This dissertation focuses on the actors and agencies in the transnational Buddhist networks that were involved in the making of Buddhism in Indonesia from 1900 to 1959. Using the framework of... Show moreThis dissertation focuses on the actors and agencies in the transnational Buddhist networks that were involved in the making of Buddhism in Indonesia from 1900 to 1959. Using the framework of transnational networks, this dissertation endeavours to understand how Buddhism gradually secured a place in Indonesian society. By viewing the late-colonial and early post-colonial period as a continuum in which Buddhism continued to take root, it connects developments that have thus far been treated as separated by the demarcation line of Indonesian independence.Furthermore it argues that modern Buddhism in the Indonesian archipelago developed as a result of global and regional religious transformations. Particularly important was the spread of Theravada Buddhism in South and Southeast Asia. Especially, the dissertation investigates the dominant roles of lay people, Buddhist missionaries and intellectuals who were living in and travelling to colonial Indonesia. The Peranakan Chinese were the primary local actors in this process because of their pivotal role in the making of modern Buddhism from the beginning of the period under consideration until the post- independence years. The Peranakan Chinese community can be seen as a “place” where people from various backgrounds articulated their ideas about Buddhism and interacted with others. Show less
This dissertation presents a description of Mankanya, an Atlantic language spoken by about 65 000 speakers in Guinea-Bissau, Senegal and the Gambia. It includes a sketch of the phonology and a... Show moreThis dissertation presents a description of Mankanya, an Atlantic language spoken by about 65 000 speakers in Guinea-Bissau, Senegal and the Gambia. It includes a sketch of the phonology and a detailed description of the morphology and syntax of the language. Some aspects of discourse level structure are also discussed and two interlinearised sample texts are included.Mankanya has a rich morphology with both nominal and verbal inflection, and a range of derivative morphemes. Like many other Atlantic languages, nouns can be grouped into classes based on the agreement of the inflections between nouns and their modifiers. Verbs have prefixes that agree with the subject. Though some verbal affixes indicate different aspects, most distinctions of tense, aspect and mode are made by using verbal auxiliaries. Clause chaining is possible with reduced subject agreement if the subject is unchanged. Where the subject does change a different subject marker is often used.A Grammar of Mankanya will be of interest for those studying of Atlantic languages, as well a resource for wider typological comparison. Show less
The research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the... Show moreThe research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the detrimental connection between them. The thesis consists of two parts. Part 1 describes multiple experimental stroke research projects in mice in which we set out to: (I) improve the methodology of stroke research, and (II) unravel the stroke-migraine connection using diff erent research strategies, methods, and transgenic mouse models. The mouse models express human pathogenic mutations found in CADASIL, RVCL-S and FHM1 and represent the clinical spectrum of monogenic disorders linking ischemic stroke and migraine. Part 2 includes multiple clinical projects in which we set out to study a large cohort of ischemic stroke patients with and without migraine in search for means to investigate stroke characteristics and vascular pathology. Show less
The fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved... Show moreThe fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved identification of patients with an unfavourable prognosis, early in their treatment course, which may facilitate proactive approaches to improve outcomes. We discussed two conceptually distinct constructs of predictors of prognosis in order to improve the identification of patients with an unfavourable prognosis. First, the level of control of the chronic condition as a predictor could reflect to some extent the presence of a multitude of other risk factors. Second, information on early treatment response had better predictive ability for long-term outcomes and so acts as a proxy for treatment effectiveness. Treatment effectiveness depends on different aspects e.g. adequateness of initial treatment and/or drugs, the mutual trust between clinician and patient and behavioral aspects such as treatment adherence. Treatment response adds an insight that can be acted upon; guiding personalized decisions in the treatment plan. In conclusion, this thesis leads to improvement of personalized medicine and thereby could increase the efficient use of healthcare resources, with the early identification of patients at risk of an unfavourable prognosis. Show less
This thesis focuses on protoplanetary disks: flattened structures of gas and dust around young stars in which planets are expected to form and grow. Physical-chemical models that compute the... Show moreThis thesis focuses on protoplanetary disks: flattened structures of gas and dust around young stars in which planets are expected to form and grow. Physical-chemical models that compute the thermal structure and chemical composition of protoplanetary disks are compared to observations to increase our understanding of the processes that shape these disks.Chapters two and three investigate the sizes of protoplanetary disks in the context of evolution of the dust. A gas disk that is observed to be four times more extended than the dust disk is found to be a clear indication that the dust has drifted inward. Detailed modeling reveals that five out of a sample of 10 disks in the Lupus star-forming region show evidence for dust evolution. Chapter four shows that observed gas outer radii are consistent with disks evolving viscously, assuming disks start out small and evolve slowly. Chapter five reveals that the chemical conversion of CO into more complex species cannot by itself explain the low observed CO isotopolog line fluxes. Finally, Chapter six uses non-detections of the HD emission line to put an upper limit on the total mass of disks and rules out that they are currently gravitationally unstable. Show less
Bacterial chemosensory arrays are protein assemblies that are the key structural and functional component for motile bacteria to sense their internal or environmental chemical signals. Cryo... Show moreBacterial chemosensory arrays are protein assemblies that are the key structural and functional component for motile bacteria to sense their internal or environmental chemical signals. Cryo electron tomography is a technique of transmission electron microscopy that allows the visualization of protein complexes in their near-native cellular context. This thesis includes a general introduction of the basics of bacterial chemosensory and the structural diversity of chemosensory arrays, as well as a description of the workflow of using cryo electron tomography to image bacterial chemosensory arrays in situ. This thesis presents the discovery of a different stoichiometry of chemotaxis proteins and a direct visualization of the kinase distribution within the chemosensory arrays in Vibrio cholerae. This highlight that a structural diversity of chemoreceptor arrays does exist, and that is the norm and not an exception. This thesis also includes studies illustrating the conformational dynamics of the Escherichia coli chemoreceptors correlated to its signaling states, which gives crucial insights on how the receptors function in a trimers-of-dimers packing arrangement. In short, studies present here broaden the appreciation of the structural diversity of chemosensory arrays and deepen our understanding of how arrays dynamically functions during chemosensory signal transduction. Show less
The field of exoplanet research is rapidly advancing through the development of new technology, observing techniques, and post-processing methods. In the last 30 years, thousands of exoplanet... Show moreThe field of exoplanet research is rapidly advancing through the development of new technology, observing techniques, and post-processing methods. In the last 30 years, thousands of exoplanet candidates have been found through various methods. These discoveries have revealed a zoo of exoplanetary systems looking very different from our own Solar System. This dissertation contains two very distinctive parts, both related to the measurement of exoplanetary systems.The first part of this dissertation, Chapter 2, investigates 8 light curves found in the Kepler data archive. These light curves show periodic brightening events that look different from a normal exoplanet signal. The second part of this dissertation, focuses on high-contrast imaging (HCI). Current HCI instruments are more sensitive to exoplanets orbiting far out from their host star. To probe the regions close-in to the star, the extreme adaptive optics (XAO) subsystem needs to improve in performance. Specifically, the XAO does not correct well enough for the continuous evolution of turbulence during the time it takes the XAO to measure the phase and subsequently correct for the aberrations (resulting in the servo-lag error). This dissertation focuses on data-driven predictive control to address the servo-lag error. Show less
Adenosine is an endogenous ligand which exerts its action by activating adenosine receptors (ARs), while its circulating levels are controlled via a variety of mechanism and proteins, amongst... Show moreAdenosine is an endogenous ligand which exerts its action by activating adenosine receptors (ARs), while its circulating levels are controlled via a variety of mechanism and proteins, amongst others the equilibrative nucleoside transporters (ENTs). Distortion of the adenosinergic tone is implicated in a multitude of pathophysiological conditions, thus numerous drug discovery efforts have been made to develop drugs targeting ARs and ENTs. Yet, there is only a limited number of drugs targeting these proteins on the market. Therefore, there is a pivotal need to develop novel concepts that allow us to increase our understanding of the mechanism of action at a molecular level, as well as physiologically relevant assays to evaluate drug candidates in early stages of drug discovery. Hence, this thesis focuses on exploring the concept of binding kinetics for two adenosinergic targets, i.e. the A2BAR and ENT1 (SCL29A1), as well as to develop novel kinetic binding and label-free functional assays. Show less
Aspergillus niger is an important industrial producer of organic acids and enzymes producing large amounts of spent fungal biomass. In the European Research Area Industrial Biotechnology (ERA-IB)... Show moreAspergillus niger is an important industrial producer of organic acids and enzymes producing large amounts of spent fungal biomass. In the European Research Area Industrial Biotechnology (ERA-IB) funded project, we effectively aimed to improve the composition of post-fermentation fungal biomass for extraction of the value-added product chitosan as a derivative of cell wall chitin (FunChi). As chitin/chitosan is not encountered in plant or human tissue, it often acts as an elicitor to plant and animal immune responses in order to fight off possible impending fungal infections. The application of both chitin and chitosan oligomers have been shown to prime plants against infection. This thesis discusses the identification of genes that are important for chitin deposition in the cell wall of A. niger. In addition, the work described here also investigates the genes that facilitate chitin cross-linking to the cell wall. The relevance of all findings are discussed in relation to both the improvement of chitin extraction from post-fermentation biomass and to the integrity of the fungal cell wall. Show less
The genetic information of all living organisms is contained in their DNA. Cells modify the degree of DNA compaction by epigenetics, which largely determines what genes are read out and which genes... Show moreThe genetic information of all living organisms is contained in their DNA. Cells modify the degree of DNA compaction by epigenetics, which largely determines what genes are read out and which genes are transcriptionally silent. Despite decades of research into this mechanism, there is no consensus on how cells realize the various degrees of DNA compaction in vivo. Eukaryotes, such as humans, compact their DNA into higher-order structures called compact chromatin fibers. We characterize these fibers through a combination of single-molecule force spectroscopy techniques like magnetic tweezers, and rigid base pair Monte Carlo simulations. We show that, for instance, the length and sequence of the linker DNA, the DNA between adjacent nucleosomes, control the mechanical properties of chromatin fibers. Our measurements suggest the formation of more than one higher-order fiber structure. A deeper understanding of the chromatin fiber and its compaction mechanism is important because the dysfunction of such regulation results in various medical conditions such as the epigenetic disorder type 1 diabetes, fragile X syndrome, or various cancers. Show less
Red blood cell transfusions are still the cornerstone of supportive care in many hemato-oncological patients. A chronic and underestimated side-effect of red blood cell transfusions is iron... Show moreRed blood cell transfusions are still the cornerstone of supportive care in many hemato-oncological patients. A chronic and underestimated side-effect of red blood cell transfusions is iron overload, which is associated with increased morbidity and mortality. This thesis focuses on red blood cell transfusion strategies and the management of iron overload due to frequently administered red blood cell transfusions. A nationwide survey showed a large variation in red blood cell transfusion practice throughout the Netherlands. This is probably due to the lack of high grade evidence-based guidelines. In a meta-analysis was demonstrated that a restrictive red blood cell transfusion strategy was safe and could lead to fewer side-effects and reduced costs in hemato-oncological patients. In order to diagnose iron overload, tissue biopsy is still the golden standard. Due to its risk of complications, tissue biopsies are not likely to be performed in this patient group. In this thesis, we assessed the value of bone marrow iron scores in frequently transfused acute myeloid leukemia patients. We concluded that bone marrow iron scores on routinely performed bone marrow aspirate specimens could guide iron-lowering therapy and/or transfusion strategies in an early stage. Finally, in a large European registry we showed that toxic iron species as non-transferrin bound iron and labile plasma iron are associated with inferior overall survival in lower-risk myelodysplastic syndrome patients. Likewise, treatment with iron chelation therapy led to an improvement in overall and progression-free survival in lower-risk myelodysplastic syndrome patients. Show less
This thesis describes research done in the field of hand osteoarthritis, and had the following three aims:1) To evaluate the current state of treatment options in hand osteoarthritis;2) To... Show moreThis thesis describes research done in the field of hand osteoarthritis, and had the following three aims:1) To evaluate the current state of treatment options in hand osteoarthritis;2) To investigate the role of inflammation as a treatment target in hand osteoarthritis; and3) To facilitate development of new treatment options by improving outcome measurement in hand osteoarthritis. Show less
Studying diseases or effects of new drugs on the human body is challenging, not least because of the lack of proper testing models that recapitulate human physiology. Most research is done using... Show moreStudying diseases or effects of new drugs on the human body is challenging, not least because of the lack of proper testing models that recapitulate human physiology. Most research is done using animal models but these often show differences with humans in disease manifestation and responses to drugs. For example, drugs that had no effect on the hearts of animals later turned out to cause lethal arrhythmias in some humans. This – and the ethical issues around animal testing – is why, as in this thesis, there is increasing interest on making human heart models based on pluripotent stem cells (hPSCs). Nowadays small numbers of cells can be collected from a patient (e.g. from blood, urine or skin), reprogrammed to hiPSCs, and then differentiated to heart muscle cells (cardiomyocytes). Since the genetics of the patient are maintained during reprogramming, the phenotype of a genetic disease affecting cardiac function can also be captured. The focus of this thesis has been developing methods to measure these cardiac phenotypes robustly and with sufficient complexity to reflects drug responses and disease of the heart. Our results supported the notion that hPSC models will become human avatars and accurate measurement models able to recapitulate essential human-specific processes. Show less
The overarching clinical aim of this thesis was to improve pharmacological pain management by characterizing the pharmacodynamics of analgesics. To achieve this aim, available advanced... Show moreThe overarching clinical aim of this thesis was to improve pharmacological pain management by characterizing the pharmacodynamics of analgesics. To achieve this aim, available advanced pharmacometric modelling approaches are used to maximize the information that can be obtained from the available clinical data. To address methodological gaps for pharmacodynamic analysis, we introduced two new model development tools, as well as two new pharmacodynamics modelling approaches for the characterization of iatrogenic withdrawal syndrome in children.In addition to expanding our pharmacodynamic knowledge, this work can increase the clinical applicability of existing pharmacokinetic models: knowing what drug concentrations will give desirable clinical outcomes, we can use pharmacokinetic models to evaluate if an analgesic dose regimen is likely to produce this concentration. The models developed in this thesis can serve as a starting point for further research into the pharmacodynamics of analgesics by extending these models to include additional patient populations or other analgesics. Moreover, the novel pharmacometric techniques that were introduced in this thesis can support future analyses in a variety of settings: repeated time-to-event data, iatrogenic withdrawal syndrome data, and composite clinical scale data. Show less
This thesis describes the role of pollution, specifically neonicotinoid insecticides, as an actor of the ongoing biodiversity decline. Using a new research facility, the Living Lab, the effects of... Show moreThis thesis describes the role of pollution, specifically neonicotinoid insecticides, as an actor of the ongoing biodiversity decline. Using a new research facility, the Living Lab, the effects of field relevant concentrations of neonicotinoids and fertilizers to aquatic invertebrates was assessed in 36 experimental ditches. This showed that neonicotinoids had profound impacts on both single species as well as macroinvertebrate biodiversity and had severe consequences for the ecosystem processes the invertebrates fulfilled. Many of the results found in this thesis have not been discovered before because of the simplicity of standardized ecotoxicological testing, which not fully incorporates the myriad of ecological factors governing toxicity. It was found that the addition of fertilizers directly stimulated primary production which in turn reduced toxic effects indirectly. In addition, the neonicotinoid thiacloprid induced indirect effects on aquatic biodiversity which persisted much longer than the presence of this insecticide in the ditch ecosystem. The results in this thesis therefore show how the inclusion of environmentally realistic testing is essential to predict the actual risks of agrochemicals in the actual environment. Show less
The aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as... Show moreThe aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as adipokines, inflammation, HDL-cholesterol and postprandial triglyceride response, and cholesteryl ester transfer protein (CETP). We showed that hs-CRP and GlycA as measures of inflammation, adiponectin, and leptin are not associated with clinical and subclinical cardiovascular disease in the general population. However, all may be relevant markers of disease risk. Also, postprandial triglyceride excursions, genetically-determined CETP and HDL-cholesterol, while not related with subclinical atherosclerosis in the general population, may be interesting targets to pursue in women and men separately, and in subgroups of individuals at high-cardiovascular risk. Show less
Annually around 5 million people die as a consequence of injuries and many more suffer from livelong disabilities. Although implementation of trauma care systems and structured trauma training has... Show moreAnnually around 5 million people die as a consequence of injuries and many more suffer from livelong disabilities. Although implementation of trauma care systems and structured trauma training has led to decreased mortality and disability in several countries, controversies remain to exist. The awareness of the current trauma burden and its expected increase has led to new initiatives for scientific research in an attempt to eventually improve trauma care worldwide. Despite the improvements there is room for further optimization of care. The primary aim of this thesis is to analyze the presence and structure of trauma systems, evaluate specific care-delivery processes, and focus on patient-centered and clinically important parameters and outcomes. The second aim is to evaluate one of these parameters, the role of the nutritional status in the outcome of polytrauma patients. Show less
Offering genetic testing to identify pathogenic variants in individuals with clinicallypresumed hereditary breast and/or ovarian cancer is currently routine clinicalpractice. In case a pathogenic... Show moreOffering genetic testing to identify pathogenic variants in individuals with clinicallypresumed hereditary breast and/or ovarian cancer is currently routine clinicalpractice. In case a pathogenic variant is identified, carriers might benefit from riskreducing measures as intensified screening programmes or prophylactic surgery.Pathogenic variants associated with high cancer risk typically disrupt protein functionvia the introduction of a premature stop codon due to a nonsense mutation or via frame shifting insertions/deletions. However, for many of the variants identified by genetic testing it is uncertain if the function of the variant protein is impaired to such an extent that cancer risk is enhanced. Those variants are therefore classified as variants of uncertain significance (VUS) and they represent a major challengefor genetic counselling and clinical management of the families in which they are identified. Most VUS are rare and insufficient information can be mined to compute a reliable cancer risk estimation, leaving large numbers of families in uncertainty. Driven by a clear clinical need to classify variants in relevant cancer risk categories (i.e. high, moderate and population level), we optimized and validated a biological assay. This assay allows functional characterization of all types of variants (intronic and exonic), including those that may affect mRNA splicing. Show less
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most prevalent hereditary small vessel disease. CADASIL patients typically develop... Show moreCADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most prevalent hereditary small vessel disease. CADASIL patients typically develop recurrent strokes from mid-adult age onwards, leading to cognitive impairment and ultimately vascular dementia. As there is currently no therapy that can delay or prevent CADASIL, the CADASIL research group of the Leiden University Medical Center is developing a therapeutic approach for CADASIL, called “NOTCH3 cysteine correction”.The aim of this PhD-project was to advance CADASIL therapy development.The work in this thesis provides the first in human evidence that the therapeutic approach of NOTCH3 cysteine correction leads to reduced protein aggregation, by describing a family with naturally occurring NOTCH3 cysteine correction. Furthermore, this thesis includes the results of the longest follow-up study to date of individuals with CADASIL, as well as and the identification of Neurofilament Light-chain (NfL) as blood biomarker in CADASIL. In a pre-clinical CADASIL disease model, potential pre-clinical biomarkers were explored and this resulted in the development of a GOM deposit classification system. Show less
Human cooperation is an astonishing phenomenon, as only humans exhibit such immense scale, complexity, and frequency in working together with other people. In this dissertation, I investigate how... Show moreHuman cooperation is an astonishing phenomenon, as only humans exhibit such immense scale, complexity, and frequency in working together with other people. In this dissertation, I investigate how nonverbal communication between two individuals affects cooperative success as well as methodological challenges when examining this topic in laboratory settings. To answer these questions, the dissertation comprises four chapters presenting two theoretical and two methodological studies. In the first two chapters, I demonstrate the beneficial effect of face-to-face interactions on cooperation. I subsequently show that physiological synchrony emerges during social interactions and is positively associated with cooperative success. This finding suggests that physiological synchrony might be an underlying mechanism for the beneficial effect of face contact on cooperation. In the methodological studies, I place the tasks typically used to measure cooperation into the broader context of prosocial behavior. Furthermore, I address the statistical challenges inherent to measuring synchrony between interaction partners. The cardinal point of this dissertation is that interpersonal processes that we are not aware of play a fundamental role in how we behave towards other people. Addressing methodological challenges that come along with studying dyadic interactions will greatly advance our understanding of social phenomena that make us human so unique. Show less
