We present a framework for automata theoretic model checking of coordination systems specified in Reo coordination language. To this goal, we introduce Buchi automata of records (BAR) and their... Show moreWe present a framework for automata theoretic model checking of coordination systems specified in Reo coordination language. To this goal, we introduce Buchi automata of records (BAR) and their augmented version (ABAR) as an operational modeling formalism that covers several intended forms of behavior of Reo connectors, such as fairness, I/O synchronization, and context dependency. To specify the properties to be verified, we introduce an action based linear temporal logic, interpreted over the executions of augmented Buchi automata of records, and show how the formulas can be translated into ABARs. This translation can be done either inductively, or by using an on-the-fly method. To deal with the large state spaces, we show that ABARs can be implemented using ordered binary decision diagrams (OBDD). For this purpose, we also introduce the necessary modifications over the basic model checking algorithm that can be applied directly over OBDD structures. Our implementation and a number of case studies that we carried out show the applicability of our method over large state spaces. We also show that the state explosion problem can be tackled by compositional minimization methods using some suitable equivalence relations. In fact, we show two equivalences that are congruencies with respect to the connector composition operators and such that they both preserves linear time temporal logic properties. Show less
Recent studies have suggested that the fetus is capable of exhibiting a stress response to intrauterine needling, resulting in alterations in fetal stress hormone levels. Intrauterine transfusions... Show moreRecent studies have suggested that the fetus is capable of exhibiting a stress response to intrauterine needling, resulting in alterations in fetal stress hormone levels. Intrauterine transfusions are performed by inserting a needle either in the umbilical cord root at the placental surface (PCI), or in the intrahepatic portion of the umbilical vein (IHV). Aim of our study was to test the hypothesis that fetal hormonal changes during intrauterine transfusion are more pronounced when the needle is inserted in the fetal abdomen. Furthermore we aimed to evaluate the effect of fetal analgesia with remifentanil on the fetal stress hormone changes. Exploring the hemodynamic changes following a noxious stimulus, we saw no differences in transfusions through the IHV or the PCI. Remifentanil did not influence the stress hormone changes. We concluded that the stress hormone changes are independent of both site of transfusion and the use of remifentanil. Our results do not confirm nor deny that the fetus is capable to react to a potential painful stimulus, or to show signs of stress or even pain. However, previous research has suggested that presumably painful fetal conditions can lead to alterations in stress reactions after birth. This phenomenon is called ‘fetal programming’. Fetal programming could possibly lead to life-long changes in stress responses and even to increased susceptibility for certain diseases. With the current understanding of fetal pain and fetal analgesia we would advocate the following: 1. Fetal analgesia for invasive procedures should be provided from at least 20 weeks gestation onwards 2. All invasive fetal procedures warrant fetal analgesia, but in procedures involving more than just a single puncture with a thin needle it is obligatory. 3. Analgesics should be given intravenously to the mother. The drug of choice should be ultra-short working (like remifentanil) therefore minimising possible undesirable side-effects to both fetus and mother. Show less
This thesis is about northerners within an urban setting in Ghana. It discusses the processes by which Alhaji Braimah, the unelected but recognised chief and spokesman of northerners in Accra, was... Show moreThis thesis is about northerners within an urban setting in Ghana. It discusses the processes by which Alhaji Braimah, the unelected but recognised chief and spokesman of northerners in Accra, was able to utilise British colonial urban policy in Accra to establish a community called Tudu. Tudu did not only become an urban space where northerners only lived but also engaged in economic activities- specifically transport and trade. The thesis therefore contributes to our understanding of the role of northerners in Accra and how northerners contributed to the economic development and physical establishment of Accra. The thesis combined the analysis of social relations, history and individual biography. This was made possible by focusing the discussion on one community (Tudu) and one social group (northerners), which were used as basis for both analysis and presentation. The field work and archival research on which the analysis was based was carried out in Tudu a sub-urban of Accra, Ghana between 2007-2009 and in the archives in Ghana and Britain in the same period. Show less
Humans have a long post-reproductive life span. In this thesis we study this post-reproductive life span from an evolutionary perspective. Why did humans evolve such a long post-reproductive life... Show moreHumans have a long post-reproductive life span. In this thesis we study this post-reproductive life span from an evolutionary perspective. Why did humans evolve such a long post-reproductive life span? We tested the hypothesis that men and women after age 50 are able to contribute to their fitness either direct by continued reproduction or indirect through improving the reproductive success of subsequent generations. In a prospective full kin analysis in the Upper East Region in Ghana, we studied the effect of different kin members on offspring production, survival and early growth patterns in a polygamous population that lives in an environment that could reflect our recent evolutionary past. We were able to confirm that post-reproductive survival in females indeed has a selective advantage. However, in this population, the advantage was not through increased survival of offspring as found by others, but through increased reproduction of their household. Also, we found that grandfathers, through continued reproduction up to high age created a selective pressure for old age survival. This direct effect was larger than the indirect effect of post-reproductive survival in women which could point to a more important role of men in the evolution of longevity than previously thought. Show less
Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterised by pain and disturbed blood flow, temperature regulation and motor control. Knowledge on CRPS... Show moreComplex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterised by pain and disturbed blood flow, temperature regulation and motor control. Knowledge on CRPS and its movement disorders is scarce. Dysfunction in small nerve fiber processing was found in CRPS patients with dystonia. Furthermore, a dominant pattern of fixed dystonia was observed in two thirds of arms and legs: finger flexion, wrist flexion, elbow flexion and/or shoulder adduction; and ankle plantar flexion/inversion, toe flexion, knee flexion and/or hip internal rotation. A modelling study demonstrated that aberrant force feedback from Golgi tendon organs may be a factor. Cerebrospinal fluid findings did not support a role of inflammatory mediators in chronic CRPS-related dystonia. Characteristics of CRPS-related myoclonus were diverse. One intrathecal administration of methylprednisolone was not efficacious in chronic CRPS. Also, continuous intrathecal glycine showed no efficacy in CRPS-related dystonia. However, intrathecal baclofen reduced severity of CRPS-related dystonia, improved quality of life and remained efficacious over a period of one year. The findings lend support to the role of GABA (gamma aminobutyric acid)-ergic mechanisms in this cause of dystonia. The findings stimulate new directions of research on this topic. Show less
Atherosclerosis is the major cause of death in the Western society due to the development of acute clinical events such as myocardial infarction and cerebral stroke. Currently, lowering plasma LDL... Show moreAtherosclerosis is the major cause of death in the Western society due to the development of acute clinical events such as myocardial infarction and cerebral stroke. Currently, lowering plasma LDL cholesterol (LDL-C) levels using statins, inhibitors of de-novo cholesterol synthesis, is the main therapeutic strategy to prevent the progression of atherosclerosis. The remaining high incidence of cardiovascular disease indicates a clear need for new therapies. Numerous epidemiological studies have established HDL cholesterol (HDL-C) levels as an inverse predictor for atherosclerosis. HDL has important anti-oxidative and anti-inflammatory properties. The most important atheroprotective function of HDL is, however, facilitation of reverse cholesterol transport (RCT), a process in which HDL removes excess cholesterol from peripheral tissues and subsequently delivers it to the liver for biliary excretion. In this thesis, the importance of RCT for prevention of atherosclerosis and the potential of RCT augmentation for the treatment of atherosclerosis were evaluated. Show less
The aim of the studies described in the thesis was to elucidate the roles of several neuro-exocytotic proteins at the motor nerve terminal in neuromuscular synaptic transmission, making use of... Show moreThe aim of the studies described in the thesis was to elucidate the roles of several neuro-exocytotic proteins at the motor nerve terminal in neuromuscular synaptic transmission, making use of genetic knockout (KO) mice, each missing one (or more) neuro-exocytotic proteins. In addition, it was investigated in a pharmacological mouse model for myasthenia gravis whether some of these proteins play a role in the phenomenon of compensatory upregulation of acetylcholine release at the neuromuscular junction in this disease. Show less
This thesis examines the attitude of the Hungarian Constitutional Court (“HCC”) and thePolish Constitutional Tribunal (“PCT”) towards EU law in their case-law. The predominantGerman legal influence... Show moreThis thesis examines the attitude of the Hungarian Constitutional Court (“HCC”) and thePolish Constitutional Tribunal (“PCT”) towards EU law in their case-law. The predominantGerman legal influence in the Central European region is explored from perspectives of legalhistory and culture in order to explain its enduring attraction. In order to provide theframework for the research, the case-law of the German Federal Constitutional Court(“FCC”) on the main principles comprehending the essential core of national sovereignty, thecontents of which are not susceptible to transfer or limitation, are set against theconstitutional requirements of EU law as enunciated by the European Court of Justice(“ECJ”) in its own foundational case-law. Such analysis thus provides the “German model,”by which the FCC has “negotiated” its position vis-à-vis the Union’s fundamental principles(e.g., primacy, direct effect, priority of ECJ rulings) which the ECJ has developed through itsjudgments. In pursuing this research, the decision-making of the two Central European courts isconsidered in the light of the putative influence of the German model. The increasingly activeparticipation of the HCC and particularly the PCT in helping to negotiate the newconstitutional context of the Union, based post-Lisbon on the respect of nationalconstitutional identities in Art. 4(2) TEU, is explored. The multilayered judicial construct ofEurope still remains replete with recognition problems for which the research seeks tosuggest some limited and focused changes. Show less
The aim of this thesis is to address how integrin-mediated signaling regulates cellular processes that have profound effects on cell morphology, motility, cancer metastasis, and FN fibrillogenesis,... Show moreThe aim of this thesis is to address how integrin-mediated signaling regulates cellular processes that have profound effects on cell morphology, motility, cancer metastasis, and FN fibrillogenesis, and how these findings can be utilized for relevant medical purposes or advancement of drug discovery. Show less
Microparticles (MPs) have important physiological and pathological roles in blood coagulation, inflammation and tumor progression. In recent years MPs also have been recognized to participate in... Show moreMicroparticles (MPs) have important physiological and pathological roles in blood coagulation, inflammation and tumor progression. In recent years MPs also have been recognized to participate in important biological processes, such as in signaling and in the horizontal transfer of their specific proteins and mRNAs. However, studies of MPs have been hampered by the lack of methods for the sensitive detection and accurate quantification of MPs. Thus, we have developed a new methodology by using atomic force microscopy (AFM) and cryo-electron microscopy (cryo-EM) to detect, quantify and characterize MPs in plasma. We have shown that AFM detects 1000-fold more platelet derived-MPs than a conventional flow cytometry does. These MPs have diameters ranging from 10-475 nm with a peak at 67.5 nm, which is clearly far below the detection limit of flow cytometry. By using cryo-EM we found that the number of lipoprotein particles exceeds that of MPs or exosomes in plasma. We also demonstrated that by using immuno-magnetic beads selected subset of MPs could directly be captured/depleted from plasma and assessed for MP-associated tissue factor activity. In the future the measurement of MPs will perhaps serve as a diagnostic tool to identify and predict diseases, like cancer. Show less
Red blood cells (RBCs) are probably the most frequently used drug given to very preterm infants; more than 90% of infants with a birth weight <1000 grams receive one or more RBC transfusions.... Show moreRed blood cells (RBCs) are probably the most frequently used drug given to very preterm infants; more than 90% of infants with a birth weight <1000 grams receive one or more RBC transfusions. Except for reduction of the amount of blood drawn for laboratory tests and use of a single donor program, no measures have been shown to be an irrefutable safe way to reduce donor exposure. Preventative measures for anemia should be used to reduce the number of RBC transfusions needed. Alternatives for allogenic RBC transfusions, such as autologous RBC cord blood transfusion, should be further explored and implemented. A restrictive transfusion strategy does not seem harmful for the children in short term or long term outcome. Thrombocytopenia is also a frequently encountered problem in neonatal medicine with an increased risk for hemorrhage. Thrombocytopenia, irrespective of the severity, increases the incidence of intraventricular hemorrhage. A more restrictive platelet transfusion policy significantly reduces the number of infants receiving a platelet transfusion without a difference in occurrence of (severe) hemorrhage. We state that both for red blood cell and platelet transfusions in (premature) newborn infants, safe thresholds are still not established. Transfusions may have (late) detrimental effects. Safe thresholds for both erythrocytes and platelets need to be found by large prospective randomized trials focusing not only on the direct effects but also on the long-term effects. Show less
My PhD research focuses on the maser emission which occurs in different regions of the circumstellar envelopes (CSEs) of evolved stars and can be studied at high angular resolution using radio... Show moreMy PhD research focuses on the maser emission which occurs in different regions of the circumstellar envelopes (CSEs) of evolved stars and can be studied at high angular resolution using radio interferometers. These masers are useful probes of the dynamics and kinematics of the outflow from AGB stars. Moreover, the masers can be important tracers of the magnetic field strength and morphology at various distances from the central stars. It is expected that the magnetic field plays an important role in transforming spherically symmetric AGB stars into a-spherical PNe. Theoretical modeling indicated that magnetically collimated jets may be responsible for the formation of the a-spherical PNe. We performed polarimetric observations of the masers (OH, H2O and SiO) in different classes of evolved stars using several radio interferometers as well as single dish radio and sub-mm telescopes, to study the role of the magnetic field throughout the AGB evolution. Show less
In recent years, modulation of mRNA has emerged as a promising therapeutic tool. For instance, in the field of neuromuscular disorders therapeutic strategies are being developed for several... Show moreIn recent years, modulation of mRNA has emerged as a promising therapeutic tool. For instance, in the field of neuromuscular disorders therapeutic strategies are being developed for several diseases, including antisense oligonucleotide (AON) mediated exon skipping for Duchenne Muscular Dystrophy (DMD). DMD patients have no functional dystrophin protein and as a result muscle fibres are damaged upon contraction. Because of the extent and chronicity of the damage this leads to a detrimental inflammatory reaction and eventually to the replacement of muscle fibres by fibro-fatty tissue. With AON mediated exon skipping, a targeted exon is skipped during the pre-mRNA splicing process, resulting in a shorter but partially functional protein. In this thesis we describe studies comparing different AON backbone chemistries and different routes of administration, we describe a reliable method to measure exon skipping, as well as pre-clinical pharmacokinetic and pharmacodynamic studies. These studies have provided valuable data for the development of AON exon skipping, which is already in clinical trials. Finally, we describe a peptide that potentially homes to muscle tissue and a method to find such peptides. These peptides could increase the amount of AON delivered to the muscle and possible further improve exon skipping in the future. Show less
This thesis consists of two parts. In part I, we have demonstrated that preoperatively administrated systemic (neoadjuvant) therapy is a feasible treatment strategy in early stage breast cancer to... Show moreThis thesis consists of two parts. In part I, we have demonstrated that preoperatively administrated systemic (neoadjuvant) therapy is a feasible treatment strategy in early stage breast cancer to achieve improved surgical options and to assess tumor response. We also demonstrated that overexpression of the breast cancer stem cell marker aldehyde dehydrogenase-1 in early stage breast cancer patients is inversely associated with age and is of prognostic importance. In part II, we have demonstrated proof-of-principle of intraoperative tumor detection and image-guided tumor resection by using the novel technique of near-infrared fluorescence imaging. We have performed two clinical trials to optimize the use of indocyanine green as a near-infrared fluorescence lymphatic tracer for the sentinel lymph node procedure in breast cancer patients. Show less
The studies of this thesis provide empirical evidence that creativity is not a homogeneous concept; rather it reflects the interplay of separate, dissociable processes such as convergent and... Show moreThe studies of this thesis provide empirical evidence that creativity is not a homogeneous concept; rather it reflects the interplay of separate, dissociable processes such as convergent and divergent thinking (e.g., Guilford, 1967). The cognitive mechanism of these two processes is different, but not opposite as assumed by Eysenck (1993). The results suggest that divergent and convergent thinking are both related to dopamine, but to different degrees and in different ways. It was observed that eye-blink rate was predicting creative performance, which provides strong support for approaches that relate creativity to dopamine (Ashby et al., 1999). However, the obtained dissociation calls for a more differentiated approach that distinguishes between convergent and divergent processes and allows for tapping different creativity-dopamine functions. The findings of this thesis also suggest that convergent thinking induces a control state that emphasizes the top-down biasing of creative solutions and/or local competition between them, whereas divergent thinking is associated with reduced top-down control and/or local competition. Taken together, results of four studies presented in this thesis show that convergent and divergent thinking are not necessarily opposite but they are not the same either, and optimal performance in different types of creativity tasks requires different conditions. Show less
The stratum corneum (SC), the thin uppermost layer of the skin, consists of dead flattened skin cells (corneocytes) embedded in a lipid matrix. The lipid matrix is considered to play a crucial role... Show moreThe stratum corneum (SC), the thin uppermost layer of the skin, consists of dead flattened skin cells (corneocytes) embedded in a lipid matrix. The lipid matrix is considered to play a crucial role in the skin barrier function. It consists of ceramides (CER), cholesterol (CHOL) and free fatty acids (FFA) forming crystalline lipid lamellae. From studies with native SC and SC lipid models much information has been gained on the phase behavior of the SC lipid matrix. However, little is known about the correlation between SC lipid organization and the permeability of the SC. This is difficult to investigate using native SC, due to its complex structure. Therefore SC lipids were casted on a porous membrane, resulting in a lipid organization and lamellar orientation similar to that in SC. This lipid membrane is referred to as the stratum corneum substitute (SCS). The SCS can be used to perform diffusion studies. Therefore, when modifying the lipid composition and thus the lipid organization in the SCS, it is possible to study the relationship between lipid organization and permeability. The main objectives of this thesis are 1) to investigate the influence of lipid organization on the barrier function in the SCS and 2) to obtain insights in the molecular organization within the unit cell of the lamellar phases in SC. Show less
The Earth’s biodiversity is disappearing at an alarming rate in the last decades. Many species, including carnivores, are becoming endangered. The lion was one of the most widely distributed... Show moreThe Earth’s biodiversity is disappearing at an alarming rate in the last decades. Many species, including carnivores, are becoming endangered. The lion was one of the most widely distributed terrestrial mammals and is today restricted to Gir ecosystem in India and to more or less fragmented populations in sub-saharan Africa. The species is considered as Vulnerable on IUCN Red List. In West Africa, due to its small and fragmented populations, the species is listed as Regionally Endangered. While the species is widely studied in other parts of Africa, it is poorly known in West Africa. The threats to lions, their ecology and their behaviour have not been assessed in the context of this region. In order to fill this gap, this research aims at investigating the ecology of the lion population and conflicts with humans in a West African protected area: Pendjari Biosphere Reserve, Benin. Pendjari Biosphere Reserve is one of the best-managed protected areas in West Africa and is part of the two most promising Lion Conservation Units in the region. It covers about 5,000 km² and is composed of the Pendjari National Park, and the Pendjari and Konkombri hunting zones. Local populations surrounding the Pendjari Biosphere Reserve suffer from livestock depredation mainly by hyena (53.6% of attacks), baboon (24.8% of attacks) and lion (18% of attacks). Most attacks occur during the rainy season when wild prey are scattered and more difficult to hunt. The depredation level is relatively low compared to many other regions in Africa. However the losses are significant, as local populations live below the poverty line. Fortunately, despite these losses and the fear of carnivores, people tolerated conflicts. No retaliatory killing of predators was reported. This could be partly attributed to the social and cultural importance of carnivores. The low level of conflicts in Pendjari is confirmed by the absence of livestock in the diet of lions. In the relatively well protected Sudanian savannah area that Pendjari represents, buffalo is the most consumed species (50% of the prey biomass consumed). However, like in other areas of West and Central Africa, the lion diet is dominated by medium prey (61.7%) while large prey composed 38.2% of the diet. Similarly to what is observed across Africa, smaller prey such as oribi and duiker were avoided and relatively large prey such as waterbuck and hartebeest were preferred. The predominance of small prey in the diet is then due to the relative abundance of these prey and not to the small size of lion groups in the region. There are about 1.6 lions/100 km² in the Pendjari Biosphere Reserve. The mean lion group size is of 2.6 lions with a significantly higher group size in the park compared to that in hunting zones. The adult sex ratio of 1 male : 1.04 female is skewed towards males. The small group size could be linked to the low prey and lion densities in the area. The lion population is particularly vulnerable to trophy hunting both in hunting zones of Pendjari and hunting zones of Burkina Faso, as the park’s lion population plays the role of source population while the hunting zone lions represent the sink populations. The mean home range of lionesses (95% MCP: 200 ± 141 km²) is consistent with findings across Africa. Riparian forests, woodlands and dry forests were the preferred lion habitats during the dry season while grasslands and swamps were used according to their availability. The few available results showed that during the rainy season, when most of the reserve is flooded, lions preferred woodlands on hills and avoid grasslands and swamps. The study of the home range and the social structure of lions in Pendjari highlighted the need for a concerted management of Benin and Burkina Faso lion populations for better efficiency. In summary, when protected areas are safe enough, lion population ecology and behaviour are similar across Africa. The Pendjari lion population was increasing and did not represent a great threat to livestock and humans surrounding the reserve. The lion population remained vulnerable, however, mainly because of legal and illegal hunting and human encroachment from neighbouring reserves. The impact of hunting and human activities on the social structure need to be better investigated. To save the lion in the region of West Africa, efforts should be made to safeguard only protected areas but also their surrounding areas. Studies on other issues such as the impact of lion trophy hunting and the relationship between the different large predators will contribute to improve the status of lions and other predators in West Africa. Show less
This thesis focuses on primary school students’ mathematical ability in the Netherlands. Starting with a systematic research synthesis of performance outcomes of different mathematics programs in... Show moreThis thesis focuses on primary school students’ mathematical ability in the Netherlands. Starting with a systematic research synthesis of performance outcomes of different mathematics programs in Chapter 1, the remaining Chapters 2 to 7 report the results of six empirical studies. These studies address the determinants of students’ ability in the domain of arithmetic (addition, subtraction, multiplication, and division). Moreover, they can be said to cross the border between the academic fields of substantive (educational and cognitive) psychology on the one hand, and psychometrics on the other. Chapters 2 and 3 report on the results of secondary analyses on data collected for CITO’s national mathematics assessment in grade six (12-year-olds) focusing on the strategies students used to solve the problems. Chapters 4 and 5 aimed to more systematically investigate the distinction between mental and written solution strategies for solving division problems. Finally, Chapters 6 and 7 address the role of realistic contexts in mathematics problems, both for students in early grades as well as in grade six. The data analyzed in the empirical studies are complex, requiring advanced psychometric modeling. It is argued that latent variable models incorporating explanatory variables are appropriate to analyze data on solution strategies and performance. Show less
The intensifying need for scalable software has motivated modular development and using systems distributed over networks to implement large-scale applications. In Service-oriented Computing,... Show moreThe intensifying need for scalable software has motivated modular development and using systems distributed over networks to implement large-scale applications. In Service-oriented Computing, distributed services are composed to provide large-scale services with a specific functionality. In this way, reusability of existing services can be increased. However, due to the heterogeneity of distributed software systems, software composition is not easy and requires additional mechanisms to impose some form of a coordination on a distributed software system. Besides functional correctness, a composed service must satisfy various quantitative requirements for its clients, which are generically called its quality of service (QoS). Particularly, it is tricky to obtain the overall QoS of a composed service even if the QoS information of its constituent distributed services is given. In this thesis, we propose Stochastic Reo to specify software composition with QoS aspects and its compositional semantic models. They are also used as intermediate models to generate their corresponding stochastic models for practical analysis. Based on this, we have implemented the tool Reo2MC. Using Reo2MC, we have modeled and analyzed an industrial software, the ASK system. Its analysis results provided the best cost-effective resource utilization and some suggestions to improve the performance of the system. Show less
The SimpleX radiative transfer method is based on the interpretation of photons as particles interacting on a natural scale: the local mean free path. In our method, light is transported along the... Show moreThe SimpleX radiative transfer method is based on the interpretation of photons as particles interacting on a natural scale: the local mean free path. In our method, light is transported along the lines of an unstructured Delaunay mesh that encodes this natural distance and represents the physical medium. The SimpleX method is fast, highly adaptive and its computational cost does not scale with the number of sources. It is therefore well-suited for cosmological applications where it is essential to cover many orders of magnitude in resolution and where millions of sources can exist within a single simulation. We describe the code, its recent developments and apply it to several relevant astrophysical problems. In particular, we perform radiative transfer calculations of cosmological reionization and of the wind-wind interaction region of the Eta Carinae binary system. Show less
