International Migration, Integration and Social Cohesion online publications
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Shaping susceptibility:The role of SIX8 and TOPLESS in Fusarium wilt disease
No full textThe Fusarium oxysporum (Fo) species complex causes Fusarium wilt disease in a wide range of economically important crops, including tomato, cotton, banana, spinach, lettuce, melon, and ornamentals such as chrysanthemum and tulip. Current management strategies are often environmentally harmful, expensive, and unsustainable. A viable alternative is to the use of genetically resistant plant varieties. This thesis identifies members of the small TOPLESS (TPL) gene family as key Susceptibility (S) genes for Fo infection. Two specific TPL proteins directly interact with the Fo-secreted effector protein, SECRETED IN XYLEM 8 (SIX8). CRISPR/Cas9-mediated knockout of these TPL genes in both tomato and Arabidopsis thaliana conferred near-complete resistance to Fo, confirming their role as S genes. The SIX8 gene is present in 14 Fo isolates with distinct host specificities, while TPL genes are conserved across all land plants, suggesting that this resistance strategy could be broadly applicable across different crop species. TPL proteins function as transcriptional co-repressors, leading us to hypothesize that SIX8 promotes disease by manipulating host transcription. To investigate this, we generated A. thaliana lines expressing SIX8 and discovered that the immune receptor SNC1 monitors both TPL and TPL-RELATED 1 (TPR1). Furthermore, expression of SIX8 in a snc1 null mutant background, followed by transcriptome profiling revealed biological pathways that are potentially targeted by the pathogen during infection.</p
Immune infiltration and activation in breast tumors
No full textIn this thesis, we explore the antitumor response of immune cells against breast tumors and investigate how these findings can be clinically applied to improve patient treatment. Tumor cells are continuously in contact with other cells in their environment and can exhibit characteristics that the immune system perceives as foreign. This enables immune cells to infiltrate the microenvironment, recognize the tumor cells, initiate an immune response, and facilitate the clearance of the tumor cells. However, tumor cells can also manipulate their surrounding microenvironment in a way that inhibits the activity of immune cells, thereby preventing an immune response. With the advent of immune checkpoint inhibition therapy, it has become possible to activate immune cells that are suppressed by the tumor, thereby enabling the clearance of the tumor.Adding immune checkpoint inhibitors to chemotherapy has markedly increased response rates for patients with primary triple-negative breast cancer. To better tailor treatment options to individual patients and more accurately predict disease progression, it is necessary to gain more knowledge about the complex properties of the tumor microenvironment.This thesis first compares methods for investigating and profiling the tumor microenvironment in patients with early-stage breast cancer. We examine the comparability of different techniques and employ methods in clinical cohort studies that go beyond merely quantifying tumor infiltrating lymphocytes. Next, we examine various determinants of the tumor microenvironment and explore how these characteristics can be used to improve immunotherapy for patients with triple-negative breast cancer (BELLINI trial, Nederlof et al. and TONIC trial Voorwerk et al.) and whether elements of the microenvironment can be used to predict clinical response
Molecular mechanisms and therapeutic targeting of Fc receptor activation in acute and chronic inflammatory diseases
Get PDFAntibodies play a crucial role in the host immune response against invading pathogens. By facilitating specific effector functions, they contribute to pathogen clearance and modulation of the immune response. Beyond well-known functions like neutralization, antibodies can trigger a powerful cytokine response mediated by Fc receptor (FcR) activation through a mechanism called antibody-dependent inflammation (ADI). ADI facilitates the rapid secretion of pro-inflammatory cytokines, which, in a pathological situation, plays an important role in effective pathogen clearance. In contrast, if mis-regulated, due to its ability to induce high levels of pro-inflammatory molecules, aberrant ADI can contribute to extensive tissue damage and worsening of disease pathology. In severe COVID-19, aberrantly glycosylated antibodies induce mis-regulated ADI, contributing to a hyperinflammatory phenotype, microvascular thrombosis and pulmonary edema. To successfully counteract aberrant ADI-induced pathology, it is important to understand the underlying molecular mechanisms causing these deteriorating effects. In this thesis, I set out to investigate the molecular mechanisms, as well as potential therapeutic targets, of pathological FcR activation in severe COVID-19 progression. Apart from antibodies, pentraxins can induce the secretion of pro-inflammatory cytokines via FcR activation in a mechanism similar to ADI. CRP-induced pathology has been described in several chronic inflammatory conditions, such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Thus, I investigated the molecular mechanism of CRP-induced cytokine induction to explore potential indications for the treatment of chronic inflammatory diseases
Water and ion dynamics at interfaces
Get PDFThis 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
Ultra-low-dose chest CT versus chest X-ray for acute pulmonary disease:Clinical and societal implications
No full textRadiological imaging plays a pivotal role in clinical decision-making in the work-up of ED patients with non-traumatic pulmonary complaints. Ultra-low-dose chest CT (ULDCT) offers the possibility to obtain detailed imaging at a radiation dose similar to that of conventional chest X-ray (CXR). Optimal implementation of such a novel imaging technique with a higher diagnostic accuracy than the default modality requires evidence on the impact on patient management and efficiency. Therefore, this thesis studied the impact on patient outcome and societal outcome of replacing CXR by ULDCT in patients presenting at the ED with non-traumatic pulmonary complaints. We designed the OPTIMACT trial, a multicenter, pragmatic, non-inferiority randomized controlled trial comparing ULDCT to CXR in consecutive adult patients presenting at the ED with non-traumatic pulmonary complaints. We demonstrated that ULDCT was non-inferior in short-term functional health with minimal differences in hospital admissions, length of stay, mortality, and economic impact compared to CXR. There were more incidental findings, but less additional imaging procedures after 28 days with ULDCT. In patients with an atypical presentation of pneumonia ULDCT performed better than CXR. ULDCT was more accurate in detecting pulmonary infections, but less accurate in detecting pulmonary congestion. Awareness for early radiological features of pulmonary congestion may improve the recognition of pulmonary congestion at ULDCT and CXR.Overall, the results of our trial do not support the unconditional use of ULDCT in the work-up of patients presenting with non-traumatic pulmonary disease at the ED. It is recommended to consider the use of ULDCT instead of CXR in vulnerable patients
Lending colour to the black box:Insights into the course and burden of primary sclerosing cholangitis
No full textPrimary sclerosing cholangitis (PSC) is a rare cholestatic liver disease marked by multifocal bile duct strictures and is strongly associated with inflammatory bowel disease (IBD). The disease runs an unpredictable course with increased risk of developing colorectal and hepatobiliary cancers, frequently culminating in liver transplantation. While its cause remains unclear, no proven medical therapy exists to halt disease progression.Part I assessed the disease burden of PSC. Although individually rare, cholestatic liver diseases pose a significant epidemiological and economical burden. Dutch registry data revealed that patients lose an average of 11.8 healthy life-years in the first 30 years post-diagnosis, spend 12 hospital days annually, incur average yearly medical costs of €12,169, and experience a 25% work productivity loss. Health-related quality of life is reduced, particularly by IBD symptoms, pruritus, and advanced liver disease, but improves post-transplant.Part II explored the gut–liver axis. Proctocolectomy with permanent ileostomy was linked to a 60% reduced risk of transplantation or PSC-related death, while colectomy with remnant colon or pouch did not show survival benefit. IBD presence or endoscopic activity showed no direct impact on transplant-free survival, presumably due to persistent microscopic gut inflammation.Part III evaluated biliary tract interventions. Cholecystectomy showed no significant survival effect and should therefore not be avoided in PSC. Ursodeoxycholic acid (UDCA) use did not improve long-term outcomes, though a possible chemoprotective effect against hepatobiliary malignancy was noted, warranting further study
New insights in the management of pancreatic diseases
Get PDFThe primary objective of this thesis is to enhance diagnostic and therapeutic approaches for patients with pancreatic diseases. In Part I, we focused on novel insights for the early detection of pancreatic cancer (PDAC). We conducted two case-control studies involving PDAC patients who had undergone imaging before PDAC diagnosis (Chapter 2 and 3). Skilled radiologists retrospectively analyzed the data, revealing that a notable portion of prediagnostic PDAC patients exhibited suspected pancreatic masses in imaging, while controls showed minimal occurrences. Additional features such as pancreatic duct dilation, pancreatic atrophy, and pancreatic steatosis were also associated with PDAC.Part II centers on the challenges in diagnosing and managing pancreatic cystic neoplasms (PCN). CEA in cyst fluid is a commonly applied biomarker for distinguishing mucinous from non-mucinous PCN, and Chapter 4 of this thesis demonstrated that a revised cutoff of ≥20 ng/mL had optimal diagnostic accuracy. In Chapter 5, we examined four biomarkers in pancreatic juice to differentiate CP and IPMN with main-duct involvement. Mutated KRAS exhibited high sensitivity for IPMN but limited specificity, whereas GNAS mutation displayed the opposite pattern. The assessment of CEA and glucose did not significantly contribute. Chapter 6 compared three guidelines for managing mucinous PCN, with the European and IAP guidelines outperforming AGA but potentially leading to excessive surgeries. Chapter 7 showcased that large BD-IPMN without other risk factors had a low prevalence of advanced neoplasia.In Part III, Chapter 8 described that the Pancreas Elastase 1 Quick Test™ was found to be less accurate than conventional methods for diagnosing exocrine pancreatic insufficiency. Chapter 9 examined vitamin D deficiency in CP patients, revealing a high prevalence but no clear difference between CP patients and controls
Molecular containers:Macrocycles, cages and photocages
Get PDFThis 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
Indulging in Paradise?:EU law and policy of holiday air travel through the lens of practice theory
No full textIn his doctoral thesis Yannick van den Berg researches how EU (consumer) law and policy have failed to reduce emissions from holiday air travel. In his thesis he argues that taking a social practice theoretical approach to holiday air travel can yield valuable insights into EU law and policy on sustainable consumption, in particular by giving new ways to frame problems of sustainability. Instead of focusing on individual choice, behaviour and green technologies, the thesis shows how it can be more fruitful to understand the problem of emissions of holiday air travel as one that requires us to recraft air travel to become more sustainable, substitute air travel by rail travel and finally to see how air travel can become less ‘locked in’ to other practices like holidaying. Taking a practice approach, Van den Berg also sheds a light on the limitations of law (and policy) in addressing unsustainable social practices
Peripheral blood compounds in schizophrenia and major depressive disorder
No full textSchizophrenia and major depressive disorder (MDD) have traditionally been considered distinct disorders, yet they share overlapping symptoms, including mood disturbances, apathy, and cognitive impairment. Increasing evidence points to shared biological mechanisms, particularly involving immune function, neuroplasticity, and energy metabolism. This thesis investigates alterations in peripheral blood markers across these domains, focusing on drug-naïve first-episode patients, the effects of psychotropic treatment, the efficacy of anti-inflammatory augmentation, and the potential utility of blood-based biomarkers for predicting outcomes and guiding treatment.Three meta-analyses were conducted. The first showed that drug-naïve first-episode patients with schizophrenia or MDD exhibit alterations in neuroplasticity- and immune-related markers, with additional disturbances in glucose metabolism specific to schizophrenia. The second demonstrated that treatment tends to normalize neuroplasticity and immune alterations while worsening glucose regulation in schizophrenia. The third, a comprehensive analysis of 51 compounds in antipsychotic-naïve schizophrenia patients, confirmed widespread abnormalities at illness onset in neuroplasticity, immune function, and energy metabolism. Longitudinal analyses revealed improvements in neuroplasticity and immune markers following treatment, but further deterioration in energy metabolism.Serum analyses from two large cohorts revealed shared metabolic alterations — elevated leptin and insulin levels — in both schizophrenia and MDD, particularly during active episodes. A population-based study linked higher body mass index and altered lipid profiles to psychotic-like experiences, suggesting that metabolic dysfunction may represent a broader vulnerability factor.A meta-analysis of anti-inflammatory augmentation therapies showed beneficial effects, particularly in early illness and for negative symptoms. Finally, a machine learning study identified baseline markers of inflammation and endothelial function as predictors of negative symptom severity in schizophrenia six years later.These findings support a biologically informed, cross-diagnostic approach to psychiatry and highlight the potential of blood-based biomarkers to guide personalized, mechanism-based care