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
