Protein posttranslational modifications by small ubiquitin-like modifiers (SUMOs) are critical for regulating a variety of cellular processes. Dysregulation of SUMOylation is increasingly... Show moreProtein posttranslational modifications by small ubiquitin-like modifiers (SUMOs) are critical for regulating a variety of cellular processes. Dysregulation of SUMOylation is increasingly associated with cancer and inhibitors that block SUMOylation are currently being explored as cancer treatment. We aimed to gain a better understanding of how the SUMO system governs the integrated network of nuclear signaling pathways, with a specific focus on genome maintenance. For this, we combined unbiased global mass spectrometry-based proteomics approaches with mechanistic follow-up studies. We found that the SUMO protease SENP6 maintains genome stability by ensuring the timely removal of SUMO chains on proteins involved in the response to DNA damage, affecting their localization, kinetics and nuclear condensation state. In addition, we found that noncovalent protein interactions with SUMOs mediated by SUMO-interaction motifs (SIMs) are also critical in maintaining genome stability, by facilitating the recruitment of DNA damage response proteins to the sites of damage. Lastly, we offer valuable new insights on noncovalent SUMO interactions by providing a comprehensive dataset of proteins that bind SUMO independently of the classical SUMO-SIM interaction. This suggests that the relevance of alternate modes of SUMO interactions is currently underestimated by the field and opens up new avenues for future research. Show less
Retinopathy of prematurity (ROP) is the most important cause of vision loss premature infants. With a continuous growth in this vulnerable population, the number of newborns at risk for severe,... Show moreRetinopathy of prematurity (ROP) is the most important cause of vision loss premature infants. With a continuous growth in this vulnerable population, the number of newborns at risk for severe, sight threatening ROP increases. In this thesis the results of the national Dutch inventory on risk factors, screening, treatment and sequelae of ROP are presented. The principal aims of the study were to determine characteristics of newborns who are at highest risk to develop severe ROP to assess quality of screening and treatment and to evaluate the national ROP guideline. Following these studies together with extensive cost-effectiveness analyses, the current Dutch ROP screening and treatment guideline was adapted and implemented in November 2023. The NEDROP 2 allowed for more stringent screening inclusion criteria, lowering the number of infants that need to undergo burdensome screening under the precondition that no severe ROP would be missed. Annually, this will lower the screening costs by nearly 60,000 euros. Show less
Posttraumatic stress disorder (PTSD) is a psychological disorder that develops following exposure to perceived life-threatening trauma. Characteristic features include behavioral changes caused by... Show morePosttraumatic stress disorder (PTSD) is a psychological disorder that develops following exposure to perceived life-threatening trauma. Characteristic features include behavioral changes caused by heightened arousal, including fear and anxiety. Glucocorticoid receptor (GR) hypersensitivity, as defined by strong negative feedback, has been one of the most robust findings of altered HPA axis function in PTSD. In this thesis, we evaluated GR-related changes that were exposed to the three consecutive stressors of the single prolonged stress (SPS) animal model for PTSD. We tested the potential of the GR antagonist RU486 treatment in reversing these stress-induced effects. We found that GR antagonism can normalize some stress-induced parameters. We demonstrated that varying the timing of RU486 administration and evaluation gave different behavioral results and dynamics of gene expression, that revealed complex interactions between stress and RU486 over time. We also tested the GR sensitivity after administered the exogenous corticosterone. Our data suggest the enhanced stress responsiveness after SPS to moderate but not mild stressors and a sensitization of brain GR signaling that extends beyond direct negative feedback regulation. Lastly, we provide evidence for a role of β-arrestin-2 as a modulator of regulating amygdala activity in response to fear/anxious memory of PTSD. Show less
In this thesis, we have studied cell images from two types of cells, including pollen grains and the immune cells, neutrophils. These images are captured using a bright field microscope and a... Show moreIn this thesis, we have studied cell images from two types of cells, including pollen grains and the immune cells, neutrophils. These images are captured using a bright field microscope and a confocal microscope. We aim to analyze the insight in the understanding of the content of these images. In order to do these analyses, we need computational methods. The two main tasks are the classification of pollen images and the dynamic analysis of neutrophils through tracking in time-lapse sequences. In this study, we have demonstrated the use of deep learning methods for different kinds of cell imagery and shown the potential for future use while illustrating pitfalls, but also presenting efficient new algorithmic approaches. Show less
This dissertation is a call to place the health of adults with autistic traits and autism-caregivers higher on the agenda of clinicians, researchers, policymakers, and autistic adults and autism... Show moreThis dissertation is a call to place the health of adults with autistic traits and autism-caregivers higher on the agenda of clinicians, researchers, policymakers, and autistic adults and autism-caregivers themselves. Primarily, clinicians should be educated about the increased health risks in autistic adults and autism-caregivers, in order to be able to prevent or recognize these comorbidities timely. This is relevant because of the higher prevalence of both metabolic syndrome and gastrointestinal symptoms in adults from the general population with higher levels of autistic traits, as shown in this dissertation. The associations we found between biopsychosocial factors and respectively metabolic syndrome and gastrointestinal symptoms ask for more psychiatric and somatic integrated care for autistic adults. Future research could use the associations we found between the biopsychosocial model and autistic traits to develop preventive interventions specifically targeted for adults with autism (or higher levels of autistic traits). To make sure future preventive measures and the treatment of physical health problems are effective for this target population to improve their health, barriers in the healthcare for autistic people should be reduced. Therefore, this dissertation also offers recommendations for improvement of primary care, the gatekeeper of adequate healthcare for autistic adults. Show less
In this thesis, we identified several novel modulators of TGF-β/SMAD signaling. We studied the role of these modulators in TGF-β-induced EMT and migration in breast and lung cancer cells, and... Show moreIn this thesis, we identified several novel modulators of TGF-β/SMAD signaling. We studied the role of these modulators in TGF-β-induced EMT and migration in breast and lung cancer cells, and elucidated the mechanisms by which they fine-tune TGF-β/SMAD signaling transduction. These studies contribute to a better understanding of the regulatory networks of TGF-β signaling and may offer new therapeutic potentials to target TGF-β signaling in patients with breast or lung cancer. Show less
Both underuse as well as overuse of medical services is associated with poor outcomes in healthcare. Underuse includes the failure to use effective medical interventions, where overuse refers to... Show moreBoth underuse as well as overuse of medical services is associated with poor outcomes in healthcare. Underuse includes the failure to use effective medical interventions, where overuse refers to providing low value medical services. This could be described as services that are more likely to cause harm, waste resources or could lead to unnecessary healthcare costs. To improve quality of care and to create a sustainable healthcare system, it is essential to prevent underuse of effective medical care and to reduce the use of low value care by implementation and de-implementation initiatives. Implementation can be described as the planned process to introduce or to improve the use of medical interventions with the aim that those medical interventions are given a structural place within care practice. In de-implementation, the use of low value medical interventions is reduced or stopped on a structural basis in a planned process. The aim of this thesis was to extend the knowledge on effective strategies for de-implementation of low value care and the implementation of underused medical services in orthopedic surgery as well as in nursing practice. Show less
Identifying, targeting, and evaluating the consequences of Acquired Brain Injury (ABI) in young individuals (4-25 years old) are essential elements of medical specialist rehabilitation care for... Show moreIdentifying, targeting, and evaluating the consequences of Acquired Brain Injury (ABI) in young individuals (4-25 years old) are essential elements of medical specialist rehabilitation care for this group. Several knowledge gaps regarding the occurrence and severity of consequences and the delivery of rehabilitation existed.This thesis enhanced the understanding of ABI-related consequences and aimed to optimize rehabilitation care provided to young Dutch individuals with ABI.Section 1 of this thesis investigated the severity and course over 2 years of persisting ABI-related problems in young people with ABI and their families. In this cohort, many problems were found in the domains of Health-related Quality of Life (HRQoL), fatigue, participation, and family impact at time of referral to rehabilitation and these problems tended to persist over time.In section 2, the structure and process of rehabilitation for young patients with ABI across Dutch rehabilitation centers and the development of a national consensus-based framework for clinical practice, including preferred assessments, interventions, and psychoeducation, for young people with ABI was described.This thesis emphasizes the importance of a holistic approach to rehabilitation and lays the foundation for future initiatives aiming to further optimize rehabilitation treatment for young individuals with ABI and their families. Show less
This dissertation examines the public presentation of fixed media electroacoustic music and investigates the performative capacities which are involved in materialising such music, in order to shed... Show moreThis dissertation examines the public presentation of fixed media electroacoustic music and investigates the performative capacities which are involved in materialising such music, in order to shed light on the question of what performing means in the context of fixed media music, which is prefabricated and presented through loudspeakers in a concert venue. While electroacoustic music production has been the main focus of academic work in this area in recent decades, less attention has been given to its public presentation. Through the process of composing a series of fixed media works and presenting them in various circumstances, I formulate an understanding of the important elements involved in such process. This has resulted in the emergence of concepts and strategies which ground the composition within its performance context, so that the work comes to full existence only in the performance space. Such perspectives shift the focus from the (alleged) fixity of the medium towards the diversity and wealth of the listening experiences that it can engender. This dissertation also includes an audiovisual part; complementary and of equal importance to the written component, by simultaneously expressing its central ideas and demonstrating them in the form of a multichannel fixed media work. Show less
The fields of historical performance and contemporary composition may not seem on first impression to share much. Insofar as the former is dedicated to reproducing the oldest music and the latter... Show moreThe fields of historical performance and contemporary composition may not seem on first impression to share much. Insofar as the former is dedicated to reproducing the oldest music and the latter to inventing the newest, they can easily be understood as fundamental opposites. In context of this precise disciplinary opposition, however, this dissertation locates an opportunity for the advancement of both fields through an interdisciplinary practice and theorisation across them. Much cross-polination has certainly occurred between the two fields already, but it has largely been confined to performance spheres. Theorisations across the two remain rare. Key to the productivity of this dissertation is the identification of a complementary pair of analyses coming out of the two fields in the 1980s: critiques of the authenticity of historical performance on the one hand, with Richard Taruskin providing the classic example, and critiques of the possibility of artistic originality on the other, especially by Rosalind Krauss. Viewed independently, each of these critiques can seem to present a vexing impasse. If historical performers cannot reproduce the past, what are they doing and why does it matter? Likewise, if contemporary composers cannot make anything new, the same questions apply. What can one do but acknowledge one’s shortcomings and carry on? As these debates of the 1980s wound down, this is exactly what happened. Each discipline resigned itself to its shortcomings and carried on as if the critiques had never been made. But a reevaluation is worthwhile, as something much more interesting happens when they are viewed across each other. The ontological problems they describe begin to look eerily similar, and a wide array of practices within both disciplines come to look like fundamental syntheses of mimesis and invention, memory and imagination. What previously obscured or devalued types of music might be freshly empowered by renewed attention to this synthesis? Through comparative study of historical theory, critical theory, art theory, Englightenment and anti-Enlightenment philosophy, and the recent histories of historical performance and contemporary composition, alongside artistic experiments in a potent gray space between the two, this dissertation seeks to understand artistry and historicity in relation to broad ontological and epistemological problems of making and remaking in music. Special potency is found in archival manuscripts of long 18th–century Britain containing anonymous, fragmentary, or damaged notation. Through both compositional and interpretive experiments with these historical extracts of music notation, as well as theoretical reflection upon them, novel ways are found for aurally presenting the rich and complex intertemporality of musical practice and its surrounding cultures and histories. Show less
A crucial step of the radiotherapy workflow is the segmentation of the tumors. Currently, this is done manually, which is very time-consuming and therefore puts a lot of burden in the clinical... Show moreA crucial step of the radiotherapy workflow is the segmentation of the tumors. Currently, this is done manually, which is very time-consuming and therefore puts a lot of burden in the clinical workflow. Deep learning techniques, currently state of the art for computer vision tasks, are a potential solution to speed up the process. Even though they have been applied to segment other structures of interest for the RT workflow, they still underperform for the case of tumors. Furthermore, there is limited research in automatic segmentation of tumors for the particular case of MRI, even though this imaging modality presents better soft tissue contrast and it is therefore ideal to visualize tumors. The goal of this thesis was to develop automatic segmentation techniques for tumors on MRI images that deliver clinically acceptable segmentations. The different automatic segmentation methods were applied in two different tasks: the automatic segmentation of the oropharyngeal primary tumor in multiparametric diagnostic MRI images and the automatic segmentation of the cervical cancer gross tumor volume in the MRI images of the brachytherapy treatment images. Show less
Oratie uitgesproken door Prof. Dr. Hans Ulrich Scherer bij de aanvaarding van het ambt van hoogleraar Reumatologie aan de Universiteit Leiden op vrijdag 21 juni 2024________________________________... Show moreOratie uitgesproken door Prof. Dr. Hans Ulrich Scherer bij de aanvaarding van het ambt van hoogleraar Reumatologie aan de Universiteit Leiden op vrijdag 21 juni 2024____________________________________________________________Text also in German : Über Barrieren und Brücken: Autoimmunerkrankungen auf dem Weg zur Heilung Show less
The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol,... Show moreThe liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesis. Δ24-Dehydrocholesterol reductase (DHCR24) converts desmosterol into cholesterol, and we previously showed that the DHCR24 inhibitor SH42 increases desmosterol to activate LXR and attenuate experimental peritonitis and metabolic dysfunction-associated steatotic liver disease. Here, we aimed to evaluate the effect of SH42 on atherosclerosis development in APOE∗3-Leiden.CETP mice and low-density lipoproteins (LDL) receptor knockout mice, models for lipid- and inflammation-driven atherosclerosis, respectively. In both models, SH42 increased desmosterol without affecting plasma lipids. While reducing liver lipids in APOE∗3-Leiden.CETP mice, and regulating populations of circulating monocytes in LDL receptor knockout mice, SH42 did not attenuate atherosclerosis in either model. Show less
Actinobacteria are well known for the production of bioactive natural products, many of which have applications in the fields of human, animal and plant health. Subject of this thesis are the... Show moreActinobacteria are well known for the production of bioactive natural products, many of which have applications in the fields of human, animal and plant health. Subject of this thesis are the anthracyclines, glycosylated aromatic polyketides with potent anticancer activity. Despite remarkable efficacy against acute leukaemia and various solid tumours, their application is limited by severe side effects, such as cardiotoxicity, therapy-related tumours and infertility.Recent insights into the mode-of-action of anthracyclines have prompted renewed interest into this important class of anticancer compounds. One of the most promising compounds is N,N-dimethyldoxorubicin, which exerts significantly reduced side effects. To date, DMdoxo has not been isolated from natural sources, but biosynthesis would be an attractive option for scaling up production of this promising compound.For this reason, we aimed to engineer the Doxo biosynthetic pathway in S. peucetius for the production of biosynthetic N,N-dimethylated anthracyclines. The challenges that we encountered instigated the study of anthracycline resistance mechanisms in Streptomyces, and potential applications of detoxified anthracyclines as antibiotics. Finally, to facilitate future screening and strain engineering efforts of Streptomyces producer strains, we developed a workflow for integrated quantitative proteomics and metabolomics from small-scale Streptomyces cultures Show less
In this thesis, we aimed to assess outcomes of local disease activity in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) who received treatment-to-target, and to... Show moreIn this thesis, we aimed to assess outcomes of local disease activity in patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) who received treatment-to-target, and to describe long-term clinical and radiographic outcomes in patients with treated-to-target RA. Show less
Languages frequently make use of spatial vocabulary to describe abstract notions. For instance, the spatial preposition by (‘by the house’) can also describe relations in the temporal and causal... Show moreLanguages frequently make use of spatial vocabulary to describe abstract notions. For instance, the spatial preposition by (‘by the house’) can also describe relations in the temporal and causal domain (‘by Monday’; ‘hit by John’). This dissertation shows that when a spatial term is extended into an abstract domain, some of its spatial meaning persists. Speakers rely on a spatial representation of the abstract domain, which they use to reinterpret the spatial term to obtain an abstract meaning. On the basis of Western European languages, the proposal is formalized for causal prepositions (e.g., French ‘de’ and ‘par’ in passives) as well as demonstratives referring to information content (e.g., the use of English ‘that’ to introduce complement clauses). The proposals are further tested in corpus studies using Biblical Hebrew. Data from the Hebrew Bible additionally show that the analysis can be extended to the use of prepositions for describing social relations. This research shows that spatial meaning often persists when grammaticalization takes place. Use of spatial vocabulary in abstract domains is not metaphorical but deeply embedded in cognition, shaping the conceptualization of abstract relations. In this way, the study of language contributes to our understanding of the human mind. Show less
Tracing the evolution of the molecular gas content in galaxies is critical for a complete understanding of galaxy formation and evolution, as it provides the direct fuel for star formation. Studies... Show moreTracing the evolution of the molecular gas content in galaxies is critical for a complete understanding of galaxy formation and evolution, as it provides the direct fuel for star formation. Studies of high-redshift (z>1) molecular gas reservoirs, most commonly traced by carbon monoxide (CO), have seen substantial growth in recent years thanks to state-of the-art sub-millimeter interferometers such as the Jansky Very Large Array or the Atacama Large Millimeter Array. However, these studies have been largely based on detections of the bright mid/high-J transitions of CO (J>=3), which have been shown to give a biased and incomplete view of the total cold molecular gas content in galaxies. This thesis presents an observational study of the cold interstellar medium of massive galaxies in the distant universe. Chapter 2 presents one of the highest—resolution studies of low-J CO in a high—redshift galaxy to-date, allowing us to map its total cold gas reservoir in unprecedented detail. Chapter 3 presents a survey targeting low-J CO emission in high-redshift unobscured quasar hosts, finding direct evidence for high gas fractions but very short depletion times. Chapter 4 introduces first results from the VLA Legacy Library of Molecular Gas at High Redshift project, which significantly expands the number of high-redshift galaxies with cold gas detections. Finally, Chapter 5 shows ALMA observations targeting emission from atomic carbon in a subset of the VLA targets, and demonstrates how this alternative gas tracer complements our view of cold molecular gas reservoirs at high—redshift. Show less
This thesis discusses the prenatal detection and outcome of fetal congenital heart defects. The first part of this thesis focuses to identify determinants for a prenatal diagnosis in fetus with a... Show moreThis thesis discusses the prenatal detection and outcome of fetal congenital heart defects. The first part of this thesis focuses to identify determinants for a prenatal diagnosis in fetus with a structural congenital heart defect. The second part provides evidence on the prognosis of specific congenital heart defects diagnoses in the fetus, as prenatal counseling remains difficult in some cases, due to the fact that little evidence is available on the outcome of congenital heart defects from a fetal perspective. Show less
Scientometrics originate from the analysis of scientific publications, the most popular ways for disseminating scientific information within the scientific community. With the increasing use of... Show moreScientometrics originate from the analysis of scientific publications, the most popular ways for disseminating scientific information within the scientific community. With the increasing use of scientometric data in research management and research evaluation, various analyses can be conducted to better understand different aspects of scientific activities. On the one hand, the analysis of scientific publications from the Middle East and North Africa region opens up a range of possibilities to characterize its science systems. Large scale analyses of bibliographic metadata capture the stories of how the scientific workforce is connected, funded and mobile within diverse science systems. On the other hand, scientometric data is also used as a guide to transform the science systems. The main objective of this dissertation is to better understand recent science systems changes in the Middle East and North Africa by examining several of their facets and their recent evolution. Show less
