Skeletal and cardiac muscle disorders are associated with substantial morbidity and mortality. Despite many improvements in the medical and surgical management of these disorders, development of... Show moreSkeletal and cardiac muscle disorders are associated with substantial morbidity and mortality. Despite many improvements in the medical and surgical management of these disorders, development of effective treatments has proven to be challenging. This is because of the limited suitability of existing experimental models for acquiring a thorough understanding of the mechanisms underlying skeletal and cardiac muscle diseases and the lack of efficiency and specificity of many of the currently available therapeutic interventions. Therefore, the aim of this thesis was to establish and use dedicated cellular models in combination with genetic interventions to study the biology of skeletal and cardiac muscles in healthy and diseased states and thereby identify potential targets for future therapeutic interventions. The experiments described in this thesis indeed emphasized the importance of cellular models for (i) elucidating the mechanisms underlying skeletal and cardiac muscle diseases and (ii) identification of novel therapeutic targets. This thesis also underlined the usefulness of viral vector-mediated gene transfer technology for development of biological assays and the evaluation of therapeutic targets. In conclusion, application of in vitro models in combination with genetic interventions can improve our understanding of skeletal and cardiac muscle diseases and aid development of new therapies for these disorders. Show less
Nature__s own building block, peptide/protein derived materials have been of great interest for supramolecular chemists. The amino acids in peptides/proteins are linked via amide bonds, which makes... Show moreNature__s own building block, peptide/protein derived materials have been of great interest for supramolecular chemists. The amino acids in peptides/proteins are linked via amide bonds, which makes them more stable against degradation as compared to other natural materials such as oligonucleotides. Peptides adopt a secondary structure which is determined by their amino acid sequence resulting in a structure with a specific fold like a beta sheet, a helix or a random coil conformation.These secondary structures can govern the supra-molecular structure of the macromolecule to achieve specific function. Peptides can be short, such as dipeptides or as long as a small protein, which are able to selfassemble into a designed nanostructure and thus providing a wide choice of biomaterials for a chemical biologist. In last decade, peptides have been shown to have great versatility and inherent high affinity for their target to carry out various functions which is the scope of this thesis presented here. Show less
This dissertation examines what network in the human brain is involved in the perception of prosody and whether activity within this network is modulated by the personality trait alexithymia. The... Show moreThis dissertation examines what network in the human brain is involved in the perception of prosody and whether activity within this network is modulated by the personality trait alexithymia. The first four chapters of this dissertation reveal that a bihemispheric network consisting of Heschl__s gyrus, the middle superior temporal gyrus, the posterior superior temporal gyrus and the pars opercularis of the inferior frontal gyrus is involved in the perception of emotional prosody. Furthermore, relative right hemispheric specialization for emotional prosody perception can be demonstrated but no hemispheric specialization can be found for linguistic prosody perception. Moreover, hemispheric specialization for emotional prosody perception seems to be driven by hemispheric specialization for non-prosody-specific acoustic dimensions of the speech signal, and not for abstract emotional processing. Additionally, automaticity of processing can be demonstrated for emotional prosody, particularly for anger, but not for emotional music. Last, alexithymia can indeed be demonstrated to modulate activity within the emotional prosody perception network, particularly at relatively early components of the emotional prosody perception pathway. This dissertation is of interest to neurolinguists, (neuro-)phoneticians, psychologists, cognitive neuroscientists, comparative biologists and neurologists specialized in aphasia Show less
For decades a large amount of research has dealt with membrane interactions of peptides and proteins as well as peptide-peptide interactions to understand the mechanisms of essential biological... Show moreFor decades a large amount of research has dealt with membrane interactions of peptides and proteins as well as peptide-peptide interactions to understand the mechanisms of essential biological processes such as protein-driven vesicle budding and fission, cell penetration and lysis by peptides, and of course protein-driven membrane fusion. The advance of these fields, in combination with recent progress in cell biology, has inspired chemists to mimic these biological processes with simple model systems. However, it becomes apparent that these model systems are more complex than initially thought and the lessons that were learned from natural systems can also be applied here. The work reported in this thesis applied and extended classical methods for the study of peptide-peptide and peptide-membrane interactions to study the properties of the fusogenic coiled-coil forming lipopeptides in different membrane model systems or in solution. Hypotheses were constructed and tested based on the current biochemical and biophysical models of natural membrane fusion. Taken together, the results reported here led to a new perspective on lipopeptide mediated vesicle fusion. Show less
The thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day... Show moreThe thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day of SXB administration. SXB was taken 2 times 3g per night for 5 consecutive nights. Both groups underwent 24-h blood sampling and many hormones (prolactin, Growth hormone, melatonin, ghrelin, leptin) were measured and compared before and during SXB treatment. A study using the golden standard on insuline sensitivity is decribed to compare insuline sensitivity between patients and controls, and between patients, before and during satisfactory SXB treatment. ANother study describes body and skintemperature differences between narcolepsy patients and controls. Another chapter describes a rarely described, common feature in narcolepsy, in which patients mistake the memory of a dream for a real experience. In another chapter describes that date of birth is not a risk factor for narcolepsy. Show less
Eta Carinae is one of the most massive and luminous binary systems known. Due to their luminosity both stars posses powerful stellar winds. These winds collide and the combination of their strength... Show moreEta Carinae is one of the most massive and luminous binary systems known. Due to their luminosity both stars posses powerful stellar winds. These winds collide and the combination of their strength and the orbital motion determines the 3D structure of the gas. The interaction of the ionizing photons emitted by the stars with the gas is the topic of this thesis. We use the SimpleX algorithm for radiative transfer to post process hydrodynamic simulations of the wind interaction in Eta Carinae. We show that SimpleX is suitable to investigate the ionization structure of colliding wind binaries. Knowing where the gas is ionized allows us to identify the areas where observed emission and absorption lines might form. This has important implications for several properties of the system, such as the line of sight and the physical parameters of the stars, such as the temperature or mass-loss rate. We also printed 3D models of the interaction region of the two winds and investigated the usage of 3D interactive figures in scientific publications. These tools not only allow for better visualization and understanding of the system, but are also of great help when presenting complex simulation results to non experts Show less
This PhD thesis is concerned with EU legislation facilitating the private enforcement of EU law, i.e. the enforcement of that law by private parties in legal proceedings before the courts of the... Show moreThis PhD thesis is concerned with EU legislation facilitating the private enforcement of EU law, i.e. the enforcement of that law by private parties in legal proceedings before the courts of the Member States. The relevant EU-level legislative developments in four fields of EU law are assessed in detail, namely those relating to public procurement law (in particular Procurement Remedies Directives 89/665 and 92/13), intellectual property law (in particular IPR Enforcement Directive 2004/48), consumer protection law (in particular Consumer Injunctions Directive 2009/22, Unfair Terms Directive 93/13 and Product Liability Directive 85/374) and competition law (in particular Article 101(2) TFEU and the recent Competition Damages Directive). These EU legal acts and related developments are analysed first separately and subsequently in a comparative and contextual manner. Specific attention is paid in this connection to the remedies and procedural provisions for private enforcement purposes that are to be made available to aggrieved private parties under the said legislation. In addition the concept of private enforcement generally and EU legislation on this subject-matter specifically are considered in a broader perspective. On this basis conclusions are drawn as to how, when and why the EU legislates to facilitate the private enforcement of EU law. Show less
The thesis deals with the question as to whether international organisations could be jointly responsible for violations of international law committed by peacekeepers deployed in a peacekeeping... Show moreThe thesis deals with the question as to whether international organisations could be jointly responsible for violations of international law committed by peacekeepers deployed in a peacekeeping operation. The study starts by exploring the development of the concept of peacekeeping operations and the relations between the UN and four specific regional organisations (NATO, EU, AU and ECOWAS) on the basis of the applicable dispositions of the UN Charter. This examination as well as the following analysis of relations among these organisations, illustrate the evolution of a division of labour and an increase of cooperation between the UN and these organisations. It justifies the formulation of a presumption that international organisations could be jointly responsible as well as the formulation of a new criterion of attribution (normative control). The case-studies of specific peacekeeping operations confirm that in certain circumstances the UN and regional organisations have to be considered jointly responsible. Show less
The studies performed in this thesis show that type 1 diabetes mellitus is characterized not only by insulin deficiency, but also by insulin resistance. Both hepatic and peripheral insulin... Show moreThe studies performed in this thesis show that type 1 diabetes mellitus is characterized not only by insulin deficiency, but also by insulin resistance. Both hepatic and peripheral insulin sensitivity were decreased in patients with type 1 diabetes mellitus, as well as inhibition of lipolysis. However, insulin resistance is not a fixed pathophysiological condition in type 1 diabetes. We demonstrated that a single night of partial sleep deprivation decreased insulin sensitivity by 14-20% in patients with type 1 diabetes and by 20-25% in healthy controls. These effects of partial sleep restriction could not be explained by a reduction of total slow wave sleep in patients with type 1 diabetes. Sleep duration is a determinant of insulin sensitivity, also in patients with diabetes. In addition, various aspects of diabetes could be linked to increased prevalence of sleep disturbances. Impaired sleep and type 1 diabetes might potentiate each other in some patients, thereby creating a negative vicious circle. Optimizing sleep duration and sleep quality could therefore be considered as a potential therapeutic target to improve metabolic control in patients with type 1 diabetes. Show less
Dit proefschrift onderzoekt de invloed van pro-inflammatoire cytokinen op de gevoeligheid van de mens voor mycobacteri_le infecties. Infecties met niet-tuberculeuze mycobacteri_n (NTM) komen zelden... Show moreDit proefschrift onderzoekt de invloed van pro-inflammatoire cytokinen op de gevoeligheid van de mens voor mycobacteri_le infecties. Infecties met niet-tuberculeuze mycobacteri_n (NTM) komen zelden voor. Omdat NTM sommige mensen ernstig en ook bij herhaling ziek maken, hebben wetenschappers zich lang afgevraagd of genetische afwijkingen daarbij een rol spelen. In de laatste vijftien jaar is dit vermoeden bevestigd. Wereldwijd zijn ruim 360 pati_nten met Mendelian Susceptibility to Mycobacterial Disease (MSMD) bekend. In dit proefschrift wordt NEMO defici_ntie voor het eerst aangemerkt als MSMD. Vervolgens legden wij het verband tussen het v__rkomen van mycobacteri_le infecties in jonge kinderen en variaties in IFNG en IL10. Ook onderzochten wij Cryopyrin Associated Periodic Syndrome (CAPS) waarbij een te hoge cytokine productie tot ontsteking leidt. Deze pati_nten bleken hun cytokine productie onvoldoende te kunnen verhogen na activatie van hun cellen. Dit bleek onafhankelijk van de IL-1_ antagonist Anakinra, een zeer effectief medicijn tegen deze ziekte, en daarom van IL-1_. Een zich steeds verder ontwikkelende medische wetenschap en toenemende hygi_ne zorgen ervoor dat immuundefici_nties slechts in gematigde vorm tot uiting komen. Tegelijkertijd blijven de meest ernstig zieke pati_nten nu veelal wel in leven. Deze pati_nten zijn een belangrijke bron van informatie over de werking van ons immuunsysteem. Show less
Fusion of lipid bilayers in cells facilitates the active transport of chemicals. Non-viral membrane fusion is regulated by a cascade of proteins as the process is highly regulated both in space and... Show moreFusion of lipid bilayers in cells facilitates the active transport of chemicals. Non-viral membrane fusion is regulated by a cascade of proteins as the process is highly regulated both in space and time. In eukaryotic cells, the so-called SNARE protein complex is at the heart of fusion. However, little is known about the actual mechanism at the molecular level. Inspired by the SNARE protein complex, our group previously developed a model system composed of a pair of lipidated complementary coiled coil peptides enabling targeted liposome-liposome fusion. This model system possesses all the key characteristics of membrane fusion similar to SNARE mediated fusion. The tetrameric coiled-coil of SNAREs is mimicked by a complementary pair of coiled coil forming peptides composed of three heptad repeat units (denoted __coil-E__ and __coil-K__). A flexible poly(ethylene glycol) spacer is conjugated to the N-terminus ensuring rotational freedom of the peptides. Lipidation warrants the anchoring of the peptides in the membrane by means of a phospholipid anchor (DOPE), mimicking the transmembrane domain of SNAREs. In order to develop future applications of this model system, the mechanism of membrane fusion needs to be studied in more detail and this has been the goal of this thesis. Show less
In this thesis, a number of observations are described in acromegaly patients with cured or biochemically well-controlled disease during long-term follow-up. These observations focus on the long... Show moreIn this thesis, a number of observations are described in acromegaly patients with cured or biochemically well-controlled disease during long-term follow-up. These observations focus on the long-term consequences of the disease on joints and bone. In addition, we investigated the role of the Growth Hormone (GH)/Insulin-like Growth Factor-1 (IGF-1) axis, including the possible effects of the exon 3 deleted GH receptor (d3-GHR) polymorphism, in patients with primary osteoarthritis (OA) that have serum IGF-1 levels within the normal range. Finally, we studied the long-term consequences of recombinant human GH (rhGH) replacement in GH Deficient (GHD) adults, focusing on the cardiovascular effects and the effects on bone in comparison to healthy controls. Show less
In recent years a flow of media reports about unsafe situations in operating rooms have reached the general public. Awareness of the importance of patient safety also reached politicians. The... Show moreIn recent years a flow of media reports about unsafe situations in operating rooms have reached the general public. Awareness of the importance of patient safety also reached politicians. The report by the Dutch inspectorate of health care __Risico__s minimaal invasieve chirurgie onderschat__ (Risks minimally invasive surgery underestimated) stressed that patient safety is especially at risk in Minimally Invasive Surgery. Therefore patient safety became a focus of research and quality improvement, also in minimally invasive surgery. The current thesis aimes to give insight into patient safety risk factors in minimally invasive surgery. Of all examined risk factors minimally invasive surgical skills appeared to be directly related to patient safety. Therefore special focus for training of these skills is necessary. Previous research has shown that during simulation training objective assessment of economy of movements and time is possible. However, until recently there was no way to objectively assess one of the most important surgical skills: tissue handling. The development of a force sensor has made it possible to measure interaction forces with artificial tissue. In this thesis the clinical implications of a force sensor and the need of this new technology within training of minimally invasive surgical skills is examined. Show less
In this thesis we showed the applicability of the zebrafish embryo as an alternative model for hepatotoxicity testing using analysis of mechanisms through toxicogenomics. By applying a variety of... Show moreIn this thesis we showed the applicability of the zebrafish embryo as an alternative model for hepatotoxicity testing using analysis of mechanisms through toxicogenomics. By applying a variety of toxicogenomics techniques, we were able to characterize specific responses. NGS revealed that hepatotoxicity-associated gene expression remains detectable even in non-tissue specific analysis in whole body zebrafish embryo homogenates. Gene and protein expression profiling resulted in identification of a set of marker genes that could be linked to pathways and processes, which are associated with a general hepatotoxic response. Application of markers will increase the throughput of the system. Finally, we showed that the zebrafish embryo model shares similarities with in vivo and in vitro models for hepatotoxicity, where the model has more commonality with the mouse in vivo and in vitro models than with the other models. The model has the advantages of the in vitro models with the biological complexicity of an in vivo response, and we anticipate that the zebrafish embryo can contribute to the 3R strategy by reducing, refining and replacing animal studies. Our observations support that this model can have added value in a tiered approach as a pre-screen for the detection of hepatotoxic potential of compounds. Show less
The Central Chadic languages are a diverse and fascinating collection of languages, spoken in Nigeria, Cameroon and Chad. The phonologies of these languages have intrigued linguists since they were... Show moreThe Central Chadic languages are a diverse and fascinating collection of languages, spoken in Nigeria, Cameroon and Chad. The phonologies of these languages have intrigued linguists since they were first studied, due to their minimal sets of phonemic vowels (sometimes only one), complex systems of vowel harmony, and extensive use of palatalized and labialized consonants. Analysis of these languages led to the proposal of phonemic units referred to as ‘prosodies’, which act on both vowels and consonants, allowing Central Chadic phonologies to be described in a neat and succinct way. This study looks at the diverse phonological systems found within Central Chadic, and reconstructs the phonological system of their ancestor language. This system is itself simple and succinct, and includes one phonemic prosody and just three phonemic vowels. The study describes the phonological processes that led from this system to the many phonological systems that are in use today, shedding light both on the history of the languages, and on issues in the analysis of these languages. Show less
The Ik language (Icé-tód), spoken in northeast Uganda, forms the Kuliak(Rub) subgroup along with So/Tepeth and Nyang’í. These latter two lectshave already succombed to assimilative pressures from... Show moreThe Ik language (Icé-tód), spoken in northeast Uganda, forms the Kuliak(Rub) subgroup along with So/Tepeth and Nyang’í. These latter two lectshave already succombed to assimilative pressures from neighboring Niloticpastoralists like the Karimojong, Turkana, and Pokot. Despite similarsociolinguistic circumstances, Ik has so far held up and still remains vital asthe mother-tongue of hundreds of young children. Since Ik is the lastmember of a waning subgroup, its documentation and description mayprovide key pieces to the puzzle of East African linguistic and ethnic prehistory. The complexity of this prehistory is embodied in Ik grammar which shows many traits shared with languages in both Afroasistic and Nilo- Saharan language families. And so a full grammatical treatment of Ik can shed some needed light on the classification of other language groups.To that end, this study offers a comprehensive but balanced grammatical analysis of Ik. It covers the basics of the Ik sociolinguistic milieu, genetic classification, phonology, morphology, syntax, and lexicon. Of particular typological interest are Ik’s unusual systems of vowel harmony, tone, and case, as well as the syntax of subordinate clauses, the grammaticalization of case in the verbal system, and sequential and simultaneous clause chains. Other fascinating topics include pre-pause devoicing, frozen prefixes, tensed modifiers, non-canonical passives, and an irrealis-realis modal distinction. Lastly, between the grammar and lexicon is provided a collection of five culturally relevant Ik texts as holistic examples of Ik in its natural context. Show less
This book explores chronologically, for the first time, the representation and redefinition of Indonesia__s regional cultures through recording media, from the introduction of the gramophone record... Show moreThis book explores chronologically, for the first time, the representation and redefinition of Indonesia__s regional cultures through recording media, from the introduction of the gramophone record through the current video compact disc (VCD) era, taking as case study the Minangkabau ethnic group. Based on extensive fieldwork and historical research, the author follows the Dutch East Indies colonial society__s initial encounter with recording media and the later adoption and social uses of various types of recording media among the Minangkabau of West Sumatra and its diaspora. The transformation of Minangkabau culture and identity that came with the extensive reproduction of Minangkabau cultural sounds on commercial recordings is examined. This transformation was facilitated by the West Sumatran recording industry, founded in the early 1970s along with the spread of the audio-cassette in Indonesia. The author describes the workings of the West Sumatran recording industry and how its products become the preferred medium of cultural expressions of the Minangkabau ethnic group to hold on to its identity and existence in the face of a changing world. The representations of Minangkabau culture in regional commercial recordings explored in this study demonstrate the use of recording media technology by a local society to contextualize and maintain the viability and existence of their culture and identity, whose features are changing, adaptive, and fluid Show less
Atopic Dermatitis (AD) is a frequent occurring inflammatory skin disease causing physical discomfort, social embarrassment and stress. This skin disease is characterized by decreased skin barrier... Show moreAtopic Dermatitis (AD) is a frequent occurring inflammatory skin disease causing physical discomfort, social embarrassment and stress. This skin disease is characterized by decreased skin barrier function and various other epidermal changes, as well as immunological changes. A decreased skin barrier function allows environmental factors such as allergens and pathogens to penetrate through the skin and evoke an immunological response, which in turn may negatively affect the skin barrier function. The skin barrier is composed of cornified keratinocytes, extracellular lipids and multiple proteins, including filaggrin. The discovery of mutations in the filaggrin gene as a major risk factor for development of AD has intensified research on this protein and its role in AD development, but its exact role in AD is still not clarified. This thesis describes the development of several reconstructed human skin equivalents (HSEs) which recapitulate various characteristics of AD. They display for example reduced filaggrin expression or alterations in epidermal characteristics due to the presence of AD-related inflammatory cytokines. These HSEs are a powerful tool that in the future might be used for screening purposes and/or development of new therapies for this life disabling skin disease. Show less
Why do certain incidents of serious violence end lethally whereas others do not? What role do personal characteristics of offenders and victims play and how do immediate situational factors... Show moreWhy do certain incidents of serious violence end lethally whereas others do not? What role do personal characteristics of offenders and victims play and how do immediate situational factors influence outcomes? So far, these questions have not been subjected to much empirical scrutiny in criminological studies. This study, conducted in the Netherlands, seeks to answer these questions by explicitly comparing violent events that ended lethally with those that ended non-lethally. By taking into account offenders’ and victims' personal characteristics as well as immediate situational factors, it offers a more complete understanding of differences in outcome. It shows that immediate situational factors contribute more significantly to the outcome of violent incidents than generally thought. The study also presents an overview of murder and manslaughter in the Netherlands and puts these figures into international perspective. A separate chapter compares different types of violent events. The findings provide crucial criminological insights which may also guide effor ts to reduce and prevent violent events from ending lethally in the future. Show less
With the development of sensing and data processing techniques, monitoring physical systems in the field with a sensor network is becoming a feasible option for many domains. Such monitoring... Show moreWith the development of sensing and data processing techniques, monitoring physical systems in the field with a sensor network is becoming a feasible option for many domains. Such monitoring systems are referred to as Structural Health Monitoring (SHM) systems. By definition, SHM is the process of implementing a damage detection and characterisation strategy for engineering structures, which involves data collection, damage-sensitive feature extraction and statistical analysis. Most of the SHM process can be addressed by techniques from the Data Mining domain, so I conduct this research by combining these two fields. The monitoring system employed in this research is a sensor network installed on a Dutch highway bridge, which aims to monitor dynamic health aspects of the bridge and its long-term degradation. I have explored the specific focus of each sensor type under multiple scales, and analysed the dependencies between sensor types. Based on landmarks and constraints, I have proposed a novel predefined pattern detection method to select traffic events for modal analysis. I have analysed the influence of temperature and traffic mass on natural frequencies, and verified that natural frequencies decrease with temperature increases, but the influence of traffic mass is weaker than that of temperature. Show less
