This thesis will first document on variation in progeny sex ratios among individual female plants of Urtica dioica at our field site in Meijendel (Chapter 2). Next, we show that there is also... Show moreThis thesis will first document on variation in progeny sex ratios among individual female plants of Urtica dioica at our field site in Meijendel (Chapter 2). Next, we show that there is also considerable sex ratio variation among male and female flowering shoots in 26 natural populations studied (Chapter 3). Additionally, we studied life history traits of male and female clones to detect sex-specific differences that might have contributed to the sex ratio bias observed in the field. Our results indicate that the sex ratio bias in natural populations may be a consequence of a bias that already originated in the primary sex ratio. Next, we investigated physiological, environmental (Chapter 4) and genetic (Chapter 5) aspects of sex determination. For the latter aspect, a series of crosses including male, female and monoecious plants of U. dioica was performed. These experiments were designed to investigate whether sex ratio variation in the primary sex ratio is due to environmental sex determination (ESD) or genetic sex determination (GSD) solely or due to an interaction of both. Genetic mapping of sex-linked markers was used as a supplementary tool to analyze the genetic mechanism of sex determination (Chapter 6). Finally, to study the inheritance pattern of the sex ratio trait, crosses were performed between individual male and female plants from different sex ratio families (Chapter 7). Show less
The presence of calcium deposits in the vessel wall is indicative of advanced atherosclerosis, and the extent of coronary calcification has been found to add prognostic significance to conventional... Show moreThe presence of calcium deposits in the vessel wall is indicative of advanced atherosclerosis, and the extent of coronary calcification has been found to add prognostic significance to conventional risk factors of coronary artery disease. However, the mechanisms underlying vascular calcification are still obscure. The major objective of the work described in the first part of this thesis was to elucidate the mechanisms involved in atherosclerotic calcification. To study the process of VSMC calcification we developed and characterized an in vitro model of neonatal rat VSMC calcification. To investigate whether pharmacotherapy may affect vascular calcifications, we have studied the effect of a calcium antagonist (amlodipine) and a statin (atorvastatin) and their combination on this process. Inflammation is an important mechanism in the atherosclerotic process, and prospective and cross-sectional clinical and epidemiological studies have shown that CRP is consistently associated with CVD. The causality of CRP in atherosclerosis is discussed. To enable the study of the effect of CRP on atherosclerosis development in vivo, ApoE*3-Leiden/hCRP transgenic mice were generated and studied. The effects of a calcium antagonist (amlodipine), administered either alone or in combination with a statin (atorvastatin), on early atherosclerosis development in ApoE*3-Leiden/hCRP was investigated. Show less
One of the most intriguing concepts of quantum mechanics is quantum entanglement. Two physical systems are said to be entangled with respect to a certain variable, if their individual outcomes of... Show moreOne of the most intriguing concepts of quantum mechanics is quantum entanglement. Two physical systems are said to be entangled with respect to a certain variable, if their individual outcomes of the variable are undetermined before measurement, but strictly correlated. Measurement of the variable for only one system immediately determines the outcome for the other system, irrespective of the distance between the two systems. It is this strong correlation that provides a basis for perspective, powerful applications like quantum cryptography and quantum computation. The most studied entangled systems, often called EPR systems (after the pioneers Einstein, Podolsky and Rosen), are pairs of light particles or photon pairs. These photon pairs, usually generated via the optical process of a spontaneous parametric down-conversion, are, in principal, simultaneously entangled in three variables, being polarization (polarization entanglement), energy or time (time entanglement), and momentum or transverse space (spatial entanglement). The contents of this thesis cover new insights in the polarization and spatial entanglement of photons. We have investigated both the entanglement quality and the yield of entangled photons for different experimental geometries that are associated with the production and detection of the photons. Show less
Autopistia offers a historical survey and a theological evaluation of the self-convincing character of Scripture in Reformed theology. Calvin adopted the term autopistos from ancient Greek... Show moreAutopistia offers a historical survey and a theological evaluation of the self-convincing character of Scripture in Reformed theology. Calvin adopted the term autopistos from ancient Greek philosophy and used it to express that faith does not rest on the human authority of the church but on Scripture as the living voice of God. After discussing the meaning of the term in Reformed Orthodoxy and analyzing the theological position of Benjamin B. Warfield and Herman Bavinck on this issue, Henk Van den Belt draws his theological conclusions in this study, advocating a revitalization of the autopistia of Scripture, because it implies that faith finds rest in Scripture itself and not in the external authority of the church or of rational arguments and that Word and Spirit are inseparably connected. Show less
The present dissertation concentrates on the study of construction rituals of the Hindu tradition, with special attention to the prathameshtakaanyaasa (the laying of the first stones), the... Show moreThe present dissertation concentrates on the study of construction rituals of the Hindu tradition, with special attention to the prathameshtakaanyaasa (the laying of the first stones), the garbhanyaasa (the placing of the consecration deposit) and the muurdheshtakaanyaasa (the placing of the crowning bricks). The basis for the study is formed, on the one hand, by Sanskrit texts on architecture and ritual, dating from ca. the 7th to the 15th centuries AD, and, on the other hand, by the archaeological material. The chief textual source is the Kaashyapashilpa, a South Indian treatise on art and architecture and ritual, usually dated 11 – 12th century AD. Three chapters from the Kaashyapashilpa, which deal with the three aforementioned construction rituals, have been critically edited, translated and provided with a commentary. In order to answer the questions whether construction rituals mentioned in the ancient Sanskrit treatises were ever performed and if so, whether they were performed according to the textual prescriptions, the information given by the Sanskrit texts have been compared with the material traces of construction rituals originating from various regions of South and Southeast Asia. Show less
Many patients in need of haematopoietic stem cell transplantation do not reach transplantation. An analysis on all unrelated donor searches for Dutch patients performed between 1987 and 2000 showed... Show moreMany patients in need of haematopoietic stem cell transplantation do not reach transplantation. An analysis on all unrelated donor searches for Dutch patients performed between 1987 and 2000 showed a significant decrease of the percentage of patients for whom no donor was available. Between 1996 and 2000, the efficiency of the donor search and transplantation process was the biggest constraint for patients of Northwest European origin. Thirty percent of patients became medically unfit for transplantation during the process, due to the duration of the process. Major Histocompatibility complex (MHC) differences between donor and patient can preclude successful transplantation. The assumption that highly diverged MHC class I molecules lead to more T cell alloreactivity was challenged. Single highly diverged (>=5alpha5beta) MHC class I molecules did not elicit an immune response by allogeneic CTL in vitro. I propose that in generating a T cell repertoire with a sufficiently narrow responsive for self-MHC, positive thymic selection limits the capacity to recognize allogeneic MHC molecules whose structure and sequence have diverged extensively. Its clinical relevance was evaluated. We could subdivide the donor-recipient pairs with a negative CTLp assay into a prognostic favourable and unfavourable group based on the (>=5alpha5beta) MHC mismatch category. Show less
Planets form in disks that are commonly found around young stars. The intimate relationship that exists between planet and disk can account for a lot of the exotic extrasolar planetary systems... Show morePlanets form in disks that are commonly found around young stars. The intimate relationship that exists between planet and disk can account for a lot of the exotic extrasolar planetary systems known today. In this thesis we explore disk-planet interaction using numerical hydrodynamical simulations. We study the growth and migration of embedded planets, as well as the condition for gap formation in the disk. These planetary gaps provide an important link to future observations of circumstellar disks. Show less
Adoptive transfer of T-cells that are ex vivo selected for tumor-specificity is an attractive treatment strategy for cancer. Epstein Barr virus (EBV)-associated malignancies are ideal candidates to... Show moreAdoptive transfer of T-cells that are ex vivo selected for tumor-specificity is an attractive treatment strategy for cancer. Epstein Barr virus (EBV)-associated malignancies are ideal candidates to develop this type of immunotherapy as EBV-specific T-cells can readily be selected and expanded from peripheral blood of EBV-seropositive individuals. The first part of thesis describes a phase 1 clinical study which demonstrates the feasibility and safety of this approach in patients with advanced stage EBV-positive nasopharyngeal carcinoma. Unfortunately only a small number of cancers express viral antigens that are easily recognized by the immune system. Therefore a strategy is required to generate large numbers of T-cells specific for antigens that normally elicit no or only a weak immune response. In the second part of this thesis a method is described of engrafting T-cells with the required specificity using retroviral transfer of T-cell receptors (TCRs). The TCRs were further modified to incorporate costimulation signals (CD28, OX40) that are essential to initiate and sustain an effective anti-tumor response but are often lacking on the target tumor cells. Finally, an inducible safety switch was developed that allows for the ablation of the infused T-cells in vivo in case of toxicity, which will facilitate the implementation of these novel immunotherapy approaches in clinical studies. Show less
Chapter I (Introduction) starts with an orientation on problems caused by the co-existence of a confusing number of Orders of St. John, all basing their lineage on the original Order, formed around... Show moreChapter I (Introduction) starts with an orientation on problems caused by the co-existence of a confusing number of Orders of St. John, all basing their lineage on the original Order, formed around 1050, which would never have ended. The much energy consuming issue of recognised versus false Orders of St. John seems mainly caused because Alliance Orders donot allow other organisations of St. John to connect on equal footing to the charitable conceptof St. John, as developed since the late 19th century, harking back to the romanticised idealistic starting phase in the 11th century, when Amalfi merchants founded the originalOrder of St. John. The issues appear to be not purely academic, because in various countrieslaw suits were and are being conducted about them. Chapter I then goes into the subject of the study more closely, i.e. how to determine whenan Order of St. John has a legitimate character. In this context, a number of observations isnecessarily devoted to the important, but difficult subject of legitimacy. Hereafter, a number of questions of an historical-legal nature are formulated and a status quaestionis is provided. The issues appear to have been studied more or less by various authors, but not always systematically, while also more than once polemic treatment seems to occur. For these reasons, but also and mainly out of pure scientific curiosity, the authordeemed it necessary to prepare this study. It is hoped it will be regarded as an objectivecontribution and a responsible attempt to a more scientific debate, as well as a helping hand to those who, in whatsoever capacity, might be called upon to determine the legitimacy of anOrder of St. John. The method used is historical/critical-legal, as well as inductive, in which context an Order, qualified by many as an important false Order of St. John, was selected as departure point. Chapters II (A critical look at the historical developments) through VIII (Sixth phase (1940-2004): several Orders disputing each other’s legitimacy; the creation of The International Alliance of Orders Of St. John), contain a critical historical/legal analysis of developments inthe history of the original Order, respectively of the phenomenon of Orders of St. John,deemed of importance for this study. This history is subdivided into six more or less traditional phases. In this context, connected to the above indicated historical developments in each phase, various remarks are made and knowledge and insight are gained, which are ofimportance for the later responding to the research questions put in Chapter I. Chapter IX (Chivalric definitions) discusses some definitions of a chivalric Order which weredeveloped in the literature. Attention is also drawn to some international developments inthis context. Also some case-law and legislation is discussed. Chapter X (The organisation of the original Order) sketches the main lines of theorganisation of the original Order, i.e. the Order of St. John founded around 1050 and whichin the author’s view at any rate ended in the late 18th century. In Chapters XI (Discussion of some important contemporary Orders of St. John) throughXV (The Sovereign Military Order of Malta), a number of leading contemporary Orders of St. 2 John, i.e. the most important Alliance Orders and their statutes and by-laws, are discussed in the light of the previous chapters and the knowledge and insights gained there. In Chapter XVI (The legal nature and organisation of The Ecumenical Order), the legalnature and organisation of the above indicated socalled false specimen-Order of St. John and its statutes and by-laws, are discussed. In Chapter XVII (The specificity of an Order of St. John), the specificity (the own nature ofan Order of St. John), is discussed, also in the light of a comparison of Orders of St. John with some important service organisations, such as Rotary and Lions and with the important spiritual movement of Freemasonry. Chapter XVIII (Some competition law aspects) contains some remarks about variouscompetition law aspects, connected to actions in the framework of the phenomenon Ordersof St. John and also summarily discusses some case law. On the basis of the foregoing, Chapter XIX (Development of legitimacy criteria andresponding to questions), discusses a number of criteria put forward in the literature and onthat basis, three categories of legitimacy criteria are found, with which one might try todetermine the legitimacy of recognised as well as false Orders of St. John. In Chapter XX (Conclusions), the questions raised are answered as much as possible and anumber of specific and supplemental general conclusions from the research, are laid down.The outcome of the research appears to be of interest, not only to the specimen Orderselected, but also to other Orders of St. John and also otherwise. Sofar, the meaning of the notion ‘legitimacy’ with regard to the ‘historical self-image’ of the various Orders of St. John, was never really systematically charted. This led to a bigconfusion of tongues. By legal-historical analysis and by using The Ecumenical Order as a case study, tools are provided to enable critical testing of the criteria applied by various Orders of St. John with regard to their legitimacy claims and to pierce possible myth building. Through this, the author hopes to have developed an instrument which may be ofuse to researchers and others to better determine the legal-historical aspects and legitimacy claims of these para-religious ‘chivalric Orders’ and similar associations, such as Freemasonry, so that testing, inter alia to operative law in The Netherlands and elsewhere, is better enabled. At any rate it is useful to clearly state the author wanted to deal primarily with the legal aspects of this much more encompassing 19th and 20th century cultural phenomenon. Show less
The muscular dystrophies are a group of neuromuscular disorders characterized by progres_sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular... Show moreThe muscular dystrophies are a group of neuromuscular disorders characterized by progres_sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are not yet clear. Furthermore, the muscular dystrophies differ in clinical presentation and severity. The processes responsible for this di_vergence are largely unknown as well. In this thesis, gene expression profiling has been applied to study the molecular and cellular mechanisms and subsequent biological processes that play a role in muscular dystrophy. To characterize the processes associated with regeneration, we have compared gene expression levels in hindlimb muscle tissue of mdx and control mice in a temporal study. Additionally, we have determined the gene expression profiles of dif_ferentiating human myoblasts in vitro, since regeneration processes recapitulate myogenesis. We also set out to compare gene expression levels of different mouse models for muscular dystrophy to find common and distinct molecular mechanisms that underlie different forms of muscular dystrophy. Accordingly, we first had to determine the effects of genetic background variation between inbred mouse strains, and to study the feasibility of alternative experimental designs. Show less
Complex traits are caused by multiple genetic and environmental factors, and are therefore difficult to study compared with simple Mendelian diseases. The modes of inheritance of Mendelian diseases... Show moreComplex traits are caused by multiple genetic and environmental factors, and are therefore difficult to study compared with simple Mendelian diseases. The modes of inheritance of Mendelian diseases are often known. Methods to dissect such diseases are well described in literature. For complex genetic traits, the inheritance pattern is not clear and difficult to understand, and genetic variants contributing to such traits probably have small effect sizes. Hence, searching for genes responsible for complex traits requires different strategies searching for genes responsible for complex traits requires different strategies as well as new methods. A common strategy for mapping complex traits is as follows: (1) perform a genome-wide linkage analysis using dense genetic markers, and identify regions showing evidence of linkage, then (2) perform association analysis to refine these regions. Along these lines we propose several methods for detecting disease genes. Show less
Modern compilers implement a number of optimization switches and they must be configured carefully in order to obtain the best performance. However, there exist few strategies to configure these... Show moreModern compilers implement a number of optimization switches and they must be configured carefully in order to obtain the best performance. However, there exist few strategies to configure these compiler switches or flags. This is caused by the fact that the performance of a code is both dependent on the target architecture and the application. Additionally, the effect of the compiler optimizations is highly dependent on other compiler optimizations which are employed, causing the actual effect to be masked and not predictable. In this thesis, we propose to use statistical analysis to determine the effectiveness of the compiler optimizations. This enables us to construct systematic methodologies for determining settings of compiler optimizations automatically. The proposed methodologies are all independent from the implementation of compilers and implementation of applications, therefore, it is easy to apply our methodologies to any combination of compilers and applications. This versatility makes our results unique compared to other approaches. Additionally, with our methodologies, users can choose their optimization objective, for example, execution time or code size, etc. From the results shown in this thesis, we can concluded that the statistical tuning of compiler optimization is both possible and useful. Show less
The main objective of this research was to increase our knowledge of the pathological mechanisms underlying LGMD 2B, to better characterize each member of the dysferlin complex and, more... Show moreThe main objective of this research was to increase our knowledge of the pathological mechanisms underlying LGMD 2B, to better characterize each member of the dysferlin complex and, more importantly, to try to identify potential modifier genes that might modulate the clinical course in patients. In chapter 2, by diverse selection methodologies on different truncated forms of recombinant dysferlin, VHH antibody fragments with specificity for two different dysferlin domains were selected from a non-immune phage display library. The selected llama antibody fragments are functional in Western blotting, immunofluorescence microscopy and immunoprecipitation. Using these antibody fragments, we found that CAPN3, which shows a secondary reduction in the dysferlinopathies, interacts with dysferlin.In order to gain functional insight into the molecular mechanisms of dysferlin, we have searched for yet unknown proteins that interact with dysferlin in skeletal muscle. By co-immunoprecipitation coupled to mass spectrometry, we demonstrated that dysferlin interacts with AHNAK. Furthermore, the binding domains in dysferlin and AHNAK were mapped and the AHNAK expression in normal skeletal muscle dysferlinopathy was assessed by immonofluorescence analysis (Chapter 3).Chapter 4 describes the proteolysis of AHNAK by CAPN3. Direct interaction of AHNAK and CAPN3 was studied by GST-pull down assay and specific AHNAK domains that were cleaved by CAPN3 were identified in a cell model. The biological relevance of this cleavage was also studied at cellular level.Finally, in chapter 5 the selection strategies of antibody phage display and the biomedical application of VHH will be discussed. This chapter will mainly focus on the role of dysferlin complex in LGMD 2B and future perspectives will be discussed in this chapter. Show less
The main objective of this thesis is to provide a conceptual framework for the use of Central Nervous System (CNS) biomarkers in early phase clinical drug development. In the Introduction the... Show moreThe main objective of this thesis is to provide a conceptual framework for the use of Central Nervous System (CNS) biomarkers in early phase clinical drug development. In the Introduction the current use of biomarkers in early CNS drug development is discussed. A conceptual framework for the classification of biomarkers is suggested, based on general questions that these markers should provide information on. The body of this thesis (Chapters 1-7) exemplifies the use of these markers within this conceptual framework. In the Conclusions and Discussion a critical evaluation of the presented conceptual biomarker framework is give and directions for future biomarker research are offered. Show less
Feature Network Models (FNM) are graphical structures that represent proximity data in a discrete space with the use of features. A statistical inference theory is introduced, based on the... Show moreFeature Network Models (FNM) are graphical structures that represent proximity data in a discrete space with the use of features. A statistical inference theory is introduced, based on the additivity properties of networks and the linear regression framework. Considering features as predictor variables leads in a natural way to a univariate multiple regression problem with positivity restrictions on the parameters, which represent edge lengths in the network representation. Theoretical standard errors and confidence intervals are obtained for the parameters and their performance is evaluated by Monte Carlo simulation. When the feature structure is not known in advance, a strategy is proposed to select an adequate subset of features that takes into account a good compromise between model fit and model complexity using Gray codes and the positive lasso. The same statistical inference theory also holds for additive trees that are special cases of FNM. Standard errors and confidence intervals, model tests and prediction error are obtained for the estimates of the branch lengths of additive trees. The dissertation concludes by demonstrating that there exists a universal network representation of city-block models based on key elements of the network representation consisting of betweenness, metric segmental additivity and internal nodes. Show less
Arnold, Ingrid Antonette; Waal, Margaretha Wilhelmina Maria de 2006
De huisarts ziet veel patienten met onverklaarde lichamelijke klachten, vaak in combinatie met angst- en depressieve klachten. Dit proefschrift beschrijft de resultaten van een prevalentie studie... Show moreDe huisarts ziet veel patienten met onverklaarde lichamelijke klachten, vaak in combinatie met angst- en depressieve klachten. Dit proefschrift beschrijft de resultaten van een prevalentie studie met een prospectieve follow-up en een daarop volgende behandelstudie. De prevalentie van somatoforme stoornissen (DSM-IV) was 16,1%: één op de zes patienten die de huisarts bezoekt had tenminste zes maanden last van onverklaarde lichamelijk klachten met aanzienlijke beperkingen. De overlap met angst en depressie was substantieel en vergrootte de ernst van de ziektelast. Deze bevindingen onderstrepen het belang van een brede diagnostiek in de huisartspraktijk die zowel angst en depressie als somatoforme stoornissen omvat. Het aantal symptomen, zowel lichamelijk als psychisch, kan een nuttig instrument zijn bij het identificeren van de ernstigste patiënten. Het gegeven dat bijna driekwart van alle patiënten met een somatoforme stoornis langdurig klachten houdt impliceert een grote behoefte aan behandeling. In een gecontroleerde behandelstudie konden we echter niet aantonen dat een cognitief-gedragsmatige interventie volgens het gevolgenmodel door getrainde huisartsen effectiever was dan gebruikelijke zorg. Aangezien de behandelde patiënten vaak ernstige klachten hadden stellen de auteurs voor om een stapsgewijze behandelmethode te ontwikkelen zodat zowel kortdurende als chronische klachten goed aangepakt kunnen worden. Show less
