapeutic target
Looking beyond the NICU:Long-term outcomes and machine learning prediction
No full textThis thesis studies the long-term outcomes after preterm birth, focussing on pulmonary and neurodevelopmental outcome and investigates the value of machine learning in the prediction of these outcomes.In Chapter 1, a meta-analysis is performed to study the pulmonary outcome of preterm infants. Preterm born children face a three times increased risk of adverse pulmonary outcome. A lower gestational age or birthweight, bronchopulmonary dysplasia and receiving invasive mechanical ventilation were all significantly associated with increased risk of adverse pulmonary outcome.Chapter 2 identifies studies using machine learning to predict neurodevelopmental outcome. This study finds that models often face risk of inflated predictive performance due to data leakage from testing to training data, and that those with sufficient quality are limited to outcome up to two years and are mainly based on predictors derived from advanced MRI imaging.In Chapter 3 and 4, machine learning models were developed to predict neurodevelopmental outcome based on readily available predictors from the neonatal period. The models reached moderate overall performances (AUC up to 0.703), yet performed significantly better than the conventional models and reached high negative predictive values (up to 95%). The models performed better predicting outcome at five than outcome at two years of age. Vital signs handled through a basic approach modestly improved prediction of motor outcome but not cognitive outcome.In Chapter 5 the design and implementation of a sturctured neonatal follow-up with integrated data-pipeline was studied. This structured follow-up of highly vulnerable neonates and their parents facilitates both individual patient care and health care innovation through evaluation and scientific research.</p