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
In het gebied tussen de Oude Rijn en de Nieuwe Maas in de huidige provincie Zuid-Holland bevond zich gedurende de eerste drie eeuwen van onze jaartelling het bestuursdistrict van de rurale... Show moreIn het gebied tussen de Oude Rijn en de Nieuwe Maas in de huidige provincie Zuid-Holland bevond zich gedurende de eerste drie eeuwen van onze jaartelling het bestuursdistrict van de rurale gemeenschap van de Cananefates (de civitas Cananefatium). De vorming van deze gemeenschap, alsmede de veranderingen die binnen de identiteit van deze groep plaatsvonden zijn onderzocht door middel van een systematische analyse van de aanwezige archeologische resten. Om de rol van de Romeinse staat in deze processen te duiden, zijn ook de stedelijke en militaire gemeenschappen in de analyse betrokken. Op deze manier is een overzicht ontstaan van een landschappelijke en administratieve regio waarbij aspecten als de interactie tussen de verschillende groepen, het karakter van de rurale gemeenschappen en het contrast met andere rurale groepen langs de grenzen van het Romeinse rijk bestudeerd konden worden. Show less
Playing a musical instrument is generally considered to be a complex human behaviour involving the integration and coordination of a broad range of human functions such as perception, imagination,... Show morePlaying a musical instrument is generally considered to be a complex human behaviour involving the integration and coordination of a broad range of human functions such as perception, imagination, memory, information processing, emotion, communication, and dexterity. From this perspective, it seems only reasonable to assume that, in an age of informational and communicational abundance, this intrinsic multifacetedness manifests itself in numerous informational contact-points between musical practice and a variety of academic and para-academic fields which zoom in on these specific elements of musical activity. Joost Vanmaele’s dissertation is directed at carefully and systematically evaluating the position of musicianship in an age of informative abundance and connectedness, to consider ways of re-balancing and broadening its epistemic grounds and attuning its information systems, with a view to artistic development, enrichment and/or liberation. By proposing a Bio-Culturally informed Performers’ Practice of Western Art Music [BCiPP], an information- and dialogue-friendly, transdisciplinary space is created where musical activities are not considered as phenomena sui generis but rather as informable cultural instances or personal particularisations of the human capacity to meaningfully generate and react to temporally patterned sounds. The potential impact of BCiPP is put to the test in two case-studies. Show less
Dissociation, emotion dysregulation, and cognitive disturbances are key features of Borderline Personality Disorder (BPD). The aim of this thesis was to investigate associations between... Show moreDissociation, emotion dysregulation, and cognitive disturbances are key features of Borderline Personality Disorder (BPD). The aim of this thesis was to investigate associations between dissociation and activity in networks relevant to affective-cognitive processing in patients with BPD compared to healthy controls. In the first part of this thesis, associations between self-reported dissociation and functional connectivity of the amygdala and anterior cingulate during resting-state and during an Emotional Working Memory Task (EWMT) were examined. The second part of this neuroimaging research combined script-driven imagery with the EWMT and with an Emotional Stroop Task. Findings suggest a detrimental effect of dissociation on cognitive functioning in BPD. After dissociation induction, patients showed reduced activity in the amygdala, posterior cingulate, superior temporal gyrus, and occipital areas (cuneus, fusiform gyrus, lingual gyrus), along with increased activity in frontal areas (inferior frontal gyrus, dlPFC). Altered interactions between the amygdala and the afore-mentioned regions may underlie disturbed information processing during dissociation in BPD. Further research with larger sample sizes and clinical control groups is needed to gain more insight into the neural mechanisms of stress-related dissociation in BPD. A combination of neuroimaging techniques with subjective, behavioral, and psychophysiological measurements may be a helpful step into this direction. Show less
Looking for a global and corrective measure to reduce greenhouse gas emissions from international civil aviation has been facing legal obstacles. These obstacles took the form of conflicts of... Show moreLooking for a global and corrective measure to reduce greenhouse gas emissions from international civil aviation has been facing legal obstacles. These obstacles took the form of conflicts of norms linked to the general challenge of the interactions between international aviation law, climate change law and the law of the European Union. Using evolutionary interpretation of the Chicago Convention in order to reconcile norms of substantive and institutional nature emerged as the best solution. However, this method perpetuates legal uncertainty and poses the general challenge of flexibly and elasticity of the Chicago Convention in response to the climate change challenge. This study examines the above mentioned issues of interactions between legal orders and provides recommendations to restore legal certainty needed to ensure sustainable development of international civil aviation. More specifically, this study reveals the underestimated relevance of the ongoing distinction between the legal regimes of air navigation and international air transport, which is a key legal element in the search for a global and corrective solution to the impact of international civil aviation on climate change. Show less
In this book, the author addresses the legal and political aspects of a multilateral tax treaty that fundamentally transforms the way states cooperate in the field of international taxation.... Show moreIn this book, the author addresses the legal and political aspects of a multilateral tax treaty that fundamentally transforms the way states cooperate in the field of international taxation. Working from a normative and pragmatic view on international tax relations, he proposes a management-focused approach to multilateral cooperation in international taxation. The resulting managerial framework treaty is drawn up on the basis of insights from political science and legal philosophy and is illustrated by means of international public law. Finally, the author evaluates the recently-adopted text of the Multilateral Convention to Implement Tax Treaty Related Measures to Prevent BEPS (the BEPS Convention) in the light of his proposed framework. Show less
In this thesis, classes of strongly interacting quantum field theories, have been studied. A non-perturbative method applied to these theories are gauge/gravity duality or holographic duality,... Show moreIn this thesis, classes of strongly interacting quantum field theories, have been studied. A non-perturbative method applied to these theories are gauge/gravity duality or holographic duality, which map a system of quantum field theory to a theory of gravity in higher dimensions. This thesis focused on the transport coefficients which govern the low energy excitations of these systems. Show less
Travel by air for persons with disabilities (PWDs) can be challenging. Their problems range from physical barriers in airports and aircraft to inaccessible information, extra fees for services,... Show moreTravel by air for persons with disabilities (PWDs) can be challenging. Their problems range from physical barriers in airports and aircraft to inaccessible information, extra fees for services, insufficient compensation for their mobility aids and different rules and practices among air carriers. This study explores issues facing PWDs from a legal perspective. The aim of this study is to balance the rights of PWDs with the duties of States, airport operators and air carriers. In light of this, multilevel legislations - namely international, regional and national rules from human rights law and aviation law - are compared, contrasted and analyzed. The study is primarily focused on access to air travel and remedial measures, for their lack of equal access for PWDs and for discrimination on the basis of disability. Suggestions have been addressed to the International Civil Aviation Organization, the Committee on the Rights of Persons with Disabilities and to States. All parties should ensure that accessibility standards on air travel, and an interpretation of remedial measures, are consistently applied. Show less
The name ‘Jambi flora’ refers to fossil plants found as part of a rock formation from the Early Permian (296 million years old), located in the Jambi Province of Sumatra, Indonesia. The flora... Show moreThe name ‘Jambi flora’ refers to fossil plants found as part of a rock formation from the Early Permian (296 million years old), located in the Jambi Province of Sumatra, Indonesia. The flora is characterized by the occurrence of both plant groups known from classic coal swamp floras, established for tens of millions of years, as well as newly emerging groups that in a number of cases are making their first known occurrence there and would play an important role in the vegetations of the Permian era. The latter are part of distinct associations with an ecology different and generally drier than that of the swamp flora species. The large amount of fossil wood collected from the Jambi region allowed for a quantitative analysis larger than anything undertaken before for this early gymnosperm wood type. Although more than 250 different species have been described worldwide for this fossil wood type in the past, the results from a morphological analysis of the Jambi material shows it to be a coherent whole wherein no individual species can be discerned. This throws great doubt on whether it is even possible to distinguish traditional species in this wood type. Show less
In de Bataafs-Franse tijd (1795-1814) was de Nederlandse buitenlandse politiek volledig gericht op het voortbestaan van de staat. Tegenover het overheersende Frankrijk voerde men een... Show moreIn de Bataafs-Franse tijd (1795-1814) was de Nederlandse buitenlandse politiek volledig gericht op het voortbestaan van de staat. Tegenover het overheersende Frankrijk voerde men een tweesporenbeleid. Enerzijds was er een ‘statelijke ongehoorzaamheid’ bij het nakomen van ongenadig harde verplichtingen en anderzijds streefde men naar internationalisering van de kwestie over het bestaansrecht van Nederland. In deze tijd gaf Maarten van der Goes van Dirxland [1751-1826], een Haagse burgemeesterszoon en Nederlands eerste minister van Buitenlandse Zaken, tien jaar lang leiding aan de Nederlandse diplomatie. Van der Goes had daarbij slechts één doel voor ogen: het handhaven van de naam Holland op de kaart van Europa. Maar zijn ambtsperiode had iets tragisch. Hoewel hij wist, zoals hij schreef, dat de dagen van Tromp en De Ruyter voorbij waren en dat zijn belangrijkste succes niet meer kon zijn dan het bij elkaar houden van het ‘overgeschoten boeltje’, weigerde hij Napoleons opmerking ‘Holland is als een satelliet van een planeet’ te accepteren. Door het prisma van het leven en de carrière van Maarten van der Goes biedt deze biografie een geactualiseerd beeld van de Nederlandse buitenlandse politiek in de overgang naar een nieuwe eeuw. Show less
The comorbidities of epilepsy include those conditions, somatic and psychiatric, that are associated with epilepsy. These associations with epilepsy may be direct and indirect, causal and spurious.... Show moreThe comorbidities of epilepsy include those conditions, somatic and psychiatric, that are associated with epilepsy. These associations with epilepsy may be direct and indirect, causal and spurious. The comorbidities of epilepsy are relevant in that they provide an opportunity to improve our understanding of the pathophysiology of epilepsy, as well as allow us to better understand factors determinant of outcome. This PhD thesis examines the comorbidities of epilepsy, as a general construct, delving into particular examples, and finally demonstrating its impact on premature mortality in epilepsy. Show less
The aim of this thesis is to explore the use of Bioorthogonal Antigens to study the cross-presentation pathway. Bioorthogonal Antigens are antigens carrying bioorthogonal groups in specific... Show moreThe aim of this thesis is to explore the use of Bioorthogonal Antigens to study the cross-presentation pathway. Bioorthogonal Antigens are antigens carrying bioorthogonal groups in specific amino acid positions within the epitope region that can be reacted selectively within/on the cell using bioorthogonal ligation strategies. Incorporation of bioorthogonal groups into antigens has an advantage over other methods because most of the groups are stable to proteolysis and are small enough to have a minimal impact on routing and loading onto MHC-I molecules. In the future, these antigens have potential to be applied for imaging of the entire cross-presentation pathway using a single bioorthogonal handle. Show less
The studies in this dissertation examined 1) how different identities that are relevant to smoking affect smoking behavior; 2) how identity changes over time in smokers and ex-smokers, both... Show moreThe studies in this dissertation examined 1) how different identities that are relevant to smoking affect smoking behavior; 2) how identity changes over time in smokers and ex-smokers, both spontaneously and in response to an intervention, and what factors affect identity change; and 3) whether associations between identity and smoking-related outcomes - as well as identity change processes - differ between people with lower and higher socio-economic status. A multi-method approach was employed, including cross-sectional and longitudinal studies; observational and experimental studies, and using quantitative and qualitative methods. First, results showed that nonsmoker and quitter identities are more important than smoker identities for intentions to quit, quit attempts, (long-term) quit success and responses to the Dutch smoking ban in hospitality venues. In addition, self-identities seemed more important than group-identities. Second, identity changes in response to smoking behavior and social norms, and identity change is facilitated by permeable identity boundaries, a continuous sense of self, and a sense of mastery of quitting. Third, lower SES smokers and ex-smokers identify more strongly with smoking - and lower SES smokers identify less strongly with nonsmoking - than their higher SES counterparts, and in lower SES groups identity is more resistant to change. Show less
This thesis addresses the problem of designing performance and energy efficient embedded streaming systems, that is, systems which process a stream of input data coming from the environment and... Show moreThis thesis addresses the problem of designing performance and energy efficient embedded streaming systems, that is, systems which process a stream of input data coming from the environment and generate a stream of output data going into the environment. The correct functionality of embedded streaming systems depends on both the correctness of output data and on the time at which the data is produced. To achieve desirable performance and energy consumption of such real-time embedded streaming systems, modern embedded systems are equipped with hardware platforms that contain multiple processors on a single chip. These hardware platforms are called Multi-Processor Systems-on-Chip (MPSoCs). To exploit such parallel hardware platforms, the streaming application which is going to be executed on an MPSoC platform has to be specified as a set of tasks that are data-dependent, but can be executed in parallel. These tasks are mapped on processors where they are scheduled in time and executed. This thesis proposes methodologies and techniques to transform a streaming application into a set of parallel tasks which closely matches an MPSoC platform and to schedule these parallel tasks onto the platform such that the desirable performance and energy consumption are reached. Show less
Currently, a large number of pharmaceutical companies focus on the development of (immunomodulatory) biotherapeutics such as recombinant proteins and monoclonal antibodies, developed for... Show moreCurrently, a large number of pharmaceutical companies focus on the development of (immunomodulatory) biotherapeutics such as recombinant proteins and monoclonal antibodies, developed for therapeutic and diagnostic purposes. The development of these biotherapeutics is challenging, among others due to a lack of robust efficacy data when administered to patients. Hence, the identification of selective, early phase biomarkers is particularly needed in their process of development. By the identification of these biomarkers (for instance using in vivo or ex vivo challenge models), question-based drug development together with the performance of concurrent engineering provides the opportunity to collect and connect data already in the early stages of drug development resulting in an earlier assessment of the potential value of a new (biotherapeutic) compound and a potential increase in the drug development success rates. This thesis provides an extended overview of different types of clinical pharmacology studies concerned with the complicated investigation of immunomodulatory biotherapeutics in the early stage of drug development. Key factors herein are the search for selective biomarkers in healthy volunteers and patients, the development of new methods, and optimization of existing methods to improve and potentially accelerate the development process of immunomodulatory biotherapeutics. Show less
The stable isotope ratios of carbon (d13C), nitrogen (d15N) and sulphur (d34S) are measured to examine human diet, social stratification, mobility and animal husbandry practices. Three locations... Show moreThe stable isotope ratios of carbon (d13C), nitrogen (d15N) and sulphur (d34S) are measured to examine human diet, social stratification, mobility and animal husbandry practices. Three locations comprising four sites from the Yellow River Valleys of north China are investigated: Nancheng (Hebei Province), Xishan (Gansu Province), Liyi and Shanren (Shaanxi Province), and this work represents one of the largest and most detailed isotopic research projects ever conducted in China. This thesis focused on time periods and cultures that were previously underrepresented, in the literature such as the early Bronze/Iron Ages to the Qin Dynasty (221-206 BC). Further, this thesis found new evidence concerning dietary patterns, social stratification (or lack thereof), animal husbandry practices and human mobility during these formative pre-Qin Empire periods. Show less
Today, virtually every country in the world has a written constitution that contains a special amendment procedure. These procedures are designed to regulate constitutional change. However, formal... Show moreToday, virtually every country in the world has a written constitution that contains a special amendment procedure. These procedures are designed to regulate constitutional change. However, formal constitutional amendment is not the only way in which constitutional norms change, and in some systems not even the most important. To the contrary, it appears to be more common for constitutional norms to adjust to changing circumstances and demands through alternative, ‘informal’ processes of change.Key questions, central to this dissertation, are: how should we understand and identify constitutional change that takes place without prior formal constitutional amendment? Why do significant constitutional developments sometimes occur without new constitutional writing? And are alternative mechanisms of constitutional change capable of functionally substituting formal constitutional amendment mechanisms?Examining and comparing topical cases from Japan, the United States and Germany, this dissertation not only sheds new light on questions regarding the phenomenon of informal constitutional change itself, it also compels us to rethink our ideas about how the realms of law and politics relate to one another across time. Exploring the important – yet understudied – phenomenon of informal constitutional change is particularly relevant at a time when the context in which constitutional norms are embedded is changing more rapidly than ever. Show less
Vulvar cancer is a relatively rare gynaecologic malignancy with an annual incidence in developed countries of approximately 2 per 100,000 women. Vulvar squamous cell carcinoma (VSCC) has two... Show moreVulvar cancer is a relatively rare gynaecologic malignancy with an annual incidence in developed countries of approximately 2 per 100,000 women. Vulvar squamous cell carcinoma (VSCC) has two etiological pathways: a high risk human papillomavirus (HPV)-dependent route, which has usual vulvar intraepithelial neoplasia (uVIN) as a precursor lesion, and an HPV-independent route, which is associated with differentiated VIN (dVIN), lichen sclerosus, and genetic alterations, such as TP53 mutations. Although most cases of early stage vulvar cancer have a good prognosis, recurrence and rapid tumour progression can oc¬cur. The etiology of HPV positive vulvar cancer is quite well understood, but the HPV in-dependent axis remains to be unravelled. This thesis aims to gain knowledge on the origin of this type of vulvar cancer through the study of two mechanisms: genetic and morphological alterations in vulvar cancer. An overview of the literature on genetic and epigenetic changes in vulvar cancer was made. We designed a mass spectrometry based mutation panel and investigated the prevalence of somatic mutations in a cohort of vulvar cancer patients. Also, markers of Epithelial-to-Mesenchimal-Transition such as spindle cell morphology and L1CAM-expression were studied in a large group of patients. These results were related to a worse survival. https://www.gildeprint.nl/flippingbook/4336-vulvar-squamous-cell-carcinoma/Show less
Diabetes mellitus is amongst the leading causes of morbidity and mortality worldwide. Insulin-producing pancreatic β-cells are central in establishing adequate glucose regulation and loss of... Show moreDiabetes mellitus is amongst the leading causes of morbidity and mortality worldwide. Insulin-producing pancreatic β-cells are central in establishing adequate glucose regulation and loss of functional β-cells results in the development of diabetes. Although it was previously thought that fully differentiated cells cannot change phenotype, murine studies recently indicated that mature β-cells can change identity into other islet cells under conditions of (metabolic) stress.We present a novel agarose based microwell culture system that can be used for aggregate formation of human or rodent islet cells. We show that this platform provides reproducible results to study aggregation of primary human islet cells. Using this culture system together with β-cell specific lineage tracing, we find that mature human β-cells can spontaneously lose their identity and convert into glucagon-containing α-cells. We then used human pancreatic tissue from donors with T2DM and matched controls to explore loss of β-cell identity in T2DM. We report that cells indicative of loss of β-cell identity are found more frequently in tissue samples from donors with a history of T2DM. Finally, we show that Pax4 and GLP-1 receptor agonists can partially prevent loss of identity β-cell in our ex vivo model. Show less
This thesis investigates different aspects of apathy - as a distinct clinical syndrome assessed with the Apathy Scale- in older persons with and without concurrent depression. In Chapter 2,... Show moreThis thesis investigates different aspects of apathy - as a distinct clinical syndrome assessed with the Apathy Scale- in older persons with and without concurrent depression. In Chapter 2, clinically relevant subtypes of apathy according to the Apathy Scale in older persons from the PROMODE study are examined, using data-driven Latent Class Analysis (LCA). Further, specific characteristics across the classes identified by LCA are investigated. Then, in Chapter 3, cross-sectionally the prevalence, severity and clinical profile of apathy in depressed and non-depressed older persons, in relation to various possible determinants is described. Chapter 4 examines which characteristics predict, over a 2-year period, the incidence and course of apathy in at baseline depressed older persons from the NESDO study. Chapter 5, using data of the NESDO and NESDA, investigates the presence of apathy in late-life compared to early-life depression, and various determinants of clinically relevant apathy in older compared to younger depressed persons. In Chapter 6 the association of the presence of apathy among community-dwelling older persons from the PROMODE study and a diminished quality of life is examined. All results are placed a current perspective in Chapter 7 that also discusses clinical implications, and makes some recommendations for future research. Show less
