International Migration, Integration and Social Cohesion online publications
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Pathogenic insights into immune-mediated sclerosing cholangiopathies:From autoantibody formation to cholangiocellular defence mechanisms
No full textIn immune-mediated cholestatic liver diseases bile flow is impaired due to biliary tree damage induced or perpetuated by an excessive immune-response often against self-antigens. Primary sclerosing cholangitis (PSC) and IgG4-related cholangitis (IRC) are characterized by inflammation and consequent sclerosing (scarring) of the bile ducts, which leads to cirrhosis and need for liver transplantation when inadequately treated. To arrive at new, increasingly selective treatment strategies that slow down disease progression, it is important to understand the potentially disrupted underlying regulatory mechanisms in cholangiocytes. This thesis focusses on identifying protective machinery and autoantigens in cholangiocytes, and investigates the potentially pathogenic role of autoantibodies against these targets in PSC and IRC. We found that: 1) The ion transporters SLC9A1, SLC26A2 and SLC26A6 protect cholangiocytes from toxic bile acids and may be transcriptionally regulated by peroxisome proliferator-activated receptors. 2) Individuals with PSC and IRC have autoantibodies against carbonic anhydrase (CA) enzymes, which catalyse the reaction CO2 + H2O ⇌ HCO3- + H+. In particular, anti-CA5B autoantibodies are highly prevalent and functionally inhibit the human enzyme. 3) Individuals with IRC possess autoantibodies against laminin 511, an extracellular matrix protein substantially secreted by cholangiocytes that enhances barrier function and protects against T cell-induced barrier dysfunction. Notably, the autoantigens galectin-3 and prohibitin 1 do not have clear protective functions in cholangiocytes.This suggests that certain – but not all – autoantibodies in PSC and IRC may disrupt protective mechanisms of cholangiocytes comprising: HCO3- production and secretion, a sensory component, and epithelial barrier tightness, collectively termed the “cholangiocyte defence triangle”.<br/
Precision medicine in acute respiratory distress syndrome
Full text linkAcute 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
Phosphate and salinity differentially affect root skewing and circumnutation
Full text linkPhosphorus (P) is essential for plant growth, forming key macromolecules like ATP, phospholipids, and nucleic acids. Inorganic phosphate (Pi) availability in soils is limited due to low solubility and mobility. This thesis investigates how plant roots perceive and respond to Pi availability. We discovered that Arabidopsis roots exhibit a clear Pi-specific directional-growth response, however, always to the left direction independent of the direction of the Pi gradient. This increasing level of Arabidopsis root skewing induced by increasing concentration of Pi was termed "Phosphate Dependent Skewing" (PDS). This response is caused by a right-handed, clockwise, circumnutation of the root tip, which is driven by left-handed, counterclockwise, epidermal cell file rotation (CFR) in the root elongation zone, and involves a reorientation of the cortical microtubule cytoskeleton. Transcriptomic and genome-wide association studies identified critical roles for the microtubule cytoskeleton, cell wall, and Pi signalling pathways in regulating PDS responses. Interestingly, increasing NaCl concentrations reverse PDS to a rightward skewing response, termed “Salt Induced-Rightward Skewing” (SIRS), with associated reversals in helicities. This work provides a deeper understanding of root behaviour under Pi availability and salinity stress, linking cellular mechanics to genetic pathways. The findings emphasise the relationship between root skewing, circumnutation, and tropisms, and offer insights into how roots adapt their growth to optimise Pi acquisition. These discoveries lay the groundwork for improving nutrient use efficiency in crops, potentially addressing challenges in sustainable agriculture
From diversity to functionality:Understanding microbial communities in haloalkaline biodesulfurization systems
Full text linkSulfur, abundant on Earth, undergoes a microbial-driven cycle across oxidation states. Microbes thriving in sulfide-rich environments enable pollution mitigation and sulfur recovery, despite H2S toxicity. Haloalkaline biodesulfurization, an eco-friendly process, employs haloalkaline sulfide-oxidizing bacteria (SOB) to convert toxic H2S into elemental sulfur (S8). It can completely remove gaseous sulfide from the inlet gas streams from various natural and industrial sources such as landfills, paper, textile, oil and gas and others. The produced sulfur can be used to make fertilizers and hence contributes to circulation of resources. Understanding key microbes and underlying mechanisms driving this bioprocess is crucial for optimizing and advancing the bioprocess. This thesis systematically investigated microbial communities in pilot- (dual reactor line-up with anoxic and oxic bioreactor) and full-scale (single-reactor line-up with only oxic bioreactor) biodesulfurization installations. It was shown that composition and source of the feed gas impacted the diversity of microbial community. Despite that, all the installations had a set of common microbes contributing to sulfide oxidation with Thioalkalivibrio as the most abundant genus. However, for dual reactor line-up, Alkalilimnicola emerged as abundant as Thioalkalivibrio, which contributed to higher selectivity of sulfur formation. The dual-reactor system, when investigated at different process conditions, variable hydraulic retention time (HRT) and sulfide concentration in anoxic reactor, suggested that both these parameters impact activity of SOB. This thesis combines substrate kinetics and molecular biology to infer the mechanisms involved in sulfur conversions up to molecular level. It also proposes indicator genes for the increased thiosulfate (undesired by-product) formation
LXR-regulated proteins:The key to unlocking cholesterol homeostasis
No full textOur body needs to manage cholesterol carefully. Too much can lead to life-threatening diseases like atherosclerosis, while too little disrupts essential functions. At the heart of this balance are the liver X receptors (LXRs), which help reduce cholesterol buildup by regulating how cells absorb and release it. This research reveals how LXRs influence not only cholesterol levels but also the composition of fats in cell membranes, which is crucial for keeping cells healthy and stable.We identified new targets of LXR regulation with important implications for health. One discovery is TMEM86a, a protein that controls special fats called lysoplasmalogens, which maintain the integrity of cell membranes. Another key player, EEPD1, helps immune cells called macrophages expel excess cholesterol. We also explored IDOL, a protein that limits cholesterol uptake by breaking down LDL receptors. Earlier findings suggest that blocking IDOL could become a powerful treatment for high cholesterol and cardiovascular diseases. We discovered several potential IDOL inhibitors that may serve as the basis for future cholesterol-lowering treatments.This thesis not only deepens our understanding of how LXRs regulate cholesterol and lipid metabolism but also opens the door to new therapeutic strategies for cardiovascular and neurodegenerative diseases. If you're curious about the hidden mechanisms that keep our bodies in balance, and how we might harness them to fight disease, this work provides valuable insights and future directions for medical science
Meta-analytic structural equation modeling with group data:Navigating the maze of <i>d</i>-to-<i>r</i> conversions
No full textThe central question of this dissertation was whether and how group data from two groups can be included in meta-analytic structural equation modeling (MASEM). Substantive researchers have raised this issue, and the aim of this dissertation was to address this methodological challenge and provide advice and support to those researchers. Including data from two groups in MASEM poses challenges because the primary studies that investigate such data typically report standardized mean differences (e.g., Cohen's d or Hedges' g), while MASEM generally uses correlations as input. This challenge can be solved by converting standardized mean differences into correlations. However, one can convert to different kinds of correlation coefficients (i.e., biserial or point-biserial correlation) and can apply different conversion formulas. In this dissertation, I outline the decisions a meta-analyst needs to make when incorporating data from two groups into MASEM, specifically regarding which conversion to apply for converting a standardized mean difference to either a point-biserial or biserial correlation. I showed that if one wants to include a dichotomized variable in MASEM and one converts the standardized mean difference to a biserial correlation, this yields unbiased MASEM parameters. On the other hand, if one wants to include a dichotomous variable in MASEM, one should convert the standardized mean difference to a point-biserial correlation. In this dissertation, I demonstrated that which conversion to use depends on the aim of the meta-analyst. Moreover, whether all relationships in the MASEM model are estimated accurately also depends on the research designs of the primary studies, as an additional adjustment to the relationships between continuous variables in the MASEM model is required in some scenarios. To assist meta-analysts in applying the various conversion formulas I recommend in this dissertation, I developed a freely available web application entitled the Effect Size Calculator and Converter (ESCACO; hdejonge.shinyapps.io/ESCACO)
Molecular symphony:Charting the transcriptional dynamics of human cardiac pacemaker cells
Full text linkThe human heart develops through tightly regulated molecular and cellular processes, ensuring the formation of specialized cardiomyocyte subtypes that govern contraction and electrical conduction. Disruptions in these processes contribute to congenital and acquired cardiac diseases. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a unique platform to study cardiac development, function, and disease in vitro. However, key challenges remain in understanding the differentiation and specialization of distinct cardiomyocyte subtypes.This thesis explores the mechanisms driving the differentiation of sinoatrial nodal (SANCMs) and atrioventricular canal cardiomyocytes (AVCMs) and their functional properties in engineered cardiac tissues. Single-cell RNA sequencing and trajectory inference reveal transcriptional regulators and signaling pathways guiding SANCM subtype specification, providing insights into pacemaker cell development. Three-dimensional cardiac models demonstrate that SANCMs functionally integrate into pacemaker-atrial interfaces, replicating physiological pacemaker activity. Additionally, the development of an in vitro model of the atrioventricular conduction system shows that AVCMs enable unidirectional conduction and recapitulate physiological AV delay.By integrating developmental biology, stem cell differentiation, and tissue engineering, this work advances the understanding of cardiomyocyte subtype specification and function. The findings contribute to the development of physiologically relevant cardiac models for studying disease mechanisms and exploring new therapeutic strategies.<br/
Bouwen langs de Maas:Huizen in Limburgse steden circa 1200-1600
Full text linkHet proefschrift ‘Bouwen langs de Maas’ behandelt de bouwpraktijk van stedelijke huizen in de late middeleeuwen in de steden Maastricht, Sittard, Roermond en Venlo. Het onderzoek richt zich op de factoren die het uiterlijk van deze huizen bepalen. Er wordt eerst gekeken naar de historische context van de steden, zoals politieke omstandigheden, de specifieke stadsgeschiedenis, handelscontacten en naar de heersende bouwvoorschriften en de organisatie van bouwambachten. Vervolgens wordt per stad de ruimtelijke ontwikkeling geschetst en de positie van de huizen daarin. In Hoofdstuk 3 wordt aandacht besteed aan de verschillende huisvormen die in de steden voorkomen: woontorens, huizen met een hofachtige aanleg (‘poorten’), diepe huizen, dubbelhuizen en dubbelbrede huizen. Hoofdstuk 4 is gewijd aan de bouwmaterialen die kenmerkend zijn voor de huizenbouw in de vier steden tot ongeveer 1600 n. Chr.. Hier wordt gekeken naar de herkomst, verspreiding en toepassing van bouwmaterialen, zoals kolenzandsteen, mergel, baksteen en eikenhout. Hoofdstuk 4 behandelt ook de constructie van de huizen. Zowel vakwerkbouw als steenbouw komen aan bod, evenals de verstening van de huizen en constructieve elementen zoals kelders, balklagen en kapconstructies. In hoofdstuk 5 wordt de vormgeving van de huizen besproken, zowel die van vroege steenbouw, als die van vakwerkhuizen in Maastricht en Sittard en bakstenen huizen in Roermond en Venlo. Het proefschrift wordt afgesloten met hoofdstuk 6, waarin de resultaten van de onderzoeksthema’s in een bredere, interregionale en internationale context worden geplaatst
Emerging fields:Their strategic implications and identification
Full text linkThis PhD dissertation explores the role of emerging fields, such as Artificial Intelligence (AI), for two key strategic decisions—entrepreneurial resource acquisition and alliance formation—and examines how these fields can be identified using computational methods. Chapter 2 examines the effects of being associated with an emerging field on initial venture financing from both scientists’ and investors’ perspectives. We demonstrate that increasing scientific involvement in a field positively influences capital raised, while increased investor involvement has a negative effect. This contrast likely arises because scientific interest signals innovation potential, whereas greater investor presence may indicate that the most lucrative opportunities have already been exploited. Chapter 3 investigates how the novelty of these fields—both to the firm making a decision and to its competitors—affects alliance formation. We further explore how the scientific background of alliance decision-makers shapes these strategic choices. Our findings show that only fields familiar to competitors of the focal firm positively impact alliance formation, while decision-makers with a scientific background tend to favor more novel solutions. Chapter 4 assesses the effectiveness of various computational methods in identifying fields, introducing a novel quantitative measure of overlap to compare their results. Our findings reveal that each method yields different insights, highlighting the need for careful interpretation as certain outputs may lack substantive meaning, necessitating human judgment. Chapter 5 extends traditional metrics, commonly applied to track topics over time within a single method, by using them to bridge topics, including fields, across different methods. We also assess the performance of traditional versus neural topic modeling in detecting emergence. Our results show that content-based metrics are particularly effective for cross-method matching, with traditional topic modeling demonstrating greater accuracy than neural topic modeling in identifying emerging fields
A focus on craniomaxillofacial giant cell neoplasms
Full text linkThis thesis investigates giant cell neoplasms occurring within the craniomaxillofacial skeleton, a group of rare bone lesions characterised by the presence of multinucleated osteoclast-like giant cells. The clinical presentation, location, biological behaviour, and treatment outcomes of these lesions vary widely, presenting significant challenges and complexities in clinical practice. The research presented in this thesis aims to explore the pathogenesis of these lesions, enhance the diagnostic capabilities and classification by evaluating both clinical and non-clinical features along with various disease patterns, and improve treatment outcomes by analysing data on the efficacy and toxicity of various (non-surgical) interventions. The findings demonstrate that the integration of clinical, radiological and new molecular data allows for better diagnostic accuracy and differentiation between the various types of craniomaxillofacial giant cell lesions. However, the complex biology of these lesions remains only partially understood, which particularly complicates the prediction of their diverse biological behaviours. The results of pharmacological therapies show promise in minimising the morbidity associated with surgery and reducing the risk of recurrence, especially in aggressive cases. Nonetheless, ongoing research is essential to optimise current treatment approaches and to identify novel, non-surgical strategies that target the underlying biological mechanisms driving these lesions