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 development process of any software has become extremely important not just in the IT industry, but in almost every business or domain of research. The effort in making this process quick,... Show moreThe development process of any software has become extremely important not just in the IT industry, but in almost every business or domain of research. The effort in making this process quick, efficient, reliable and automated has constantly evolved into a flow that delivers software incrementally based on both the developer's best skills and the end user's feedback. Software modeling and modeling languages have the purpose of facilitating product development by designing correct and reliable applications. The concurrency model of the Abstract Behavioural Specification (ABS) Language with features for asynchronous programming and cooperative scheduling is an important example of how modeling contributes to the reliability and robustness of a product. By abstracting from the implementation details, program complexity and inner workings of libraries, software modeling, and specifically ABS, allow for an easier use of formal analysis techniques and proofs to support product design. However there is still a gap that exists between modeling languages and programming languages with the process of software development often going on two separate paths with respect to modeling and implementation. This potentially introduces errors and doubles the development effort. \par The overall objective of this research is bridging the gap between modeling and programming in order to provide a smooth integration between formal methods and two of the most well-known and used languages for software development, the Java and Scala languages. The research focuses mainly on sequential and highly parallelizable applications, but part of the research also involves some theoretical proposals for distributed systems. It is a first step towards having a programming language with support for formal models. 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
Advanced sensing techniques require graphene with high quality and well-controlled surface chemistry. The intrinsic high mobility, low electrical noises and uniform graphitic crystallinity are the... Show moreAdvanced sensing techniques require graphene with high quality and well-controlled surface chemistry. The intrinsic high mobility, low electrical noises and uniform graphitic crystallinity are the prerequisites for high-performance graphene electronics. More importantly, chemical functionalization contributes to unlock the sensing potential of the graphene basal plane. This thesis focuses on manipulating the surface chemistry of a graphene monolayer and explores the impacts on the electrical and electrochemical properties for sensing applications. Heteroatoms like hydrogen, nitrogen and oxygen were systematically introduced into the graphene lattice as defect sites to modify the surface chemistry, and consequently the electronic properties and sensing performance. In summary, a correlation between the in-plane electron transport and the electrochemical activity of hydrogenated graphene was studied by modulating the density of H-sp3 defects. Moreover, cleaning effect on the graphene surface caused by hydrogenation process and the corresponding mechanism were discussed. The electrocatalysis of oxygen reduction reaction on nitrogen doped monolayer graphene was conducted to pinpoint the catalytic active sites. The mechanics of a centimeter-scale graphene floating on water was characterized by biaxial compression. Finally, the chemically modified graphene was tested for field-effect sensing of gas molecules. Show less
This thesis is a collection of theoretical works aiming at adjusting quantum algorithms to the hardware of quantum computers. The overarching topic of these efforts is to enable digital quantum... Show moreThis thesis is a collection of theoretical works aiming at adjusting quantum algorithms to the hardware of quantum computers. The overarching topic of these efforts is to enable digital quantum simulation, the process of approximating the ground state of an arbitrary physical system with elementary operations of a quantum computer. For fermionic systems, a class including molecules and materials, the impact of quantum computing would be undoubtedly high, and algorithms exist for their simulation. However, there is a certain gap between the requirements of those algorithms and what actual quantum devices can provide: it seems that our expectations of a fully-fledged quantum computer still exceed our capabilities to build it. To make quantum simulation feasible, we seek to adapt quantum algorithms to three different types of device limitations within this thesis. Show less
Lysosomal glycosidases are acid hydrolases that fragment glycoconjugates in lysosomes. Their inherited deficiency in human is the cause of a number of lysosomal storage disorders (LSDs),... Show moreLysosomal glycosidases are acid hydrolases that fragment glycoconjugates in lysosomes. Their inherited deficiency in human is the cause of a number of lysosomal storage disorders (LSDs), showing characteristic lysosomal accumulation of undegraded glycoconjugates. In the past, activity-based probes (ABPs) based on cyclophellitol or cyclophellitol aziridine scaffold have emerged as powerful tools enabling sensitive quantification of a number of lysosomal glycosidases in extracts of cells and tissue, as well as in intact cells. This thesis describes the characterization of several novel ABP classes targeting α-glucosidase, β-glucuronidase, α-L-iduronidase, α-mannosidase, β-mannosidase, and β-galactosidase, as well as a broad scale of applications for ABPs in LSD research. Novel glucocerebrosidase inhibitors based on the cyclophellitol scaffold are also described, which are brain-permeable, selective, and potently inactivate the enzyme in adult zebrafish. Additionally, a protocol for gel-based and microscopy-based detection of glucocerebrosidase is described. Show less
This thesis revolves around the electronic spectroscopy of molecules in the laboratory and the search for the carriers of the diffuse interstellar bands (DIBs). The electronic spectra of carbon... Show moreThis thesis revolves around the electronic spectroscopy of molecules in the laboratory and the search for the carriers of the diffuse interstellar bands (DIBs). The electronic spectra of carbon chains are measured and analyzed in the lab, and the abundance of molecules in the diffuse interstellar regions of our Galaxy is quantified to provide some insight on the nature of the DIB carriers and of the environments where they might be found. In particular, cavity-enhanced absorption methods are employed to record spectra of linear hydrocarbons with which molecular constants are obtained. The wavelength positions of the electronic bands found in the lab are then compared to DIB spectra. Finally, absorption lines of interstellar OH+ are searched for in the near-UV spectra of starlight through diffuse and translucent clouds. These lines are used in deriving the abundance of OH+ and inferring the cosmic-ray ionization rates in these interstellar regions. These rates, in turn, are relevant to link to potential DIB carriers in these environments. Show less
The Low Frequency Array enables studies of low-frequency carbon radio recombination lines with unprecedented sensitivity, spectral and spatial resolution. In this thesis we benefit from the... Show moreThe Low Frequency Array enables studies of low-frequency carbon radio recombination lines with unprecedented sensitivity, spectral and spatial resolution. In this thesis we benefit from the capabilities of LOFAR to study the cold interstellar medium through carbon radio recombination lines. We find that at low-frequencies these lines trace cold gas, associated with the C+/CI/CO interface of photo-dissociation regions. This opens up the possibility to study these interfaces over large regions of the Milky Way. Show less
This thesis studied in depth the energy use and CO2 emissions of the industrial sector in China. As discussed in chapter 1, being responsible for about 84% of the Chinese CO2 emissions in 2015, the... Show moreThis thesis studied in depth the energy use and CO2 emissions of the industrial sector in China. As discussed in chapter 1, being responsible for about 84% of the Chinese CO2 emissions in 2015, the industrial sector plays a vital role in achieving the emission goals for China. The regional and sectoral heterogeneities have been considered since the industrial sector is distributed in different regions and consists of different sub-sectors. Chapter 2 studied the regional heterogeneity in industrial carbon intensity and its drivers in specific years of 1999. 2005, 2010 and 2015. Chapter 3 investigated the driving forces of industrial aggregate energy intensity (IAEI) and the contribution of each industrial sub-sector to the changes in IAEI. Chapter 4 studied to what extent performance convergence of energy-intensive industries across provinces can contribute to CO2 emission reductions and China’s emission goals. Chapter 5 provided a critical literature review on the historical drivers of industrial CO2 emissions and the projected ranges for future emissions against the backdrop of policy goals, both for the industrial sector as a whole, and for the major industrial sub-sectors (electricity generation, cement production, steel production, chemicals, petroleum and non-ferrous metals). Show less
Of all the mass in our Universe, 80% is thought to consist of a hypothetical and invisible substance called dark matter (DM). So far, all observations of DM are based on its gravitational... Show moreOf all the mass in our Universe, 80% is thought to consist of a hypothetical and invisible substance called dark matter (DM). So far, all observations of DM are based on its gravitational interaction, either through the dynamics of normal (baryonic) matter or through the deflection of light. The latter approach, called ‘gravitational lensing’, is a unique way to probe the distribution of DM without making any assumptions on its dynamical state, and on scales larger than the extent of baryons. Using weak gravitational lensing with the Kilo-Degree Survey (KiDS), we first study the relation between galaxies and their dark matter halos on the scale of individual galaxies and galaxy groups. We then attempt to measure the effect of the local and large scale (cosmic web) density distribution on galaxies and halos, and we measure the interplay between galactic and DM structures at the scale of the cosmic web. Finally, we perform the first test of Verlinde’s theory of Emergent Gravity, all with the ultimate goal of gleaning some insight into the possible nature of the elusive ‘missing mass’. Show less
Drug-target binding kinetics determine the time course of the central event in pharmacotherapy: Drug-target interaction. However, the time course of a drug effect is also influenced by many... Show moreDrug-target binding kinetics determine the time course of the central event in pharmacotherapy: Drug-target interaction. However, the time course of a drug effect is also influenced by many other physiological processes such as the metabolism and excretion of a drug and the transduction of the relevant biological signals. In this study, we investigate when target binding kinetics are determining the time course of drug effect and generate understanding into the relation between the parameter values and the rate-limiting step in the duration of a drug effect. Show less
In this thesis we will explore the use of fuzzy systems theory for applications in bioinformatics. The theory of fuzzy systems is concerned with formulating decision problems in data sets that... Show moreIn this thesis we will explore the use of fuzzy systems theory for applications in bioinformatics. The theory of fuzzy systems is concerned with formulating decision problems in data sets that are ill-defined. It supports the transfer from a subjective human classification to a numerical scale. In this manner it affords the testing of hypothesis and separation of the classes in the data. We first formulate problems in terms of a fuzzy system and then develop and test algorithms in terms of their performance with data from the domain of the life-sciences. From the results and the performance, we will learn about the usefulness of fuzzy systems for the field, as well as the applicability to the kind of problems and practicality for the computation itself. Show less
Clinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates. This high attrition is mainly due to lack of... Show moreClinical development of drugs for central nervous system (CNS) disorders has been particularly challenging and still suffers from high attrition rates. This high attrition is mainly due to lack of efficacy during clinical development. To improve the prediction of CNS drug effects, knowledge of the drug concentration at the CNS target-site is indispensable. Unfortunately, measuring drug concentrations in the human CNS has major practical and ethical constraints. Therefore, alternative approaches to predict the drug pharmacokinetics (PK) at the target-site(s) in the human CNS should be searched for.In this research, a comprehensive CNS physiologically based PK (PBPK) model for prediction of drug concentration-time profiles in multiple CNS compartments was developed for both rats and humans. The CNS PBPK model only requires knowledge of physicochemical properties of the drugs, with the influence of the net active transporters on the drug exchange across the BBB and the BCSFB that can be obtained from in silico predictions, literature information and in vitro studies (if needed). Because of this, the developed CNS PBPK model is a powerful tool to predict drug PK in the CNS in the early stage of the drug development. Show less
The thesis describes experimental steps towards reduction of friction on the macroscopic scale by scenarios of thermo- and superlubricity well-known on the nanoscale. The friction study involves... Show moreThe thesis describes experimental steps towards reduction of friction on the macroscopic scale by scenarios of thermo- and superlubricity well-known on the nanoscale. The friction study involves experiments on tailored Si nanopillar arrays, micropatterned Diamond-Like Carbon coating and high-quality graphene. Show less
The lipid membrane is a basic structural component of all living cells. Embedded in this nanometer-thin barrier, membrane proteins shape the membrane and at the same time respond to the shape... Show moreThe lipid membrane is a basic structural component of all living cells. Embedded in this nanometer-thin barrier, membrane proteins shape the membrane and at the same time respond to the shape of the membrane. This two-way interaction gives rise to a force between membrane-deforming objects that is mediated by the membrane. In this thesis, this effect is measured by employing micron-sized colloidal particles. In Chapters 2 and 3, methods for extracting local forces from video images of colloidal particles are described. Then, in Chapter 4, the development of colloidal particles that strongly attach to specific lipid membranes is described. These are then used in Chapters 5 and 6, in which membrane-mediated forces and assembly pathways between membrane-attached colloidal particles are investigated and quantified. Finally, in Chapters 7 and 8, the preparation of micron-sized oil droplets is studied and their use as lipid monolayer support is demonstrated. The results from this thesis contribute to fundamental microbiological questions about forces between membrane proteins, as well as to the understanding of the toxicity of microplastics. Show less
We study the interplay of topology and geometry with chirality for several passive and active systems, employing both analytical and numerical methods. In chapter 1, we explain how nematic liquid... Show moreWe study the interplay of topology and geometry with chirality for several passive and active systems, employing both analytical and numerical methods. In chapter 1, we explain how nematic liquid crystals confined in toroidal geometries undergo structural phase transitions depending on the slenderness of the confining toroid. In chapter 2, we consider a system of active polar swimmers that align with their neighbors. When confined in the right geometry, the system will self-assemble into a state with topologically protected chiral acoustic modes. The chirality in this system manifests itself as a temporal one, rather than a spatial chirality. Chapter 3 shows how systems of Yukawa charged active spinning dimers self-assemble into a crystal phase with spatiotemporal order, a liquid phase or a glass phase depending on the density. Depending on the phase and the confinement geometry of these systems of actively spinning dimers, the system will allow for rigid body rotations or edge currents. Finally, in chapter 4 we introduce a novel method of doing molecular dynamics on curved surfaces by developing a symplectic integrator. We present preliminary results on two-dimensional crystal melting in the presence of curvature. We find that the crystal may melt inhomogeneously. Show less
A plasma is an ionized gas with very low electrical resistivity. As such, magnetic field lines are 'frozen in' and move with the fluid. Magnetic field lines that are linked, knotted and... Show moreA plasma is an ionized gas with very low electrical resistivity. As such, magnetic field lines are 'frozen in' and move with the fluid. Magnetic field lines that are linked, knotted and tangled, cannot be undone by the fluid motions. In this thesis we investigate how this linking and knottedness influences the plasma dynamics through numerical simulations. One of the main results is the identification of a novel, self-organizing equilibrium, where every field line is linked with every other one. In such a structure all the field lines lie on toroidal magnetic surfaces, and the entire structure resembles the famous topological structure of the Hopf fibration. This magnetic equilibrium is localized, and kept in balance by a finite external pressure. Through resistive effects the structure slowly expands while the magnetic energy is dissipated. This research, and the novel structures identified have implications for nuclear fusion research and the study of astrophysical plasma phenomena. 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
Anti-thymocyte globulin (ATG) and alemtuzumab are both used in hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure. Main toxicities include... Show moreAnti-thymocyte globulin (ATG) and alemtuzumab are both used in hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure. Main toxicities include absent or slow immune reconstitution. This thesis aims to develop evidence based dosing regimens for both agents. We found that current weight-based dosing of ATG and alemtuzumab lead to highly biased exposures across the different age groups in the pediatric population. Furthermore, ATG clearance was not found to increase with increasing body weight in patients over 50 kg (i.e. adolescents and adults). Timely CD4+ T-cell immune reconstitution after HCT is essential for reducing viral reactivations and relapse following HCT, and thereby improves survival chances. High exposure to ATG after infusion of the graft diminishes chances for CD4+ T-cell reconstitution. Therefore, exposure to ATG has a major impact on the clinical outcomes including survival following HCT in children and adults. We conclude that individualizing dosing and timing of ATG potentially makes HCT a safer and more effective treatment option, and will lead to improved survival chances. Individualized dosing regimens for ATG in children have been designed based on the results in this thesis, and are currently being evaluated in prospective clinical trials for efficacy and safety. Show less
