Molecular imaging plays a vital role in current medical diagnostics. There is a constant need for new and improved molecular imaging agents in terms of resolution, specificity, stability, safety... Show moreMolecular imaging plays a vital role in current medical diagnostics. There is a constant need for new and improved molecular imaging agents in terms of resolution, specificity, stability, safety and cost. The research described in this thesis deals with the development of activatable luminescence lifetime imaging agents as well as with the use of supramolecular chemistry to introduce cell surface modifications to living cells. Show less
This book defends political obligation, stating that people are morally obligated to obey the law of their state, if the law is at least reasonably just. The defense is based on the tradition of... Show moreThis book defends political obligation, stating that people are morally obligated to obey the law of their state, if the law is at least reasonably just. The defense is based on the tradition of the Kantian political philosophy and legal philosophy, and it is a defense mainly against political anarchists. They believe that the only possible justification for political obligation should be voluntarist, proving people’s deliberate undertakings to incur the obligation. Since no attempt in the voluntarist approach is justifiable, political obligation does not exist from the a posterior point of view. As a consequence, political legitimacy, which is claimed to be the other side of the same concept of political obligation, fails to obtain its justification, and no state is legitimate. The exploration in this book contends that a voluntarist basis is neither necessary nor sufficient for people to be obligated to obey the law. And this contention earns the space for justifying political obligation on an involuntarist ground, meaning that people can be imposed on a moral obligation to obey the law without any voluntary actions incurring this obligation. This involuntarist ground is what I name the “moral necessity thesis”. Show less
During my PhD research, I studied the photon statistics of light emitted by a microcavity that contains a single quantum dot (QD) on resonance. The work encompasses an experimental part,... Show moreDuring my PhD research, I studied the photon statistics of light emitted by a microcavity that contains a single quantum dot (QD) on resonance. The work encompasses an experimental part, simulations and a theoretical element. In the experimental part, we developed a fiber-coupled single-photon source, which can easily be integrated with existing quantum technologies. The developed source is state of the art in terms of single photon rate and purity. Further, I performed extensive simulations on the quantum master model. This is a theoretical model describing the interaction between light and the quantum dot in a microcavity. These simulations lead to a better theoretical understanding of the physics behind single photon light and other non- classical states of light. Through a theoretical study, we reported of an alternative way to produce single photons called unconventional photon blockade. In my PhD research, I learned to develop new quantum technologies such as single photon sources, thoroughly analyze them using numerical simulations for improvement, as well as being able to perform a theoretical analysis for physical understanding. Show less
The power of personalized nutrition lies in being able to conduct clinical research on healthy people while capturing metabolic markers sensitive to the impact of environmental and metabolic... Show moreThe power of personalized nutrition lies in being able to conduct clinical research on healthy people while capturing metabolic markers sensitive to the impact of environmental and metabolic stressors (e.g. diet, changing sex hormones and the menstrual cycle). Using clinical biomarkers, metabolomics, and diet interventions with intake analyses, we demonstrated the metabolic impact of vegan and animal diet interventions using fasting plasma analysis after 48 hours and using postprandial plasma analysis after meals and snacks. Sexually dimorphic responses were differentiated using proteomics and pathway analyses in two larger, sex-balanced cohorts. Finally, clinical biomarker and metabolomics analyses identified metabolic subtypes across menstrual cycle phases. Although challenges with integrating –omics technology and nutrition remain, the fundamental information generated from these research studies may provide a foundation for future novel personalized nutrition strategies. Show less
In this dissertation we developed statistical tools for analyzing multivariate binary data. In many disciplines multivariate binary data, in which there are multiple binary dependent variables and... Show moreIn this dissertation we developed statistical tools for analyzing multivariate binary data. In many disciplines multivariate binary data, in which there are multiple binary dependent variables and one or more independent variables, are often collected. In this dissertation we further developed the IPC model for analyzing multivariate binary data. The IPC model is a probabilistic multidimensional unfolding model and closely related to the Ideal Point Discriminant Analysis (IPDA). In Chapter 4, we proposed a Multivariate Logistic Distance (MLD) model for analyzing multivariate binary data. The MLD model unifies two domains of statistical methods, i.e., Multidimensional Scaling (MDS) and Generalized Linear Model (GLM). The MLD model can be used to simultaneously assess the dimensional structure of the data and to study the effect of the predictor variables on the response variables. For the NESDA data, for example, a researcher can use the MLD model to determine the dimensional structure of the mental disorders, and to investigate effect of the personality traits and the background variables on prevalence of the mental disorders. Show less
BAV morphology and especially the presence and extent of a raphe is of clinical importance, as a complete raphe predisposes to more valvular dysfunction and aortopathy. Regarding variations in... Show moreBAV morphology and especially the presence and extent of a raphe is of clinical importance, as a complete raphe predisposes to more valvular dysfunction and aortopathy. Regarding variations in coronary anatomy, it turns out that patients with left-right BAVs without raphe and patients with BAV and CoA more often have a left dominant coronary artery system. Patients with left-right BAVs without raphe also seem more at risk of developing significant coronary artery disease. In addition, separate ostia of the LAD and LCX are more common in these patients. Patients with Turner syndrome and BAV do not show significant differences in coronary dominance as compared to patients with Turner syndrome with TAV and to patients with isolated BAV. However, patients with TS and BAV show more separate ostia of the LAD and LCX as compared to patients with isolated BAV. In BAV with associated complex congenital heart disease, a high take-off of the coronary arteries, occurred more frequently than reported in structurally normal hearts and in hearts with isolated BAV. Finally, there should be awareness of possible bilateral semilunar valvular disease, which is associated with strictly bicuspid BAVs and in many cases related to chromosomal abnormalities. Show less
The aim of this thesis is to expedite and ensure the systematic accuracy of clearance scaling from adults to paediatric patients, with a special focus on drugs undergoing hepatic metabolism. A... Show moreThe aim of this thesis is to expedite and ensure the systematic accuracy of clearance scaling from adults to paediatric patients, with a special focus on drugs undergoing hepatic metabolism. A physiologically-based pharmacokinetic simulation workflow was developed to unravel the conditions for accurate scaling of drug clearance from adults to children as young as term neonates of one day for various methods. This disproved the belief that a universal allometric exponent can scale size-related changes in clearance across the paediatric age range, and showed that isoenzyme maturation and drug properties, especially extraction ratio and drug binding to alpha-1-acid glycoprotein, should be accounted for when scaling clearance to young children. Based on these results, a clearance scaling decision tree is proposed, which allows pharmacologists for the first-time to select scaling method(s) that require a minimum but still sufficient amount of information to accurately scale clearance of drugs with known properties to a desired paediatric age-range. Moreover, an analysis framework is provided to assess the feasibility and clinical trial requirements for the estimation of PBPK parameters using population pharmacokinetic modelling, which has the potential to expedite development of PBPK models for understudied paediatric subpopulations. Show less
The principal aims of this book are to provide a comprehensive reconstruction of the urban systems of the Iberian Peninsula during the High Empire and to explain why these systems looked the... Show moreThe principal aims of this book are to provide a comprehensive reconstruction of the urban systems of the Iberian Peninsula during the High Empire and to explain why these systems looked the way they did. While some chapters focus on settlements that were cities or towns from a juridical point of view, the implications of using a purely functional definition of towns are also explored. Key themes include continuities and discontinuities between pre-Roman and Roman settlement patterns, the geographical distribution of cities belonging to various size brackets, economic relationships between self-governing cities and their territories, and the role of cities as nodes in road systems and maritime networks. In addition, it is argued that a considerable number of self-governing communities in Roman Spain and Portugal were polycentric rather based on a single urban centre. Show less
Kidney transplantation is the preferred treatment of patients with end stage renal disease, as it provides longer patient survival and better quality of life compared to dialysis. Prediction of... Show moreKidney transplantation is the preferred treatment of patients with end stage renal disease, as it provides longer patient survival and better quality of life compared to dialysis. Prediction of DGF, response to steroid resistant rejection and long-term graft outcome remain difficult when using merely clinical parameters. Numerous studies have reported on the predictive value of molecular markers for AR and worse graft outcome. However, the heterogeneity of AR and the variation among transplant centers leads to controversial results and preclude a more general clinical application. In the first part of this thesis, we aimed to investigate the molecular markers of steroid resistance and long-term graft survival on the basis of acute rejection biopsies. In the second part, we focused on genetic variants associated with acute rejection in kidney transplantation. In the final part we described the possible immune regulatory effect of S100 calcium binding proteins. Show less
Cathodic corrosion is a relatively unknown phenomenon that can severely etch metallic electrodes at cathodic (negative) potentials. In spite of these remarkable changes that are caused by cathodic... Show moreCathodic corrosion is a relatively unknown phenomenon that can severely etch metallic electrodes at cathodic (negative) potentials. In spite of these remarkable changes that are caused by cathodic corrosion, the phenomenon is stil not fully understood. Cathodic corrosion is therefore the focus of this PhD thesis. The first three experimental chapters of the thesis focus on characterizing platinum, rhodium and gold electrodes before and after cathodic corrosion in a variety of working solutions. In doing so, these chapters establish surprisingly mild corrosion onset potentials and reveal an etching anistropy that depends on the cation in the working solution. Additional density functional theory calculations suggest a similarly significant role for adsorbed hydrogen. These result suggest the existence of ternary metal hydrides during cathodic corrosion. The role of hydrides is further studied in the fourth experimental chapter through X-ray absorption spectroscopy. These four fundamental chapters are followed by two more applied chapters. The first of these tailors the activity of a platinum single crystal towards oxygen reduction, by using cathodic corrosion. The second applied chapter uses cathodic corrosion to create and thoroughly characterize alloyed nanoparticles. Combined, these fundamental and applied chapters provide valuable new information towards understanding and applying cathodic corrosion. Show less
This thesis explores the influence of prescriptivism on language use in American English. It does so by studying the relationship between language advice literature, patterns of language use,... Show moreThis thesis explores the influence of prescriptivism on language use in American English. It does so by studying the relationship between language advice literature, patterns of language use, and speakers’ attitudes. The thesis shows that the genre of usage guides, routinely associated with prescriptivism, is undergoing change to reflect processes of change in progress in American English. Furthermore, prescriptivism and language use are shown to mutually influence each other. Show less
This PhD thesis concerns the topic of arithmetic geometry. We address three different questions and each of the questions in some way is about counting how big some set is or can be. We produce... Show moreThis PhD thesis concerns the topic of arithmetic geometry. We address three different questions and each of the questions in some way is about counting how big some set is or can be. We produce heuristics for counting rational points on surfaces given by one diagonal quartic equation. Our results match with experimental data obtained by van Luijk a few years ago. A different result concerns a certain type of conic bundles over low degree hypersurfaces. We count rational points on the base over which the fibre has rational points. We are able to produce asymptotic results where most results in the literature only produce upper bounds. Moreover we investigate the leading constant in this asymptotic formula, matching it up with expected conjectural behaviour that can be found in the literature. Lastly, we study Brauer groups of Kummer surfaces. We give a way to obtain upper bounds for their sizes. Our way is effective (one only needs to use a formula), but the bounds obtained seem not to be sharp. Our method is based on effective versions of Faltings' theorem on finiteness of abelian varieties. Show less
Is de geboden cardiologische zorg `sufficiently safe' ? Dit proefschrift richtte zich op de vraag hoe je kwaliteit van zorg kan meten om te kijken of de geboden zorg voor de behandeling van acuut... Show moreIs de geboden cardiologische zorg `sufficiently safe' ? Dit proefschrift richtte zich op de vraag hoe je kwaliteit van zorg kan meten om te kijken of de geboden zorg voor de behandeling van acuut coronair syndroom sufficiently safe is en deed dit middels twee methoden: lokaal dossieronderzoek ten aanzien van patiëntveiligheid (Deel 1) en nationaal declaratie data-registratie voor kwaliteit-van-zorg onderzoek (Deel 2). Waar declaratiedata in detail moet inleveren, levert dossieronderzoek in op de efficiëntie. De twee verschillende methodes vullen elkaar aan en dienen een verschillend doel: veiligheid en kwaliteit van zorg. De geboden zorg lijkt veilig, maar toch ervaart 13% zorggerelateerde schade bij de behandeling van een acuut coronair syndroom. Welk onderzoek is hiervoor nodig? Dossieronderzoek is zeer arbeidsintensief, zelfs een onderzoek binnen het heldere MISSION!-protocol leidt nog tot heterogene antwoorden op causale relaties van zorggerelateerde schade. Real-time monitoring van afwijkende processen met reeds geregistreerde data biedt meer inzicht in zorggerelateerde schade. De geboden zorg lijkt volgens de richtlijnen te gaan, maar toch krijgt slechts 49% zijn preventieve medicatie. Ook hier is ruimte voor verbetering. Toekomstige analyses met declaratiedata, gecombineerd met klinische data en andere databronnen, kan meer inzicht geven om zo de kwaliteit van zorg continu te blijven verbeteren. Show less
Quality and safety improvement is a relatively novel discipline in healthcare practice and research that solidified in the early 21st century. Since then, various systems have been installed to... Show moreQuality and safety improvement is a relatively novel discipline in healthcare practice and research that solidified in the early 21st century. Since then, various systems have been installed to collect information on various types of adverse outcomes, such as adverse events, incidents and patient complaints. Data from these systems can be used to evaluate care delivered to individual cases as well as to study aggregated data for patterns, trends and other insights. More research is warranted to assess whether these systems actually meet the objective of continuous, systemwide learning and improvement. It was expected that existing practices could benefit from individual optimization as well as better integration, because most of this intelligence is currently stored and used in isolation. The research in this PhD thesis focused on how we can learn most effectively from various types of adverse outcomes in healthcare, in order to continuously improve the care delivered to patients. Specific research questions included how we can learn from: i) case discussions at morbidity and mortality conferences ; ii) integrating available information sources (e.g., incidents, patient experiences); iii) the context of everyday practice that produces both adverse and desired outcomes. Show less
HPV has evolved mechanisms to resist immune attack. I showed that HPV impaired necroptosis induced by IFNγ and TNFα by down-regulation of RIPK3 expression. Methyltransferase inhibitor DZNeP... Show moreHPV has evolved mechanisms to resist immune attack. I showed that HPV impaired necroptosis induced by IFNγ and TNFα by down-regulation of RIPK3 expression. Methyltransferase inhibitor DZNeP restored the expression of RIPK3 in HPV+ keratinocytes, and increased the necroptosis in HPV+ keratinocytes. Simultaneously, hrHPV effectively inhibited IFNγ/TNFα-mediated arrest of cell growth by down-regulating IFITM1. Then I studied HPV associated oropharyngeal squamous cell cancer (OPSCC). The OPSCC infiltrating HPV specific CD4+ Tcells produce cytokines such as IFNγ and TNFα. I found that HPV16-positive tumor cells lacked expression of RIPK3, which were not sensitive to the necroptosis induced by IFNγ /TNFα. I also showed that a combination of IFNγ and TNFα with cisplatin synergized in killing tumor cells. Last but not least I showed that combination of the clinically applied EGFR inhibitor Cetuximab and IFNγ/TNFα increased gene expression of multiple cytokines, including CXCL9, CXCL10 and CCL5, which may attract more lymphocytes to the tumor site. By using the inhibitors of the targets downstream of EGFR, I found that JNK and MEK1 played major role in mediating the suppression of CCL5, CXCL9 and CXCL10 expression. Show less
Chapter 2 describes a post-synthetic methodology to introduce a fluorescent label in highly lipophilic, Pam3Cys based conjugates. The fluorescent labels were appended to the peptide part of the... Show moreChapter 2 describes a post-synthetic methodology to introduce a fluorescent label in highly lipophilic, Pam3Cys based conjugates. The fluorescent labels were appended to the peptide part of the conjugate with the aid of a strain promoted [3+2] azide-alkyne cycloaddition. In Chapter 3 a synthesis is discussed of a structurally simple human specific TLR-2 ligand with diminished lipophilicity, as compared to Pam3Cys. Conjugation of such moiety to peptide is studied and optimized to produce human specific analogues of the conjugates described in Chapter 2 with higher solubility and an equal propensity to activate TLR-2. The synthesis of a newly designed TLR-7 agonist is demonstrated in Chapter 4 as well as the synthesis of a selection of self-adjuvanting immunogenic peptides that contain a model MHC-I epitope (SIINFEKL). A biocompatible methodology to reduce an azide in a side chains of peptides is described in Chapter 5 with a particular focus on side reaction occurring during the reduction. A selection of phosphines is evaluated under biocompatible aqueous conditions. 6 describes the development of a convergent synthesis of the naturally occurring conjugate between the 5’- terminal fragment of genomic RNA from Coxsackie virus and the full-length viral genome-linked protein (VPg). Show less
Metal-based prodrugs based on ruthenium(II) polypyridyl complexes have proven to be very suitable for application in both photodynamic therapy (PDT) and photo-activated chemotherapy (PACT). As most... Show moreMetal-based prodrugs based on ruthenium(II) polypyridyl complexes have proven to be very suitable for application in both photodynamic therapy (PDT) and photo-activated chemotherapy (PACT). As most of these complexes unfortunately require poorly-penetrative, potentially-toxic blue light for their photo-activation, a lot of research effort has been dedicated to the development of prodrug systems that can be activated using near-infrared light, which is less harmful and penetrates deeper into human tissue. Thulium-doped upconverting nanoparticles (UCNPs) produce the desired blue light upon excitation with near-infrared light, allowing for the development of a drug delivery system in which ruthenium prodrugs are activated with near-infrared light. This thesis deals with the development of several new photo-activatable ruthenium polypyridyl complexes and the investigation of their photochemistry. Furthermore, a multicentre comparative study of the upconversion quantum efficiencies of LiYF4 UCNPs is reported. Finally, it describes the formation of water-dispersible UCNPs decorated with the newly-developed ruthenium complexes, as well as their stability in aqueous media and the successful photo-activation of the surface-bound ruthenium complexes using near-infrared light. The work has resulted in new insights into the design principles that are essential for the successful development of photo-activatable ruthenium-decorated upconverting nanoparticles. Show less
Should GNSS cause damage to its users or any third parties, who shall be responsible or liable, and how? Is it fair enough to force a GNSS provider to bear the burden of compensation given GNSS... Show moreShould GNSS cause damage to its users or any third parties, who shall be responsible or liable, and how? Is it fair enough to force a GNSS provider to bear the burden of compensation given GNSS open signals are provided free of charge to an undetermined scope? Could a GNSS provider release its civil liability by the doctrine of Sovereign Immunity if that provider is a public authority? This research is designed to explore whether current international laws are adequate to deal with those questions. If so, how those international laws apply? If not, where is the legal gap, and how should we move forward? This research is composed of four parts. Part I transfers the focus gradually from GNSS technical matters to legal issues, and then to civil liability in particular. Part II concerns a conceptual analysis of GNSS civil liability, serving as a basis for any further study. Part III checks the applicability and the adequacy of current international air and space laws to the case where GNSS cause damage. Part IV tries to find a roadmap to move forward for the issue of GNSS civil liability in a feasible way. Show less
Het oostelijk deel van West-Friesland was in de midden- en late bronstijd (ca. 1600-800 v. Chr.) een dichtbevolkt gebied met vele boerendorpjes. Door de goede conserveringsomstandigheden is de... Show moreHet oostelijk deel van West-Friesland was in de midden- en late bronstijd (ca. 1600-800 v. Chr.) een dichtbevolkt gebied met vele boerendorpjes. Door de goede conserveringsomstandigheden is de regio een schatkamer van de overblijfselen uit die tijd. In deze studie zijn oude opgravingsgegevens uitgewerkt en vertaald naar nieuwe inzichten in de inrichting en ontwikkeling van dit indrukwekkende prehistorische cultuurlandschap. Een van de opvallende resultaten van dit onderzoek is dat de nederzettingsterreinen vaak vele generaties bewoond zijn, maar tegelijkertijd een dynamisch karakter hebben. Continuïteit was er op locaties waar een huisplaats is ingericht: nieuwe boerderijen werden vaak generaties lang op dezelfde plaats als de voorgangers gebouwd. Maar we zien ook dat huisplaatsen die generaties lang bewoond zijn geweest, op een zeker moment werden opgegeven en een andere functie krijgen. Door de lange bewoningsduur van terreinen en goede conservering en herkenbaarheid van grondsporen, zijn de Westfriese vindplaatsen bij uitstek geschikt om deze dynamiek in beeld te brengen. Veel beter dan elders in Nederland is het mogelijk inzicht te krijgen in de keuzes die men in de bronstijd heeft gemaakt bij de inrichting van het landschap. Dat maakt deze studie een ijkpunt voor bronstijdonderzoek in Nederland, maar ook in Noordwest-Europa. Show less
The research contained in this dissertation explores the origins of fire making in prehistory, focusing primarily on the fire use practices and fire production capacities of Neandertals. The... Show moreThe research contained in this dissertation explores the origins of fire making in prehistory, focusing primarily on the fire use practices and fire production capacities of Neandertals. The dissertation is comprised of four peer-reviewed articles published in the journals Quaternary International, PLoS ONE, Journal of Archaeological Science and Scientific Reports, respectively, which are flanked by an introductory and synthesis chapter. The early chapters confront the debate surrounding the prevalence of fire use by Neandertals and discuss avenues by which we, as archaeologists, can better understand how fire use manifests in the Palaeolithic archaeological record. The latter chapters seek to provide a means for identifying artefactual evidence for fire making by Neandertals, ultimately presenting a series of French Middle Palaeolithic tools that exhibit use traces suggesting they were employed as fire starters, making these the earliest evidence for the regular production of fire by humans currently known. Show less
