Of the various biomolecular building blocks in use in nature, coiled-coil forming peptides are amongst those with the most potential as building blocks for the synthetic self-assembly of... Show moreOf the various biomolecular building blocks in use in nature, coiled-coil forming peptides are amongst those with the most potential as building blocks for the synthetic self-assembly of nanostructures. Native coiled coils have the ability to function in, and influence, complex systems composed of multiple building blocks. However, there have only been a limited number of synthetic coiled-coil assemblies that mimic native coiled coils by incorporating multiple assembling components. This thesis represents efforts at extending this aspect of coiled-coil self-assembly. In order to achieve this, a range of hybrid molecules were synthesized which combine coiled-coil peptides with a hydrophobic component. In this way the highly specific coiled-coil self-assembly is juxtaposed with the non-specific, but structure-inducing aggregation of the hydrophobic section. This thesis asked simple questions: can coiled coils function when covalently attached to large hydrophobic blocks? How large can the hydrophobic blocks be? Can coiled coils function when incorporated noncovalently with a supramolecular assembly? By answering these fundamental questions the possibilities of prescriptive self-assembly have been probed and expanded, novel preparative methods have been developed, and specific applications have arisen. Show less
The main subject of this thesis is pelvic pain in women in secondary and/or tertiary medical care. Studies aim to examine: 1. The clinical course of acute abdominal pain and risks of pain... Show moreThe main subject of this thesis is pelvic pain in women in secondary and/or tertiary medical care. Studies aim to examine: 1. The clinical course of acute abdominal pain and risks of pain persistence. 2. The clinical course of chronic pelvic pain (CPP) and predictors of recovery. 3. The moderating and /or mediating factors of sexual functioning. 4. The reliability of videotaped compared to real-time laparoscopic findings. Results show that pain persisted in 30% of women after an acute episode of abdominal pain. A low education level and an abuse history at a younger age were risks for chronicity. Recovery from pain was observed in 20% to 25% of women with CPP. Only a decrease in catastrophizing pain was associated with an improvement in pain and adjustment. Women with CPP reported more sexual problems than pain free controls. Anxiety and depression moderated sexual problems, while sexual abuse was a non-specific predictor. Finally, the evaluations of videotaped laparoscopies to score endometriosis were reliable, apart from ovarian lesions. In case of adhesions such evaluations were inconsistent. Main conclusion: CPP in women has to be considered as a chronic pain condition in general. A model to assess women with CPP and facilitate pain management is suggested. Show less
Results from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in... Show moreResults from this thesis have elucidated potential genetic markers, which were associated with treatment outcome to MTX and adalimumab. Furthermore, a model for predicting the efficacy of MTX in patients with RA was validated in two cohorts indicating that predicting efficacy by a pharmacogenetic model is feasible in RA patients treated with MTX. Importantly, definitive conclusions about the role of genetic predictive factors in treatment outcome to DMARDS could not be drawn, since these results have to be further validated and replicated in future pharmacogenetic studies. Large randomized prospective studies should be planned to demonstrate its legitimate predictive and cost-effective value before a genetically individualized approach is applicable in daily clinical practice. The potential role of pharmacogenetics in the prediction of efficacy and adverse events in RA patients treated with DMARDs is presented in this thesis. Hereby, new knowledge is added to the relatively young research field of pharmacogenetics, which may hopefully lead to a better treatment strategy for RA patients Show less
Although institutional care jeopardizes children’s development, some studies suggest that well-functioning child-care institutions may offer children a better environment than their own... Show moreAlthough institutional care jeopardizes children’s development, some studies suggest that well-functioning child-care institutions may offer children a better environment than their own dysfunctional families. For the growing number of HIV-infected children who often live in underprivileged families or institutions, comparative studies on their care arrangements are crucial. In her dissertation Natasha Dobrova-Krol examined the impact of institutional care and HIV-infection on several developmental domains of more than 60 Ukrainian preschoolers. Physical growth, stress regulation, cognitive and social development, as well as organization of attachment and children’s indiscriminately friendly behavior were addressed in this study. Developmental outcomes of HIV-infected children reared in disadvantaged families were compared with the outcomes of children reared in institutions providing adequate medical and physical care. In search for possible risk and protective factors in the development of the children individual characteristics and various aspects of the rearing environment were explored. The findings of this study demonstrated that institutional rearing impeded the development of children in all domains. Both for children with and without HIV family care, even of compromised quality, was better than institutional care, even of good quality. HIV-infection was found to be associated with less favorable outcomes in physical growth and cognitive development. The negative impact of institutional care, however, was larger than the presence of HIV. In three out of six developmental domains that were examined, HIV-infected children reared in disadvantaged families showed significantly better results than both HIV-infected and uninfected children reared in institutions, and no difference was found in the other domains. The quality of the child-caregiver relationship had a larger impact on children’s physical growth and cognitive performance than either HIV-infection or the quality of the physical environment and thus represents an important intervention target. The study has important implications for intervention efforts in child-care institutions. Show less
SMALL Savannah is an Environmental Information System designed for the integrated analysis and sustainable land management in the savannas region of the Far North of Cameroon. This system combines... Show moreSMALL Savannah is an Environmental Information System designed for the integrated analysis and sustainable land management in the savannas region of the Far North of Cameroon. This system combines an observation and spatial analysis module for the representation of phenomena from various geographic data sources, with a module for the explanation and prediction of land use pattern and changes, and a dynamic modelling and simulation module for the exploration of possible land use change trajectories. Due to a high demographic pressure combined with an increasing human mobility, many changes have occurred in the land use of the study area during the last two decades. These dynamics have led to land saturation resulting in more competition between land uses and conflicts between actors. The spatial and quantitative analysis for the observation period (1987-1999) indicates that accessibility to the main urban centre, soil suitability and population pressure, have been the main driving factors behind this process. According to assumption formulated for future development, it is expected that changes in land use of this area will continue to depend on these factors. But, the land use trajectories will be mainly influenced by the implication of urban actors and the potential investment of local actors for improving land quality and management. The simulations performed for the period 1999 to 2010 indicate areas where changes are likely to occur, thus providing a possibility to evaluate the spatial impact of a given land management policy. The information system under development is an appropriate tool for a regional monitoring system of land use change and rural development. It can be used by scientist and actors involved in land use planning for decision making and adaptive land use management. Another utilisation can be considered with local actors in order to discuss and prepare any concertation or negotiation when dealing with participatory approach of land use and management. Show less
Atherosclerosis is a chronic inflammatory disease of the vasculature in which both a disturbed lipid metabolism and inflammatory immune responses against several self-antigens are involved. In this... Show moreAtherosclerosis is a chronic inflammatory disease of the vasculature in which both a disturbed lipid metabolism and inflammatory immune responses against several self-antigens are involved. In this thesis we have explored the effectiveness of DC-immunotherapy in atherosclerosis. We have used different strategies to target the immune component in different stages of atherosclerosis. First we used DCs as a vaccination strategy to induce a protective antibody response trough the injection of oxLDL-pulsed DCs or to target NKT cells by the injection of OCH-pulsed DCs. Next we assessed the potential of DC-immunotherapy in a model of established atherosclerosis. We also evaluated the effects of a disturbed TGF-_ signaling in DCs and the subsequent effects on atherosclerosis by using ApoE-/- which have a dysfunctional TGF-__ Receptor II under the CD11c promoter. Next, we were interested in the effect of foam-cell formation on the antigen-presenting capacity of DCs and macrophages. Therefore we studied the effect of oxLDL-loading on antigen uptake and antigen presentation by DCs and macrophages. Finally, by depleting or inducing Tregs we investigated the potential role of regulatory T cells in a mouse model for aneurysm formation. Show less
We investigated the role of cortisol (an important stress-hormone) in the regulation of social fear and avoidance behavior in socially anxious individuals, which are characterized by extreme fear... Show moreWe investigated the role of cortisol (an important stress-hormone) in the regulation of social fear and avoidance behavior in socially anxious individuals, which are characterized by extreme fear and avoidance of social situations. Previous studies in animals and children showed a relation between increased fearfulness and avoidance and elevated cortisol levels, but the causal role of cortisol in these processes is not known. We found that, only in high socially anxious participants, cortisol administration or stress induction increased avoidance of social threat on an affect-evaluation computer task. Concurrent event-related potentials (brain activity measured with electrodes on the scalp) showed an associated increase in early processing of social threat. Another experiment indicated that the effects of cortisol on early threat processing are task dependent. We conclude that cortisol increases avoidance and facilitates or inhibits early processing of social threat in an adaptive manner, in line with the task goal. This effect is strongest in high anxious individuals, which are particularly sensitive to these threat signals. This knowledge can be relevant for the treatment of SAD, as cortisol levels may increase during exposure therapy, and also because cortisol administration has recently been proposed as a treatment for this disorder. Show less
Centraal in dit proefschrift staat het begrip interactie - wederzijds beinvloedend gedrag. In hedendaagse computersystemen speelt interactie een steeds belangrijker rol. Software wordt meer en meer... Show moreCentraal in dit proefschrift staat het begrip interactie - wederzijds beinvloedend gedrag. In hedendaagse computersystemen speelt interactie een steeds belangrijker rol. Software wordt meer en meer ontwikkeld als een verzameling zelfstandig werkende componenten die services aanbieden aan andere componenten. Iedere component kent een eigen "levenscyclus" - hij wordt ontwikkeld, doorontwikkeld, uitgebreid, gesplitst, samengevoegd, en weer weggegooid. Concrete toepassingen ontstaan doordat componenten worden samengesteld tot een groter geheel. Zulke toepassingen zijn alleen bruikbaar als er sprake is van zinvolle interactie tussen de componenten.De modelleertaal Paradigm, ontwikkeld aan het Leiden Institute of Advanced Computer Science (LIACS), is een taal die speciaal geschikt is voor het modelleren en analyseren van interactie. Een Paradigm-model beschrijft op een abstract niveau het gedrag van individuele componenten, de rollen die de componenten kunnen spelen in interactie met andere componenten, en de manier waarop die interactie tussen de rollen plaatsvindt. De taal heeft een aantal interessante eigenschappen, niet in de laatste plaats het feit dat het een executeerbare taal is: Paradigm-modellen kunnen door een computer worden uitgevoerd. Als bijzondere bijkomstigheid kunnen Paradigm-modellen zo worden ingericht dat ze zichzelf veranderen terwijl ze worden uitgevoerd - zo kunnen we ook de levenscyclus van componenten modelleren. Show less
The content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other... Show moreThe content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other part. The thesis starts with a systematic review of the literature about the growth of infants born preterm. Next, three specific methodological issues related to early origins of adult disease studies are addressed. A: the most favorable regression model for analyzing and interpreting the effect of both prenatal and subsequent postnatal growth on adult health outcomes. B: the efficiency of reliability studies in the context of a multi-centre study. And C: the correct and clear assessment of reliability in case of log transformed outcomes. These methods are used ind the second part, in which three topics about the effects of prenatal and early postnatal growth on adult health outcomes are addressed, namely: A the association between birth weight and adult renal function in non-premature subjects. B: The association between birth weight and the adult metabolic syndrome, and its separate components in the same population. And finally, C: the association between early growth and adult body composition in subjects born very preterm. Show less
Background: It is assumed that the endogenous subtype of depression is a form of depression with various biological abnormalities and a genetic predisposition. The clinical picture rarely shows... Show moreBackground: It is assumed that the endogenous subtype of depression is a form of depression with various biological abnormalities and a genetic predisposition. The clinical picture rarely shows prior stress and/or an abnormal personality. According to the DSM-IV, this subtype is reproduced as the melancholic subtype, but this subtype has insufficient external validity. This is mainly due to the specific operational method used in the categorical DSM system. Question: Reformulating the melancholic subtype by means of a multidimensional approach. This would be formulated and tested on different external validity levels, which should result in better external validity. An improvement at one level of investigation could lead to improvements in relation to other levels, and vice versa. The development of diagnostic concepts could therefore progress according to a cyclic validation process. For this reason, we also investigated whether a later-found subgroup with above-normal plasma AVP could be a more useful endophenotypic parameter as well. This subtype was also tested on different external validation levels. Results: We found a two-dimensionally based, highly anxious retarded subcategory, with better external validation criteria than the melancholic subtype. We also found a second subtype, namely above normal AVP depression, that also had better external validation criteria. Show less
The first half of this thesis describes the synthesis of several conformationally restricted alkylated and bicyclic sugar amino acids (SAAs). The second half of the thesis describes the application... Show moreThe first half of this thesis describes the synthesis of several conformationally restricted alkylated and bicyclic sugar amino acids (SAAs). The second half of the thesis describes the application of the SAAs and their intermediates presented in the first half, as components of tools applied for the probing of biological systems. Show less
Top-down guidance of behavior in a complex and dynamically changing world is often based on information held in working memory. Such guidance serves to bias decision-making processes in directions... Show moreTop-down guidance of behavior in a complex and dynamically changing world is often based on information held in working memory. Such guidance serves to bias decision-making processes in directions consistent with externally set rules or internally maintained intentions. Orthogonal to this goal-driven guidance, decisions may be biased also by stimulus-driven factors, such as the automatic reactivation of episodic associations that accompanied the current stimulus in a previous instance. We investigated whether top-down and bottom-up processes account for variation in context based decision making as measured by the AX-CPT in a behavioral [1] and fMRI study [2]. Moreover, several behavioural studies have indicated that transiently induced positive affect modulates control processes in context-based decision making, generally leading to enhanced flexibility. Using ERPs in a classic AX-CPT, we studied the temporal dynamics of a positive affect induction on control processes in context-based decision making [3]. Additionally, we studied learning the associations between a situation, the response to it, and the outcome of that decision and the effect of basal ganglia modulations on this learning process by means of a Parkinson’s patient study. Studies [1] and [2] pointed out that in decisions with rapidly changing environmental demands, goal-driven preparation is often beneficial but may also hamper performance which can be overcome by applying increased control. Moreover, this top-down bias is regulated more efficiently when the specific stimulus is presented in the same context it was previously associated with, compared to when it is presented in a new and unusual context. Additionally, fMRI study shed light on the way these stimulus-driven performance changes may be represented in the brain. Study [3] showed that a positive affect induction influenced reactive and evaluative components of control (indexed by the N2 elicited by the target, and by the Error-Related Negativity elicited after incorrect responses) in an AX-CPT task, whereas cue-induced preparation and maintenance processes remained largely unaffected (as reflected in the P3b and the Contingent Negative Variation components of the ERP). The patient studies suggest that moderate dopaminergic medication and STN stimulation in Parkinson’s patients [chapter 5,6] both improve learning functions relying on caudate and putamen. However, the improvement induced by dopaminergic medication largely depended on individual patient characteristics. Show less
In this thesis, the effect of information-processing overload on working-memory dependent information processing was examined using dual-task paradigms. The experiments described strengthen the... Show moreIn this thesis, the effect of information-processing overload on working-memory dependent information processing was examined using dual-task paradigms. The experiments described strengthen the importance of a functional explanation for dual-task limitations. First, it showed evidence for a unified coding medium (as put forward in the theory of event coding; Hommel, Müsseler, Aschersleben, & Prinz, 2001) in which features, operations and responses are available and can influence each other. Additionally, it was shown that the response to the first of two stimuli is facilitated in case the processes are compatible. Furthermore, it showed that the psychological refractory period and the attentional blink share limitations with respect to a common resource that originates in working memory operation span and that the use of individual differences can aid in examining the relation between the psychological refractory period and the attentional blink. Additionally, it showed that it is plausible that visual-spatial attention, mental rotation and response selection share limitations with respect to a common resource. Finally, research in this thesis showed that processes that can facilitate a response can be simultaneously implemented but not simultaneously executed. Show less
After experiencing distraction or temptation, people tend to be better able to cope with future conflict. In cognitive psychology, this is often shown by using sequential conflict tasks, such as... Show moreAfter experiencing distraction or temptation, people tend to be better able to cope with future conflict. In cognitive psychology, this is often shown by using sequential conflict tasks, such as the Stroop task, in which people are required to name the colour of the ink of a word, and ignore the word itself. After presentation of the word “red” in a green colour, for example, people show a smaller conflict effect if later shown the word “green” in a red colour. According to established theory, this is related to the working of executive control: initial conflict triggers increased attention (towards the colour instead of the word) or inhibition (of the word), thus making it easier to cope with repeated conflict. In this dissertation, I argue for a revision of this prominent theory towards a more memory based explanation of executive control. Instead of initial conflict working forward in time to affect the later task, the behavioural and psychophysiological experiments reported here show that the previous task is remembered due to the similarity with the current task, triggering similar modes of behaviour. Show less
Aim of the work is to illustrate a possible way of dealing with a regional landscape and its long-term settlement history based on the integration of archaeological data applying a GIS based... Show moreAim of the work is to illustrate a possible way of dealing with a regional landscape and its long-term settlement history based on the integration of archaeological data applying a GIS based approach to the social dimension of the landscape. The large province area (ca 2,500 sqkm) of Boeotia (Central Greece) is examined by means of GIS (Geographical Information System), processing data from different archaeological, historical and environmental sources. The methodology established, dealing jointly with material culture and the environment, follows a critical comparative regional approach and opts for both region and micro-regions as the analytical unit. It aims mainly to assess landscape characters and the interface between human and social actions and landscape by critically assessing, first of all, the available archaeological record constituted by diverse, variegate and often incoherent data sets. Main periods of interest are the historical periods from Archaic to Late Roman, while earlier (Neolithic to Geometric) and later periods are taken into account for the analysis and understanding of diachronical processes which took place at the micro-regional and regional levels. Show less
The increase in capabilities of information technology of the last decade has led to a large increase in the creation of raw data. Data mining, a form of computer guided, statistical data analysis,... Show moreThe increase in capabilities of information technology of the last decade has led to a large increase in the creation of raw data. Data mining, a form of computer guided, statistical data analysis, attempts to draw knowledge from these sources that is usable, human understandable and was previously unknown. One of the potential application domains is that of law enforcement. This thesis describes a number of efforts in this direction and reports on the results reached on the application of its resulting algorithms on actual police data. The usage of specifically tailored data mining algorithms is shown to have a great potential in this area, which forebodes a future where algorithmic assistance in "combating" crime will be a valuable asset. Show less
In 1659 startte Anthoni van Noordt, organist van de Nieuwe Zijdskapel te Amsterdam, voorbereidingen voor het publiceren van een Tabulatuurboeck. Dit boek met psalmen en fantasieën bedoeld voor het... Show moreIn 1659 startte Anthoni van Noordt, organist van de Nieuwe Zijdskapel te Amsterdam, voorbereidingen voor het publiceren van een Tabulatuurboeck. Dit boek met psalmen en fantasieën bedoeld voor het orgel, heeft nooit een grote oplage bereikt. Hoewel het een getuigenis is van muzikale creativiteit heeft het in eigen tijd en ook vandaag de dag slechts een kleine kring van specialisten bereikt. Van Noordt werd in 1664 organist van de Nieuwe kerk en bereikte zo de top van de muziekelite in metropool Amsterdam. Om dat beter te begrijpen is het culturele kapitaal van de zeventiende‐eeuwse Amsterdamse organisten – ook Sweelinck – onderzocht. Tevens is geanalyseerd hoe de orgelbouw zich in de periode 1630‐1675 ontwikkelde. Uit het onderzoek naar de orgelbespelingen – typisch fenomeen uit het publieke domein – dat nog nauwelijks in de cultuurhistorische literatuur aandacht heeft gekregen bleek dat het hier ging om voortzettingen van traditionele sociale evenementen, gericht op harmonie in de samenleving. Wat betreft het orgelrepertoire is opvallend dat er in die tijd geen strikte scheiding was tussen componeren en improviseren zoals vandaag de dag. Dat werpt nieuw zicht op de kwaliteit van het muziekleven in de 17e eeuw waardoor we muzikale ideeën kunnen reconstrueren die allang verdwenen zijn. De muziek uit het Tabulatuurboeck was enerzijds sterk bepaald door strenge regels voor de polyfonie, anderzijds komt een vrije en gedurfde benadering naar voren waarbij met een motivische schrijfwijze geavanceerde muzikale structuren zijn gebouwd. Deze muziek roept denotatieve betekenissen op die duidelijk maken dat de componist de affecten centraal stelde. Dat vraagt in de uitvoering om een hoge mate van expressiviteit. Deze dissertatie kan gezien worden als een uitbreiding van onze kennis over het orgelleven in Amsterdam in de Gouden Eeuw, tegelijk is het een pleidooi voor het uitvoeren van Van Noordts muziek op een meer expressieve wijze dan nu gebruikelijk. Show less
As a result of agricultural intensification, farmland bird populations have been declining dramatically over the past decades. Organic farming is often mentioned to be a possible solution to stop... Show moreAs a result of agricultural intensification, farmland bird populations have been declining dramatically over the past decades. Organic farming is often mentioned to be a possible solution to stop these declines. In order to see whether farmland birds really benefit from organic farming a study was carried out comparing breeding bird densities, breeding success and bird food abundance between organic and conventional arable farms in Flevoland, the Netherlands. skylark (Alauda arvensis) and lapwing were both found in higher densities on organic farms, but for other species no differences were found. Differences in skylark densities were caused by relative large areas of spring cereals grown on organic farms. Differences in lapwing densities were probably caused by higher food abundance and greater availability of suitable breeding habitat on organic farms. In contrast with the higher densities of breeding pairs, indications were found that breeding success of lapwings is lower on organically managed farms. This is a result of mainly mechanical weeding and other agricultural operations. Also for skylarks breeding on organic farms agricultural operations are the most important cause of nest failure. Greater food availability on organic farms might compensate for this high nest loss through higher chick survival rates. Show less
