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 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
In the search for sustainable energy solutions, the idea of artificial photosynthesis has been proposed as an approach with which to use water and sunlight to produce hydrogen. Key in the... Show moreIn the search for sustainable energy solutions, the idea of artificial photosynthesis has been proposed as an approach with which to use water and sunlight to produce hydrogen. Key in the development of hydrogen production technologies is the splitting of water using a water oxidation catalyst. In this thesis, the water splitting catalytic process was investigated using a number of different computational techniques. Computationally, the water splitting catalytic process has traditionally been considered statically as a number of snapshots, and in vacuum. The traditional approaches also often include a number of correction factors for the charge carriers in the reaction. But because catalytic processes are dynamic, a novel approach was also developed in this thesis. With this approach, one can examine the dynamic transition from one catalytic intermediate to another, in a fully solvated environment. In optimising water oxidation catalysts it is important to consider the interaction with the surrounding environment, and how this can impact the catalytic reaction. Furthermore, in the new approach all the charge carriers–protons and electrons–are included in a dynamic simulation. These techniques give us a better idea of the things needed in the optimisation of water oxidation catalysts. Show less
This thesis describes the design, characterization and application of dextran based crosslinked network. Dextran, a neutral and hydrophilic polysaccharide, was functionalized with maleimide or... Show moreThis thesis describes the design, characterization and application of dextran based crosslinked network. Dextran, a neutral and hydrophilic polysaccharide, was functionalized with maleimide or vinyl sulfone groups which are able to form covalent bonds with nucleophilic thiols via a thiol-Michael addition reaction. The functionalized dextran polymers are liable to be crosslinked to generate 3D networks. Novel drug delivery platforms, including dextran-albumin hydrogels and dextran-poly(ethylene glycol)-albumin hydrogels, were established in which human serum albumin acts simultaneously as an affinity-based drug carrier and crosslinker. The obtained drug delivery platforms showed high drug loading efficiency and demonstrated sustained release of drug molecules. This thesis also explores emerging applications of hydrogels. New method to form giant unilamellar vesicles was established by assisting the hydration process of a lipid film with a dextran-poly(ethylene glycol) hydrogel film. Using this approach, polymer and additive-free GUVs can be prepared rapidly in high yield under physiological ionic strength conditions. Show less
This dissertation presents methodological advances in the field of frailty models. Time to event data is very common in biomedical applications. Multivariate data, such as recurrent event... Show moreThis dissertation presents methodological advances in the field of frailty models. Time to event data is very common in biomedical applications. Multivariate data, such as recurrent event histories or clustered failures, typically require special modeling techniques. Frailty models extend the proportional hazards models by employing random effects. In this book, the first chapter represents an introduction to the field of frailty models. The second chapter studies the small sample properties of such models in more depth. In particular, it addresses the questions of identifiability of frailty models. The third chapter describes a score test that may be used to test whether a recurrent events process is associated with a terminal event. The fourth chapter studies the problem of event-dependent selection in the context of recurrent events data. This problem is relevant when the data are collected from registries. The fifth chapter introduces a novel R package and presents an overview of available software for estimating frailty models. Show less
The majority of platelet transfusions are given to patients with a hematological malignancy to prevent or treat bleeding complications. The adhered transfusion trigger for patients with an... Show moreThe majority of platelet transfusions are given to patients with a hematological malignancy to prevent or treat bleeding complications. The adhered transfusion trigger for patients with an increased risk of bleeding varies among hematologists. Although almost 20.000 donors are HLA typed in the Netherlands, adequate transfusion support cannot be guaranteed for all immunized patients, especially not for patients from a non-Caucasian background. From a clinical perspective, major hemorrhage is the most relevant outcome to measure effectiveness of platelet transfusions. We developed a model consisting of drop in hemoglobin, transfusion support, and CT-brain to enable the identification of major hemorrhage among leukemic patients in routinely recorded data. In the Netherlands, the standard platelet concentrate is derived from buffy coats and resuspended in plasma or platelet additive solution (PAS) and can be stored for seven days. Storage has a negative effect on safety and efficacy of platelet transfusions. Using routinely collected health care data, we demonstrated a lower risk of a positive blood culture after transfusion of platelet concentrates stored for five to seven days. Using the database of TRIP, we showed an increased risk of transfusion transmitted bacterial infections for platelet concentrates stored in PAS compared to those stored in plasma. Show less
The cannabinoid receptor type 2 (CB2R) is associated with several inflammatory diseases with an unmet medical need (e.g. Alzheimers, multiple sclerosis, reumatoid arthritis). Development of... Show moreThe cannabinoid receptor type 2 (CB2R) is associated with several inflammatory diseases with an unmet medical need (e.g. Alzheimers, multiple sclerosis, reumatoid arthritis). Development of new chemical biology strategies to study this protein is essential to aid future development of drugs for these diseases. 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
