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
This thesis describes the Multi-site All-Sky CAmeRA (MASCARA), which consists of two small robotic telescope designed to detect exoplanets around the brightest stars in the sky. These telescopes... Show moreThis thesis describes the Multi-site All-Sky CAmeRA (MASCARA), which consists of two small robotic telescope designed to detect exoplanets around the brightest stars in the sky. These telescopes search for exoplanets by continuously taking images of the sky and measuring the brightness of stars in these images, searching for the characteristic dimming that occurs when a planet passes in front of the star, blocking some of the starlight. An introduction to exoplanets is provided in chapter 1. The optical and mechanical design of the MASCARA telescopes, as well as the image processing algorithms, are described in chapter 2. The primary and secondary calibration methods used to remove systematic effects from the brightness measurements, as well as the transit search algorithm used, are described in chapter 3. The first planets discovered by MASCARA, two hot Jupiters orbiting the stars HD 201585 and HD 185603, are described in chapters 4 and 5. 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
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
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
Whenever someone makes a statement, they take stance on what they are talking about. Their utterance presents the propositional content of their message and at the same time shares their position... Show moreWhenever someone makes a statement, they take stance on what they are talking about. Their utterance presents the propositional content of their message and at the same time shares their position regarding the subject of talk. They convey their support or opposition, affiliation or disaffiliation, their like or dislike of the topic of talk. Subsequent, related, contributions similarly do not only react to the content of the earlier message, but to the associated stance taken by the other participant as well. Every interaction thus requires careful management of both the content discussed and the interpersonal relations between those involved. This dissertation investigates how people manage their informal interactions by means of phatic communicative structures. It explores to what extent the choices made by speakers are cross-linguistically stable or language specific, as differences in conversational style could affect intercultural communication and understanding. Three types of linguistic behavior are addressed: offering support and agreement, reproducing meaning (and form), and collaboratively constructing a single message. The preferences across and within these three types are contrasted for Dutch and Indonesian speakers. Show less
De precieze aard van de rechtsverhouding tussen leerling, ouders en school in het primair en voortgezet bekostigd onderwijs is geen uitgemaakte zaak. De wet zwijgt hierover en de rechtspraak biedt... Show moreDe precieze aard van de rechtsverhouding tussen leerling, ouders en school in het primair en voortgezet bekostigd onderwijs is geen uitgemaakte zaak. De wet zwijgt hierover en de rechtspraak biedt geen uitsluitsel. De literatuur ziet verschillende mogelijkheden, van civielrechtelijke, bestuursrechtelijke of gemengde aard, met referte aan onder meer het onderscheid tussen openbaar en bijzonder onderwijs en publiekrechtelijke normering van het onderwijs. Dit proefschrift bekijkt de rechtsverhouding tussen leerling, ouders en school vanuit contractenrechtelijk perspectief. Het neemt als uitgangspunt dat de rechtsverhouding gekwalificeerd kan worden als overeenkomst: een onderwijsovereenkomst. Wat brengt toepassing van het contractenrecht in de onderwijsverhouding mee? Wat heeft het contractenrecht de onderwijsverhouding te bieden? Fundamentele leerstukken van het contractenrecht op het gebied van de totstandkoming, de inhoud en de remedies worden toegepast in de context van het onderwijs, telkens met inachtneming van publiekrechtelijke normen. Show less
The research described in this thesis focused on identifying novel drug targets and synergistic combinations for triple-negative breast cancer (TNBC), a virulent subtype of breast cancer with a... Show moreThe research described in this thesis focused on identifying novel drug targets and synergistic combinations for triple-negative breast cancer (TNBC), a virulent subtype of breast cancer with a dismal prognosis and limited therapeutic options. In particular, the work centred on reversing resistance of TNBC cells to EGFR inhibitors. High-throughput kinase inhibitor library-based screens were utilised to evaluate the potential of novel targeted agents in a panel of TNBC cell lines and subsequently identify TNBC-specific genetic dependencies using siRNA-based screening. The signal transduction pathways perturbed by drug treatment were delineated and subsequently scrutinised using transcriptomic profiling and western blotting. The impact of drug treatment or gene silencing on cell death, proliferation, cell cycle progression and migration was assessed simultaneously. This work demonstrated that TNBC cell lines resistant to both MEK and Akt inhibitors are sensitive to disruption of CDK function. Additionally, it revealed that novel CDK inhibitors with strong activity against P-TEFb/CDK9 are highly effective against TNBC cells as single agents and in combination with multiple targeted therapies. These agents provoked profound down-regulation of multiple oncogenic pro-proliferative pathways, the silencing of which was detrimental to TNBC cell proliferation, thus defining several genes as potential future drug targets. Show less
This dissertation provides new insights into language variation and change in late eighteenth- and early nineteenth-century Dutch. More specifically, it investigates whether and to what extent... Show moreThis dissertation provides new insights into language variation and change in late eighteenth- and early nineteenth-century Dutch. More specifically, it investigates whether and to what extent official language policy measures exerted influence on actual language practice.During the nation-building period around 1800, the Northern Netherlands witnessed the introduction of a national language policy, which aimed at the spread of a homogeneous written standard variety of Dutch, symbolising 'the' nation. In concrete terms, these top-down endeavours resulted in the first official codification of the Dutch orthography (Siegenbeek 1804) and grammar (Weiland 1805). Despite marking a decisive turning point in the standardisation history of Dutch, the effectiveness of the so-called schrijftaalregeling 'written language regulation' has never been investigated empirically.Taking a historical-sociolinguistic approach, this dissertation aims to fill this research gap by examining the impact of language policy on patterns of variation and change. How successful was the schrijftaalregeling in disseminating the officialised norms across the population at large, as envisaged by the government? Making use of the newly compiled Going Dutch Corpus, a diachronic multi-genre corpus comprising more than 420,000 words of authentic usage data (private letters, diaries and travelogues, newspapers), a wide range of orthographic and morphosyntactic features is analysed. Show less
The research is dedicated to Gilbert Blin’s work in staging operas of the seventeenth and eighteenth centuries. Nourished by a decade of productions for the Boston Early Music Festival, the first... Show moreThe research is dedicated to Gilbert Blin’s work in staging operas of the seventeenth and eighteenth centuries. Nourished by a decade of productions for the Boston Early Music Festival, the first objective of his dissertation is to enable a better understanding of both his creative and interpretive processes in the operatic field. The main research question he attempts to answer in his dissertation can be phrased as follows: how can a post-modern stage director use historical research for creative purposes? The title of this dissertation, The Reflections of Memory, is the appellation Gilbert Blin has been giving to his current approach as an artist and constitutes a conceptual answer to this question Show less
