The adoption of agriculture is one of the major developments in human history. Archaeological studies have demonstrated that the trajectories of Neolithisation in Northwest Europe were diverse.... Show moreThe adoption of agriculture is one of the major developments in human history. Archaeological studies have demonstrated that the trajectories of Neolithisation in Northwest Europe were diverse. This book presents a study into the archaeology of the indigenous communities involved in the process of Neolithisation in the Lower Rhine Area (5500-2500 cal BC). It elucidates the role played by these in relation to their environmental context. This work brings together a comprehensive array of excavated archaeological sites in the Lower Rhine Area and indicates that the successive Late Mesolithic, Swifterbant culture, Hazendonk group and Vlaardingen culture societies represent a continuous long-term tradition of inhabitation of the wetlands and their margins. After demonstrating the existence of a diverse Mesolithic background to Neolithisation, the subsequent developments are studied by foregrounding the relationship between local communities and the dynamic wetland landscape. This points to long-term flexible behaviour and pragmatic choices in livelihood, food economy and mobility. For the interpretation of Neolithisation this study emphasises the persistent traditions of the communities involved. New elements are shown to be attuned to existing hunter-gatherer practices. By documenting indications of the mentalité of the wetland inhabitants, it is demonstrated that their mindset remains essentially ‘Mesolithic' for millennia. Show less
This thesis explores a conception of the EU as a modified confederal system of sovereign member peoples and their states. A confederal conception which demonstrates how, contrary to popular belief... Show moreThis thesis explores a conception of the EU as a modified confederal system of sovereign member peoples and their states. A confederal conception which demonstrates how, contrary to popular belief, European integration does not conflict with sovereignty or democracy. For, properly conceived and constituted, the EU reasserts the sovereignty of the member peoples, and liberates national democracy from the confines of the state.To this end, this thesis reconnects the EU to two classic constructs of constitutional theory: confederalism and sovereignty. Two powerful but unfashionable constructs whose joint potential for European integration remains largely unexplored and undervalued. The primary instrument to explore this potential is comparative. The EU is contrasted with the rather unknown but rich example of the American Articles of Confederation, and their evolution into the now famous American federate system. A comparison with the confederal roots of the United States which is revealing for both confederalism and sovereignty, and illustrates the potential of linking both for a constructive constitutional theory of the EU. A theory which does not have to overcome history and the statal system it has created, but connects with it. A theory, therefore, that may help to recapture the EU and the increasing authority it wields, both in theory and in practise. The thesis is subdivided in three parts. Part I addresses confederalism. It demonstrates how the constitutional system of the EU combines a confederal foundation with a federate superstructure, and explores the particular strengths, weaknesses and limits of this modified confederal system. Part II discusses sovereignty. It first demonstrates how the EU forms a logical confederal evolution of popular sovereignty, and how European integration does not conflict with sovereignty. Subsequently, it shows how the concept of confederal sovereignty equally helps to dispel the presumed conflict between statism and pluralism, how it respects and conciliates national and EU claims to supremacy, and how it allows a confederal evolution of national democracy, which updates democracy to the global reality it is to control. Part III applies the findings of Part I and II to the EMU crisis and the challenge of establishing an effective democratic foundation for the EU at the national level. An application which demonstrates the concrete and attractive contributions a confederal approach can make to addressing some of the core challenges facing the EU. Show less
The aim of this thesis was to identify in the human blood transcriptome, relevant pathways and potential biomarker profiles that associate with chronological age and discriminate between __healthy... Show moreThe aim of this thesis was to identify in the human blood transcriptome, relevant pathways and potential biomarker profiles that associate with chronological age and discriminate between __healthy agers__ from long-lived families and normative ageing controls. Such profiles may harbor determinants of the biological ageing rate. We studied genome-wide gene expression profiles in blood of members of the Leiden Longevity Study (LLS) and replicated our findings by extended sampling within the unique LLS cohort. The findings of the exploratory analysis prompted us to investigate multiple genes in the IL7R and MTOR pathways for association with familial longevity. The results obtained by examining mRNA from blood samples brought us to study mTOR protein levels and signalling in primary skin fibroblasts from the corresponding donors in the LLS. Finally, to discover robust, biologically relevant gene networks as markers of chronological ageing in larger sample sizes, we performed an explorative network-based meta-analysis on large publicly available transcriptomic datasets. We have identified several networks, pathways and candidate genes potentially marking the biological age and the rate of ageing Show less
he papers in which are part of this theses describe the global diversity and conservation status of damselflies and dragonflies, contain a moleculair revision of the damselflies and discuss the... Show morehe papers in which are part of this theses describe the global diversity and conservation status of damselflies and dragonflies, contain a moleculair revision of the damselflies and discuss the biogeography of damselflies and dragonflies in the Australasian region. Show less
We have developed novel fluorescence bio-imaging based automated models to screen for novel candidate targets involved in prostate cancer metastasis. Utilizing these models and adopting a... Show moreWe have developed novel fluorescence bio-imaging based automated models to screen for novel candidate targets involved in prostate cancer metastasis. Utilizing these models and adopting a functional genomics based approach; we identified SYK as a novel regulator of prostate cancer progression. We also identified functional involvement of MST1R in regulating the progression of prostate cancer. For both of these targets, there is supporting human clinical data to validate our results in prostate cancer. Show less
In this thesis, nanochannels as well as nanofluidic phenomena are used to provide new and miniaturized bioanalytical tools for the life sciences. Isotachophoresis performed in nanochannels showed... Show moreIn this thesis, nanochannels as well as nanofluidic phenomena are used to provide new and miniaturized bioanalytical tools for the life sciences. Isotachophoresis performed in nanochannels showed the focusing and separation of analytes in a 0.4 picoliter volume, which is a volume in the order of a sample from a single cell. Depletion zone isotachophoresis (dzITP) is demonstrated which uses a nanofluidic phenomenon, concentration polarization, to enable isotachophoresis in a microchannel while using only a single electrolyte. A concept for surface enhanced Raman spectroscopy (SERS) sensor (SERSOR) is explored; a coating protecting the SERS surface from irreversible adsorption may enable dynamic measurements of biomolecules in solution in minute volumes. Working with nanochannels has led to the discovery of new unexpected fundamental phenomena: the very high surface to volume ratio in nanochannels causes acidification of solutions introduced in them, despite the presence of up to 1 mol/L of buffer. Also, extreme pressures of more than a 1000 bar may be induced in a nanochannel by what we named electrocavitation, an effects shown to impose a limit on further downscaling of ITP. Show less
We develop a new technique for Run-time Checking for two object-oriented languages: Java and the Abstract Behavioral Specification language ABS. In object-oriented languages, objects communicate by... Show moreWe develop a new technique for Run-time Checking for two object-oriented languages: Java and the Abstract Behavioral Specification language ABS. In object-oriented languages, objects communicate by sending each other messages. Assuming encapsulation, the behavior of objects is completely determined by the order of the messages, and their content. Traditional methods for Run-time Checking focus either exclusively on the description and testing of the order of the messages (Monitoring), or they focus on specifying and testing the content of those messages (Run-time Assertion Checking). Our method combines Monitoring with Run-time Assertion Checking.The basic idea behind our technique is that the behavior of objects can be described formally by means of an attribute grammar extended with assertions. The underlying (context-free) grammar specifies the valid orderings of the messages, the attributes define properties of the contents of the messages, and assertions specify the desired values of those properties. We develop a new Run-time Checker for attribute grammars in the form of a meta-program in the language Rascal and applied the Run-time Checker to an industrial case of the e-commerce company Fredhopper. We also investigated the efficiency of the run-time checker, and successfully discovered and solved several bugs in the Fredhopper software. Show less
The referendum is one of the most studied and practiced institutions of semi-direct democracy around the world, in several latitudes and historical times, in different systems and political regimes... Show moreThe referendum is one of the most studied and practiced institutions of semi-direct democracy around the world, in several latitudes and historical times, in different systems and political regimes, at international, national, regional or local levels, with different legal frameworks and with various political consequences. However, Portugal, whose constitutional experience begins in 1820 with the liberal revolution, had its first democratic referendum only in 1998. This study try to conceptually characterize the referendum, in order to establish its fundamental typologies regarding the most relevant experiences in this field and to situate the case for and against the referendum as an expression of semi-direct democracy in the political and philosophical debate of different historical moments. In the next chapters, entirely dedicated to the Portuguese case, we shall present the historical evolution of the nation al and local referendum in the constitutional and political life in Portugal since 1820. An added emphasis will be given to the referendum experience of the Portuguese democracy born in 1974, particular attention being payed to the political debate about the formal introduction of the referendum in the 1976 Constitution and to the concrete experience of referendums proposed and held since then. Show less
In the present thesis we report our findings assessing individual differences in perception of infant signals due to early-life experiences and variability in the oxytocinergic system. We found... Show moreIn the present thesis we report our findings assessing individual differences in perception of infant signals due to early-life experiences and variability in the oxytocinergic system. We found that the perception of infant cues differs between individuals with fewer versus more experiences of emotional maltreatment (Chapter 5). These adverse experiences seem to change the activity and responsiveness of the oxytonergic system, such that higher levels of oxytocin are secreted, which in turn are associated with a more positive evaluation of infant mood (Chapter 2). Moreover, intranasal administration decreases the memory for negative infant cues in individuals who experienced childhood emotional maltreatment (Chapter 4). Our results may suggest that developmental changes in the oxytonergic system might help maltreated individuals to be open to new, potentially positive relationship experiences and to facilitate new attachments. Moreover, we suggest that reward training might be helpful in changing individuals__ perception of an infant for the better (Chapter 3). Overall, our findings might serve as a first step toward identifying cognitive and neurobiological mechanisms that might help to improve (future) parenting Show less
The subject of the research is __difference and repetition,__ an area which bears a direct relationship to Wjm Kok__s practice, in which the production of work always emerges and passes through... Show moreThe subject of the research is __difference and repetition,__ an area which bears a direct relationship to Wjm Kok__s practice, in which the production of work always emerges and passes through series. It is also the title of a book by Gilles Deleuze that has been used as source and reference to explicate the research. Taking this book Difference and Repetition as a departure point, an ongoing series of writings was produced that sought to expose the different angles of the subject. The majority of these texts were published in diverse platforms, constituting an exchange with related subjects and his practice as a foundation for exploring other territories. A selected collection of these texts constitutes the dissertation. The presentation of this research will take place during the defense in the Grand Auditorium of Leiden University. Show less
In this thesis, patterns of variation in plant metabolomes and insect communities were described in GM and non-GM potato plants in both laboratory and field experiments. Differences between plant... Show moreIn this thesis, patterns of variation in plant metabolomes and insect communities were described in GM and non-GM potato plants in both laboratory and field experiments. Differences between plant genotypes in insect abundances were small when compared to year-to-year differences, location effects and differences between developmental stages of plants. Standardized effect sizes are discussed as an alternative scale for measuring effects. Leaf age, aphid infestation and virus infection were found to cause significant alterations in leaf metabolism in a laboratory study as measured by 1H NMR. However, these changes were similar in quantity and quality in both GM and non-GM plants. Furthermore, 1H NMR metabolomic profiles of potato plants were measured in a 2-year field study. Large changes in metabolomic profiles occurred across years and locations, and throughout the growth period of plants within years. Only weak relationships were found between metabolomics data and insect abundances on the same experimental fields. GxE interactions imply that conclusions from field trials are not valid outside the range of tested environments. This emphasizes the need for a careful choice of representative geographical zones for risk assessment studies. However, it also shows that a residual level of uncertainty in NTO safety is unavoidable. Show less
The thesis analyses international law and practice in relation to terrorism and counter-terrorism in the post 9/11 environment. It finds terrorism to be a term of acute and wide-ranging political... Show moreThe thesis analyses international law and practice in relation to terrorism and counter-terrorism in the post 9/11 environment. It finds terrorism to be a term of acute and wide-ranging political significance yet one which is not defined under generally accepted treaty or customary international law. Despite this, a detailed international legal framework existed before 9/11 but has been supplemented since then, that provide the parameters for state responses to international terrorism. The thesis explores the proliferation of counter-terrorism practice on national, regional and international levels since 9/11 alongside this framework. Many particular responses and the legal issues they give rise to are explored, including Guantanamo and other examples of arbitrary detention, extraordinary renditions, targeted killings, terrorism trials, the erosion of safeguards against torture, sanctions regimes, surveillance pr actices, the prohibition on ‘association’ and the increasingly ‘preventive’ role of criminal law. It is suggested that this practice does not reveal seismic Grotian moments of international legal transformation, gaping holes in international protection or the need for new law. It does however reveal certain characteristics as regards the approach to the legal framework, which include extreme selectivity of application, a spreading ‘exceptionalism,’ distorted ‘purposive’ legal interpretations, excessive secrecy, arbitrariness and a lack of accountability. Evolving international reactions, including judicial reactions, have been and will continue to be critical to the ultimate impact of the ‘war on terror’ on international standards. The study questions the long term implications of the ‘war on terror’ for states and individuals responsible, for third states and for the international rule of law Show less
In this thesis the thermal- and photo-substitution behavior of polypyridyl ruthenium complexes is described at the surface of lipid bilayers and in homogeneous solutions. It is shown that the... Show moreIn this thesis the thermal- and photo-substitution behavior of polypyridyl ruthenium complexes is described at the surface of lipid bilayers and in homogeneous solutions. It is shown that the successive thermal binding and light-induced unbinding of the cationic ruthenium complex at the surface of the lipid bilayer requires negatively charged liposomes and ruthenium complexes containing moderately hindered N-N bidentate ligands. Our results in homogeneous solution show that changing the steric hindrance of the bidentate ligand influences both the photo- and thermal reactivities of these complexes, by altering the mechanism of the Ru-S bond formation. It is also shown that the Ru-S bond formation at the surface of negative lipid bilayers is faster than the same reaction in homogenous aqueous solutions, and a two-steps mechanism is proposed for the thermal coordination of ruthenium aqua complexes at membrane-embedded ligands. Furthermore, the application of ruthenium-functionalized liposomes in drug delivery is discussed. In vitro tests on cancer cell lines show that neutral liposomes functionalized with ruthenium compounds are more readily taken up by cancer cells than ruthenium-free liposomes. The liposome samples with ruthenium compounds are shown to be poorly cytotoxic in the dark. After light irradiation, the cytotoxicity increased at least up to five times for ruthenium complexes supported on non-PEGylated liposomes. Finally, the photoactivation of polypyridyl complexes with low-energy photons was studied using a photosensitization approach. A photosubstitution reaction was made faster upon yellow light irradiation than upon blue light irradiation by covalently linking a rhodamine B dye to the ruthenium complex. Show less
A system-level design methodology such as Daedalus provides designers with a forward synthesis flow for automated design, programming, and implementation of multiprocessor systems-on-chip. Daedalus... Show moreA system-level design methodology such as Daedalus provides designers with a forward synthesis flow for automated design, programming, and implementation of multiprocessor systems-on-chip. Daedalus employs the polyhedral process network model of computation to represent applications. These networks are automatically derived from sequential C code. A forward synthesis flow greatly increases designer productivity. Still, the designer needs to perform a time-consuming forward synthesis step to learn if a network satisfies his performance constraints. Furthermore, it is not trivial to select a set of transformations and transformation parameters for a network such that performance requirements are met. A forward synthesis flow thus solves only part of a design problem, as it does not provide fast feedback on the transformations a designer should apply to meet his performance constraints. This dissertation intro duces different performance estimation techniques for polyhedral process networks. The most promising technique is the profiling-based cprof technique that works directly on the sequential application code. This makes cprof an easy-to-use, robust, and fast technique, without the need to derive a polyhedral process network. This dissertation then discusses four transformations and analyzes factors that affect the efficacy of each transformation. Show less
The aim of this thesis is to introduce the readers to the importance of bio-based products and their potential applications in chemical industries. Alternative routes to the widely used nylon... Show moreThe aim of this thesis is to introduce the readers to the importance of bio-based products and their potential applications in chemical industries. Alternative routes to the widely used nylon precursor caprolactam are discussed and compared with the current fossil-based synthesis. Furthermore, the aim of the research - the development of a novel synthesis route to caprolactam based on biomass - is reported; the envisaged reaction sequence includes the development of new catalytic chemistry, namely reductive amidation and hydroamidomethylation. Show less
The main goal of this work is to develop a method that, operating on top of an Evolutionary Algorithm, increases its likeliness of finding innovative solutions. This likeliness is laid out to be... Show moreThe main goal of this work is to develop a method that, operating on top of an Evolutionary Algorithm, increases its likeliness of finding innovative solutions. This likeliness is laid out to be increased with the diversity of the solutions found, provided that they are of sufficient quality. The developed method needs to be applicable in a scenario in which the search is required to be started from a single, fixed solution. Therefore, a scheme is envisioned in which the search is performed in a sequential fashion, zooming in on a locally-optimal solution, and then exploring for a new potentially high-quality region based on a memory of solutions encountered earlier in the search. Two exploration criteria, one using an archive of earlier solutions as memory and the other deriving from a surrogate model trained on earlier solutions, were established to be worthwhile for integration into quality-based search. The resulting schemes were applied to a real-world airfoil optimization task, showing both to perform better than the baseline method of multiple standard optimization runs. The model-based approach delivers the best results, in the sense that it finds more solutions, more diverse solutions, and better-quality solutions than the baseline method. Show less
Cellulose makes up one of the most abundant renewable materials, present in all kinds of plant biomass (Pauly and Keegstra 2010). However, to be able to utilize the cellulose as feedstock, it needs... Show moreCellulose makes up one of the most abundant renewable materials, present in all kinds of plant biomass (Pauly and Keegstra 2010). However, to be able to utilize the cellulose as feedstock, it needs to be separated from lignin which cements the cellulose and hemi-cellulose fibers. Lignolytic peroxidases can be produced by Aspergillus niger, and its production was found to be improved by heme supplementation, suggesting a limiting effect of this co-factor during heterologous expression. The research described in this thesis explores fungal heme biosynthesis and its regulation by means of heme deficient mutant strains and overexpression strains of heme biosynthesis genes or corroborated iron metabolism with the final aim to increase the available intracellular heme for peroxidase production. Using heme deficient strains, we demonstrated that A. niger is capable of heme uptake and utilzation and that siroheme synthesis derives from the first half of the heme biosynthesis pathway as well. The tight regulation on heme biosynthesis on transcription and (post)translational level prohibits large changes in heme content, and indicated a bottleneck on the level of ferrochelatase and possible uroporphyrinogen III decarboxylase and coproporphyrinogen III oxidase and questions whether A. niger would be the most suitable host for heterologous peroxidase production. Show less
The law of the European Union requires effective enforcement of EU policy, for which criminal law can, and sometimes must be used. This means that the scope of policy freedom that criminal law... Show moreThe law of the European Union requires effective enforcement of EU policy, for which criminal law can, and sometimes must be used. This means that the scope of policy freedom that criminal law authorities can utilize, varies dependent on the applicable legal context. The principle of expediency, which gives the Public Prosecution Service the authority to drop cases conditionally or unconditionally, should be interpreted in a differentiated way, leaving more room for policy choices in certain areas and less in areas where European interests are particularly important. Show less
Population growth and the drop in the returns from the major cash crop (coffee) for small farmers are the main drivers that have influenced the farming systems and mobility of farmers in the... Show morePopulation growth and the drop in the returns from the major cash crop (coffee) for small farmers are the main drivers that have influenced the farming systems and mobility of farmers in the Western Highlands of Cameroon (WHC). The main objective of this research activity was to determine the interactions between farming systems and human mobility in the WHC. A comparative study was conducted through household and field surveys in three villages and conceptualized based on the systems approach. The different types of mobility were influenced by household social factors, the quest for ‘high valued' farm plots and hired labour. Urban-rural migration contributed to occupation diversification and social mobility. The sustainability factor was a function of land use intensity, intensity of off-farm inputs, the household adjustment factor and mobility of the household. The sacred groves were rich in plant diversity of varied ecological and economic importance. Nitrogen mining was common at all levels of the farming system. These determinants and types of mobility claims are pertinent to the research area; the sustainability results of the farming systems reflect the reality on the ground; the nutrient flux evaluated at the crop and farm levels constitute a valuable database for future research. Show less
Since the 1990s, the number of National Human Rights Institutions (NHRIs) has grown rapidly worldwide. NHRIs are widely believed to be able to contribute to the realisation of human rights, by... Show moreSince the 1990s, the number of National Human Rights Institutions (NHRIs) has grown rapidly worldwide. NHRIs are widely believed to be able to contribute to the realisation of human rights, by embedding international norms in domestic structures. Promoting Human Rights: National Human Rights Commissions in Indonesia and Malaysia addresses this issue by a comparative analysis of two NHRIs in Southeast Asia. It traces the development of both organisations since their inception, as well as their performance and effectiveness in three case studies regarding the freedom of religion, the right to a fair trial and the right to adequate housing. It reveals that the manner in which NHRIs address human rights issues differs between categories of rights, and that the promotion of international human rights standards is often hampered by the contestation of these norms, both within and outside of the organisation. At the same time, this study highlights some of the contributions the NHRIs have made to the realisation of human rights in challenging circumstances. The author therefore argues that NHRIs play a crucial role in making human rights an integral part of both the state and society. Show less
