For many students, algebraic formulas are abracadabra: they lack symbol sense. Symbol sense includes identifying the structure of algebraic formulas, giving meaning to them, and reasoning with and... Show moreFor many students, algebraic formulas are abracadabra: they lack symbol sense. Symbol sense includes identifying the structure of algebraic formulas, giving meaning to them, and reasoning with and about formulas. Besides basic skills, symbol sense is needed to solve algebraic problems and it is not known how to teach symbol sense systematically.In this research we have studied how teaching graphing formulas by hand (i.e. sketching a graph of a formula) could promote grade 11- and 12-students’ symbol sense. Our GQR-design (Graphing formulas through recognition and qualitative reasoning) is based on expert research and pays explicit attention to recognition of basic function families and features, and to qualitative reasoning, that focuses on the global shape of a graph, with global descriptions and ignoring what is not relevant. These aspects get little attention in regular education, that often focuses on algebraic manipulation.We found that students improved their insight into formulas and found a positive correlation between students’ abilities to graph formulas and their abilities to solve non-routine algebra problems with symbol sense. The students were able to use essential aspects of symbol sense, learned in the context of graphing formulas, such as taking a global view for recognition, qualitative reasoning, and questioning a formula, when solving algebra problems.In the future, when technology will take over the manipulation of algebraic formulas, symbol sense will become even more important. Graphing formulas could promote students’ symbol sense in upper secondary school, and therefore deserves a prominent place in mathematics curriculum. Show less
The term “cardiometabolic disease” describes a cluster of sub-clinical disorders that are shared by cardiovascular diseases and type 2 diabetes, including dyslipidaemia, and glucose intolerance. In... Show moreThe term “cardiometabolic disease” describes a cluster of sub-clinical disorders that are shared by cardiovascular diseases and type 2 diabetes, including dyslipidaemia, and glucose intolerance. In clinical settings, fasting measurement is still the gold standard for the diagnosis of hyperglycemia and dyslipidaemia. However, due to irregular meal intake, we spend the majority of our waking hours in a non-fasting state. The non-fasting state is a dynamic condition that is affected by many factors, including diet, lifestyle, physiological factors, pathological conditions, and genetics. Thus far, the genes and genetic loci that affect postprandial glucose and lipid metabolism have not been fully understood. By using the data from the Netherlands Epidemiology of Obesity study, we found 1) postprandial measures after a liquid mixed meal were as robust as fasting measures by repeated measures; 2) to stratify pre-diabetic individuals into high- and low-risk of developing to type 2 diabetes, the model performance by using postprandial metabolites was similar to the model performance using fasting metabolites; 3) the genetics of fasting and postprandial metabolite levels are highly overlapped. All the findings suggest that postprandial measures after a liquid meal are as reliable and clinically relevant as fasting measures for cardiometabolic disease research and diagnosis. Show less
The dissertation consists of research in three subjects in two themes—Bayes and networks: The first studies the posterior contraction rates for the Dirichlet-Laplace mixtures in a deconvolution... Show moreThe dissertation consists of research in three subjects in two themes—Bayes and networks: The first studies the posterior contraction rates for the Dirichlet-Laplace mixtures in a deconvolution setting (Chapter 1). The second subject regards the statistical inference in preferential attachment networks, in three different but related settings: for the general sublinear preferential attachment functions, we develop the empirical estimation (Chapter 3); in the case of affine preferential attachment model with random initial degrees, we employ the maximum likelihood estimation on the affine parameter with results on the estimator's asymptotic normality (Chapter 4); and for the parametric sublinear preferential attachment functions, we apply again the maximum likelihood estimation (Chapter 5). The last subject is about the modeling and inference of the movie-actor network with preferential attachment models (Chapter 6), and based on the data made publicly available by the internet movie database. Show less
Cardiac tachyarrhythmias are a vast contributor to morbidity and mortality worldwide. Still, the mechanisms underlying these arrhythmias are incompletely understood. As a result, many of the... Show moreCardiac tachyarrhythmias are a vast contributor to morbidity and mortality worldwide. Still, the mechanisms underlying these arrhythmias are incompletely understood. As a result, many of the treatment options available for these arrhythmias rely on sole alleviation of symptoms or prevention of complications secondary to the arrhythmia, or are associated with non-trivial adverse effects. An increased understanding of the mechanisms underlying cardiac tachyarrhythmias as well as the means to reverse them is a critical prerequisite if we are to shift towards more specific, more effective and less harmful arrhythmia treatment. Therefore, the research described in this thesis investigates the molecular and cellular determinants of cardiac tachyarrhythmias in ex vivo and in vitro models of cardiac hypertropfy/fibrosis, ventricular fibrillation and atrial fibrillation using state of the art electrophysiological and genetic tools. Show less
This thesis describes the evaluation of pain perception in acute and chronic pain patients and the strength of the endogenous pain modulation system in chronic pain patients. Additionally, pain... Show moreThis thesis describes the evaluation of pain perception in acute and chronic pain patients and the strength of the endogenous pain modulation system in chronic pain patients. Additionally, pain phenotypes are determined in patients with chronic pain. The ability of patients with acute pain after surgery and patients with fibromyalgia to consistently score random painful stimuli on a numerical rating scale is assessed, and the influence of opioids on this ability is evaluated. In patients with fibromyalgia, the offset analgesia paradigm is also evaluated. Offset analgesia is defined as the reduction in pain perception after a small decrease in a nociceptive heat stimulus, that is larger than would be expected from the magnitude of the stimulus decrease. This paradigm can be used to assess the endogenous ability to modulate incoming pain signals. Another manifestation of endogenous pain modulation is conditioned pain modulation (CPM). This is the reduction of pain perception of a nociceptive stimulus by the application of a second nociceptive stimulus on a remote area on the body. In this thesis the ability of a new device specifically developed to induce CPM is evaluated. In the last 2 chapters, the signs and symptoms of chronic pain patients with fibromyalgia, diabetes and sarcoidosis are used to construct 4 pain phenotypes. These phenotypes represent groups with more homogeneous patterns of signs and symptoms, which may be important to identify and evaluate targeted drug therapy. Show less
The aim of the research described in this thesis entitled ‘The use of transcriptomics data in detecting non-genotoxic carcinogens’ was to develop in vitro tests to improve testing strategies for... Show moreThe aim of the research described in this thesis entitled ‘The use of transcriptomics data in detecting non-genotoxic carcinogens’ was to develop in vitro tests to improve testing strategies for cancer hazard assessment of chemicals, to reduce the use of in vivo experiments. The scope of this thesis was twofold. First, an improved in vitro approach to assess genotoxicity was developed, with the intention to reduce the number of misleading positive test results. The emphasis was on characterization of the cell system, primary hepatocytes derived from transgenic mice. Results showed that this cell system will be of added value in genotoxicity testing. In the second part of this thesis, the focus was on the development of a ‘trancriptomics’-based approach to detect modes of action of non-genotoxic carcinogens. It has been demonstrated that the described comparison approach is promising in recognizing gene expression patterns, which can be related to modes of action. In addition, the approach is also suitable to detect toxicity of chemicals in general. In conclusion, through the development of in vitro approaches, as described within this thesis, an important contribution in the improvement of testing strategies for cancer hazard assessment of chemicals has been delivered. Show less
Schistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most... Show moreSchistosomiasis is a tropical disease affecting over 230 million people worldwide. Although effective drug treatment is available, reinfections are common, and development of immunity is slow. Most antibodies raised during schistosome infection are directed against glycans, some of which are thought to be protective. Developing schistosomula are considered most vulnerable to immune attack, and better understanding of local antibody responses raised against glycans expressed by this life stage might reveal possible glycan vaccine candidates for future vaccine research. In this tehsis we adressed the spatial and temporal expression of glycans expressed during the critical larval stages of schistosome development and we studied the (protective) antibody responses against these glycans in animals and infected human populations. Together these studies thereby contribute to an important basis for the understanding of the anti-glycan antibody responses towards Schistosoma in general and towards the vulnerable schistosomulum in particular. Show less
This thesis describes the synthesis of various teichoic acid (TA)-fragments, capsular polysaccharide (CPS)-mimics and a toolbox of glycerol phosphate probes. Most of these molecules feature one or... Show moreThis thesis describes the synthesis of various teichoic acid (TA)-fragments, capsular polysaccharide (CPS)-mimics and a toolbox of glycerol phosphate probes. Most of these molecules feature one or more phosphodiester functions, the introduction of which has been accomplished with phosphoramidite chemistry. The versatility of glycerol- and carbohydrate building blocks provided with a 2-cyanoethyl-protected phosphoramidite is illustrated by their application both in solution and in automated solid phase syntheses of TA and CPS oligomers as well as probes. The CPS-mimics are based on a polysaccharide present in the capsule of the gram negative bacterium Neisseria meningitidis, the pathogen that is the major cause of bacterial meningitis. The TA-fragments described in this thesis correspond to lipoteichoic acids (LTA) and wall teichoic acids (WTA) from Enterococcus faecalis and Enterococcus faecium, two commensal Gram-positive bacteria inhabiting the gastrointestinal tract. In both these bacterial families multi-drug-resistant strains have evolved and they are responsible for the majority of hospital-acquired infections. Enterococcal LTA generally consists of sn-glycerol-1-phosphate repeating units that can be decorated with carbohydrate- or D-alanyl appendages on the 2-OH of the glycerol moieties. The biosynthetic machinery of WTA is more complicated and can result in completely different structures. Show less
Focusing on state and peace building in Kosovo, this research brings a new, more local perspective to the established literature. State and peace building is analyzed by using the methodology of... Show moreFocusing on state and peace building in Kosovo, this research brings a new, more local perspective to the established literature. State and peace building is analyzed by using the methodology of life stories, looking at the biographies of individuals whose life experiences reveal new aspects about the processes of state and peace building. Show less
Combining ferromagnetism and superconductivity can lead to the development of a completely new generation of technology, with unique and powerful characteristics, called superconducting spintronics... Show moreCombining ferromagnetism and superconductivity can lead to the development of a completely new generation of technology, with unique and powerful characteristics, called superconducting spintronics. The task of developing this, however, is challenging because at the microscopic level the superconducting and ferromagnetic states are intrinsically incompatible. Under certain conditions, however, the conventional (singlet) superconducting state can be converted into the triplet one, with the spins of the electrons forming the Cooper pairs aligned parallel. The triplet state can coexist with ferromagnetism and is very interesting both for applications and from a fundamental point of view. In this thesis we study the electrical properties of small hybrid devices that mainly consist of superconducting and ferromagnetic layers. By measuring the electrical resistance of these devices as a function of parameters such as the temperature or the applied magnetic field, it is possible to indirectly infer important information about the state of the (super)conductivity in the different layers. We investigate different types of devices (multilayers, triplet spin valves and Josephson junctions), in order to address different aspects related to the generation of the triplet state, for a better and better control of the process. Show less
In dit proefschrift hebben wij de invloed van mestcellen in dierexperimentele modellen voor reumatoïde artritis en aderverkalking bestudeerd met een focus op de rol van mestcellen in de (sub)... Show moreIn dit proefschrift hebben wij de invloed van mestcellen in dierexperimentele modellen voor reumatoïde artritis en aderverkalking bestudeerd met een focus op de rol van mestcellen in de (sub)-klinische fases van het ziekteproces, waarin er een actieve immuunrespons ontwikkeld was. Ook hebben wij de aanwezigheid van verschillende soorten antistoffen in het serum van cardiovasculaire patiënten onderzocht. Wij hebben de niveaus van antilichamen gecorreleerd aan klinische observaties zoals body mass index (BMI), lipidenprofiel, klinische diagnose van vaatlijden, samenstelling van de atherosclerotische plaque en de uitkomst van de ziekte. Show less
The thesis explores the nature of VOC diplomacy using the seventeenth century interaction between the Company and the sultanate of Makassar on the western coast of South Sulawesi as its case. I... Show moreThe thesis explores the nature of VOC diplomacy using the seventeenth century interaction between the Company and the sultanate of Makassar on the western coast of South Sulawesi as its case. I analyse the Directors’ reflections on diplomacy in the general and approach towards Makassar in particular as well as Batavian reports on relations with Makassar, and the treaties concluded between the Company and the Sultanate. Discussions within the Company on policy towards Makassar in Batavia, as well as reflections on policy by ‘the man on the spot’, Cornelis Speelman, who in his memorie van overgave of 1669 pondered how to maintain the hegemonic position created by the Bongaya treaty complex of 1667-68.. I argue that both the Director’s concerns and the determining factor in policy decisions in Batavia were predominantly based on contextual considerations. By its very nature such an approach begged for precise and accurate information about local conditions and affairs. This led to a constructivist perception of “treaty,” whereby treaties were particularly designed for the specific and particular context to which they were applied. Show less
This thesis reviews the available coral studies in the Persian Gulf at a large scale, discusses the environmental challenges for corals in the context of climate change, and expands our... Show more This thesis reviews the available coral studies in the Persian Gulf at a large scale, discusses the environmental challenges for corals in the context of climate change, and expands our knowledge of coral biodiversity and biogeography of the region, highlights the remaining gaps in our knowledge and goes on to provide recommendations for further research. This is of special importance given recent international interest in the region as a harbinger of coral adaptation to climate change as the impacts to the global environment, human society and the economy unfold. Show less
Humanities scholars currently have access to unprecedented quantities of machine-readable texts, and, at the same time, the tools and the methods with which we can analyse and visualise these texts... Show moreHumanities scholars currently have access to unprecedented quantities of machine-readable texts, and, at the same time, the tools and the methods with which we can analyse and visualise these texts are becoming more and more sophisticated. As has been shown in numerous studies, many of the new technical possibilities that emerge from fields such as text mining and natural language processing can have useful applications within literary research. Computational methods can help literary scholars to discover interesting trends and correlations within massive text collections, and they can enable a thoroughly systematic examination of the stylistic properties of literary works. While such computer-assisted forms of reading have proven invaluable for research in the field of literary history, relatively few studies have applied these technologies to expand or to transform the ways in which we can interpret literary texts. Based on a comparative analysis of digital scholarship and traditional scholarship, this thesis critically examines the possibilities and the limitations of a computer-based literary criticism. It argues that quantitative analyses of data about literary techniques can often reveal surprising qualities of works of literature, which can, in turn, lead to new interpretative readings. Show less
In this thesis, we explored pituitary functioning and extra-pituitary implications of two pituitary disorders in humans. In part A, we focused on the long-term consequences of the diagnosis and... Show moreIn this thesis, we explored pituitary functioning and extra-pituitary implications of two pituitary disorders in humans. In part A, we focused on the long-term consequences of the diagnosis and treatment of nonfunctioning pituitary macroadenoma (NFMA) on hypothalamic regulation of circadian rhythmicity. These patients are at theoretical risk for damage of especially the hypothalamic suprachiasmatic nucleus (SCN), harboring the seat of the body’s central clock, and its projections. The studies aimed to explore symptoms of SCN dysfunctioning and their implications for patients, in order to formulate strategies to prevent or manage these long-term disabilities. In part B, we focused on the clinical characteristics and pathophysiology of the X-linked IGSF1 deficiency syndrome, in order to aid physicians in providing the necessary diagnostic procedures and long-term care for these patients, and to learn about IGSF1’s role in endocrine physiology. Show less
LCH lesions are characterized by accumulating LCH-cells, which are related to Langerhans and/or Dendritic cells, and the presence of other elements of the immune system. A significant proportion of... Show moreLCH lesions are characterized by accumulating LCH-cells, which are related to Langerhans and/or Dendritic cells, and the presence of other elements of the immune system. A significant proportion of LCH-cells display somatic mutations in proteins that drive the constitutive activation of the MAPK-pathway. Outcome is heterogeneous and unpredictable. The main goal of this thesis was to gain insight to the pathogenesis of Langerhans Cell Histiocytosis (LCH) by studying the genetic and immunologic ‘finger-prints’ of therapy-naive LCH lesions. We found a few biomarkers that could predict the outcome of LCH. These include the expression of a chemokine receptor, CXCR4, on LCH-cells and the degree of lymphoid aggregation within the LCH lesions. We found an ever functionally intact IFN-γ-signalling loop in LCH patients and the presence of activated and regulatory T-cells. However, neither an activated or immunosuppressive environment in LCH lesions was associated with a particular LCH manifestation form or outcome. We found another MAPK-pathway activating mutation in LCH-cells which was sensitive towards the FDA approved BRAF-inhibitor vemurafenib. The research described in this thesis support the concept that LCH lesions should be seen as a ‘cocktail’ of genetically aberrant LCH-cells which accumulate at sites with a mixed immunological background. Show less
The worldwide resurgence of whooping cough (pertussis), even in highly vaccinated populations, demands improved pertussis vaccines. In this thesis a systems vaccinology approach is applied to... Show moreThe worldwide resurgence of whooping cough (pertussis), even in highly vaccinated populations, demands improved pertussis vaccines. In this thesis a systems vaccinology approach is applied to deepen knowledge of the immune responses evoked by different pertussis vaccines and compare this with a Bordetella pertussis infection since the latter induces robust protection. Infection-induced responses in mice conferred sterilizing protection that is caused by systemic immunity but more importantly by mucosal IgA, T-helper (Th)1/Th17 responses, and ‘trained’ innate immune cells in the lungs. An experimental outer membrane vesicle vaccine (omvPV) was compared with the two licensed vaccines, acellular vaccine (aPV), whole-cell vaccine (wPV) as well as a B. pertussis infection. OmvPV evoked a different immunoproteomic profile with respect to antibody levels, antigen specificity, and subclass distribution. Furthermore, omvPV confers equal protection in mice as wPV, but with a lower inflammatory response. In this thesis it is also shown that the immunization route is critical. Although subcutaneous omvPV immunization is effective, pulmonary administration lead to superior protection, comparable to infection-induced immunity and included hallmarks of protection such as pulmonary Th17 cells and mucosal IgA. The molecular and cellular signatures described in this thesis may have an important contribution to enhanced pertussis immunity. Show less
Chapter 2 investigated the generation of knockin mESC line in order to study the biallelic distribution of Nanog expression at the protein level. Chapter 3 investigated the generation of human ECs... Show moreChapter 2 investigated the generation of knockin mESC line in order to study the biallelic distribution of Nanog expression at the protein level. Chapter 3 investigated the generation of human ECs from hESCs using a spin-EB differentiation approach. Chapter 4 described the rst derivation of three human iPS cell lines in the Netherlands: two from healthy individuals and one from a patient with HHT. Chapter 5 investigated the use of hiPSC-EC as a model for studying HHT1 in vitro.Chapter 6 investigated the role of Gja5 that encodes for the gap junction protein Cx40 in the development of AVMs in the HHT2 mouse model. Show less
Barry Mazur famously classified the finitely many groups that can occur as a torsion subgroup of an elliptic curve over the rationals. This thesis deals with generalizations of this to higher... Show moreBarry Mazur famously classified the finitely many groups that can occur as a torsion subgroup of an elliptic curve over the rationals. This thesis deals with generalizations of this to higher degree number fields. Merel proved that for all integers d one has that the number of isomorphsim classes of torsion groups of elliptic curves over number fields of degree d is finite. This thesis consists of 4 chapters, the first is introductory and the other tree are research articles. Chapter two deals with the computation of gonalities of modular curves, and the application of these computations to the question which cyclic subgroups can occur as the torsion subgroup of infinitely many non-isomorphic elliptic curves over number fields of degree <7. In the second chapter a general theory for finding rational points on symmetric powers of curves is developed that is similar to symmetric power Chabauty. Application of this theory to symmetric powers of modular curves allows us to determine which primes can divide the order of the torsion subgroup of an elliptic curve over a number field of degree <7. The last chapter studies elliptic curve with a point of order 17 over a number field of degree 4. Show less
Dissertation. We study the topological properties of strongly externally driven quantum non-interacting quantum systems, focussing on the example of the quantum walk and closely related systems.
