The growing interest in using zebrafish for genetic and functional dissection of malignancy and infection was highlighted by the second international workshop on Zebrafish Models of Cancer and the... Show moreThe growing interest in using zebrafish for genetic and functional dissection of malignancy and infection was highlighted by the second international workshop on Zebrafish Models of Cancer and the Immune Response in Spoleto, Italy ( July 20–22, 2009). The overarching theme of the state-of-the-art reports featured the unique suitability of zebrafish for in vivo monitoring of fundamental biologic and pathologic processes. For example, in vivo imaging was employed for the first demonstration of direct development of hematopoietic stem cells from hemogenic epithelium and for visualization of T-cell homing and interaction with thymic epithelial cells. In addition, in vivo monitoring was instrumental for developing disease models of solid tumors, leukemia, and of inflammatory conditions, and for assessing the efficacy of small molecule drugs under physiologic and pathologic conditions. The success of zebrafish small molecule screens was underscored by the identification of prostaglandin E2 (PGE2) as an efficient inducer of stem cell expansion that led to the initiation of the first human trial on the efficacy of PGE2 in bone marrow transplantation. Further, zebrafish models of infectious diseases such as tuberculosis have been established that are now amenable to high-throughput in vivo drug screens, a much-needed development in the fight against drug-resistant microorganisms. The success of this workshop and the rapidly growing field of cancer and the immune response in zebrafish have spawned follow-up meetings in Boston ( June 2010) and Edinburgh (2011). Show less
By calculating the linear response of packings of soft frictionless disks to quasistatic external perturbations, we investigate the critical scaling behavior of their elastic properties and... Show moreBy calculating the linear response of packings of soft frictionless disks to quasistatic external perturbations, we investigate the critical scaling behavior of their elastic properties and nonaffine deformations as a function of the distance to jamming. Averaged over an ensemble of similar packings, these systems are well described by elasticity, while in single packings we determine a diverging length scale ℓ∗ up to which the response of the system is dominated by the local packing disorder. This length scale, which we observe directly, diverges as 1/Δz, where Δz is the difference between contact number and its isostatic value, and appears to scale identically to the length scale which had been introduced earlier in the interpretation of the spectrum of vibrational modes. It governs the crossover from isostatic behavior at the small scale to continuum behavior at the large scale; indeed we identify this length scale with the coarse graining length needed to obtain a smooth stress field. We characterize the nonaffine displacements of the particles using the displacement angle distribution, a local measure for the amount of relative sliding, and analyze the connection between local relative displacements and the elastic moduli. Show less
Glycoconjugates (a carbohydrate connected to a lipid, protein or other carbohydrate) play a key role in great variety of biological processes. The synthesis of these constructs is tightly regulated... Show moreGlycoconjugates (a carbohydrate connected to a lipid, protein or other carbohydrate) play a key role in great variety of biological processes. The synthesis of these constructs is tightly regulated by enzymes. Defects in these enzymes may result in an impaired degradation of the glycoconjugate. Consequently, the levels of glycoconjugates are increased and this may eventually lead to storage disorders such as Gaucher disease. The research described in this thesis focuses on the synthesis of chemical tools (activity-based probes, ABPs) to study the enzymes involved in the degradation of glycoconjugates. Using these probes, it was demonstrated that the activity of peptide N-glycanase (the enzyme that is responsible for the hydrolysis of N-linked glycoproteins)inhibitors is determined by its reactive group. Furthermore, the activity-based protein profiling strategy was used to study degradation of glycosy lated proteins. It appeared that deglycosylation of O-GlcNAclated proteins is not a prerequisite for proteasomal degradation. To study beta-glucosidases (enzymes that catalyze the hydrolysis of O-glycosidic linkages), ABPs based on cyclophellitol have been developed. Especially fluorescently labeled probes bind efficiently and selectively to beta-glucosidases. These probes have been used to investigate Gaucher disease. Both wild-type and mutant forms of the enzyme could be labeled in vitro and in living cells which allowed rapid identification activity of this glucosidase. Show less
In this thesis we look at three counting problems connected to orders in number fields. First we study the probability that for a random polynomial f in Z[X] the ring Z[X]/f is the maximal order in... Show moreIn this thesis we look at three counting problems connected to orders in number fields. First we study the probability that for a random polynomial f in Z[X] the ring Z[X]/f is the maximal order in Q[X]/f. Connected to this is the probability that a random polynomial has a squarefree discriminant. The second counting problem counts the number of subrings within maximal orders. We know that the number of subrings of given index is finite. We determine bounds for the number of suborders in terms of the rank of the maximal order and the index of the suborder. Connected to this is a question from Manjul Bhargava on the number of suborders in quintic rings. The final problem deals with class groups. There are bounds known for the class number of a maximal order, and we use these bounds to bound the class number of general orders. Show less
So-called "extended techniques" have suffered a consistent lack of understanding from a theoretical, historical and practical point of view. Although most of them __ e.g. playing directly on the... Show moreSo-called "extended techniques" have suffered a consistent lack of understanding from a theoretical, historical and practical point of view. Although most of them __ e.g. playing directly on the strings, cluster- and glissando-techniques __ exist in a substantial part of the repertoire for the piano and have done so for more than a couple of centuries now, the use of the techniques on stage still sparks off negative reactions by audiences, composers, performers and tuners as well as owners of pianos. Any one-sided approach towards appreciation has proven to be inadequate: academic analyses do not succeed in handling the matter satisfactorily, endeavors by musicians to teach and advise on the "proper" use of the techniques have come short of applying an in-depth and a historically informed perspective. A comprehensive and exhaustive survey of the extended techniques as a whole can serve to alleviate the risk that the relevant repertoire sinks into oblivion, contributing to a reassessment of the subject, in turn benefitting contemporary professional performance practice, concert programming, composers__ interest and musical as well as music-historical education. The subject and its related terminology are scrutinized and (re)defined where necessary. The acoustical properties of the techniques are explained from the perspective of the performer to ensure proper insight in the way they produce sound. Over 16.000 compositions have been considered to write the history of improper piano playing, comparing manuscripts with first and subsequent editions of solo as well as chamber and concerto music, original compositions as well as transcriptions, from the "classical" as well as the "entertainment" sector. Original preparations collected by John Cage were tracked down and described in minute detail so that alternatives can be considered on the basis of professional information. Historical recordings as well as personal experiences and interviews with composers are used to pinpoint historical performance practices. To help the pianist prepare for concerts with the relevant repertoire, measurements of the internal layout of the most common grand pianos are listed in order to anticipate possible problems in advance. Show less
This Thesis deals with the design, synthesis and biological evaluation of peptide-based drugs. In chapters 1-4, the development of peptides derived from natural gluten which can serve as drugs to... Show moreThis Thesis deals with the design, synthesis and biological evaluation of peptide-based drugs. In chapters 1-4, the development of peptides derived from natural gluten which can serve as drugs to combat the symptoms of celiac disease is described. These symptoms are caused by a misdirected immune response towards dietary gluten in genetically predisposed individuals. Peptides which can inhibit this immune response possibly can be used as an addition to the gluten-free diet, which is the only therapy available today. In Chapters 5 and 6, the synthesis and biological evaluation analogs of the antibiotic peptide Gramicidin S is described. Gramicidin S is a naturally occurring antibiotic peptide. It is very effective against bacteria, but also exhibits toxicity towards human red blood cells which limits its use to topical applications. Analogs of this natural peptide may lead to efficient antibiotics which are broadly applicable. Show less
This research provides a novel, empirically tested, actionable theory of cluster innovativeness. Cluster innovativeness has for long been subject of research and resulting policy efforts. The... Show moreThis research provides a novel, empirically tested, actionable theory of cluster innovativeness. Cluster innovativeness has for long been subject of research and resulting policy efforts. The cluster's endowment with assets, such as specialized labor, firms, research institutes, existing regional networks and a specific culture are, among others, recognized as sources of innovativeness. While the asset structure of clusters as been subject to a variety of research efforts, the evidence on the "soft" factors remains largely anecdotal. This theory building effort aims at providing a comprehensive picture of the contributors to technology cluster innovativeness. In doing so, it applies a dynamic capability framework in combination with a dynamic, network-level research approach in across five European satellite navigation application clusters. It shows that cluster innovation capabilities not only exist, i.e. community building, strategic alignment, reconfiguration, opportunity recognition and networking, but also impact perceived cluster performance. In contrast, the cluster's asset base assumes rather a moderating role. These results and the research approach add to existing theories of regional innovativeness. Furthermore, the research strengthens the dynamic capability view by providing evidence on inter-organizational capabilities. Accordingly, cluster managers and policy makers should focus their activities on their cluster's capabilities in an ongoing optimization process. Show less
In this thesis, a configurable generalisation of some well-known distance measures is introduced. Parameters are given to use this metric in the area of law enforcement, but also molecular biology.... Show moreIn this thesis, a configurable generalisation of some well-known distance measures is introduced. Parameters are given to use this metric in the area of law enforcement, but also molecular biology. With a valid distance measure, it is possible to analyse data by using a dimension reduction technique. One of these techniques is analysed and extended. Show less
Chemotaxis, the process in which cells detect a concentration gradient of a specific substance, interpret that information, and subsequently initiate movement towards the source is an essential... Show moreChemotaxis, the process in which cells detect a concentration gradient of a specific substance, interpret that information, and subsequently initiate movement towards the source is an essential part of many biological phenomena. It___s central to the processes in wound healing, in immune defense and in the formation of a viable embryo. In this thesis I used the well characterized social amoeba Dictyostelium discoideum to investigate, in depth, the dynamics that govern the first steps in the detection of a chemical gradient. D. discoideum detects cyclic adenosine mono-phosphate (cAMP) by a special receptor protein, cAMP receptor 1 (cAR1). Inside the cell this receptor activates a G protein which subsequently initiates a complex signaling cascade. Using fluorescence single-molecule microscopy I investigated the movements of both cAR1 and its associated G protein. During chemotaxis both proteins show striking differences in mobility between the leading and trailing edge of the cell. Those differences are presumably key to our understanding of gradient sensing by cells that have been ignored in models so far. Show less
This thesis aspires to contribute to the study of change instigated by social engineering projects that were devised and executed by state elites upon targeted populations. Focusing on the Turkish... Show moreThis thesis aspires to contribute to the study of change instigated by social engineering projects that were devised and executed by state elites upon targeted populations. Focusing on the Turkish case of social engineering in the 1930s and 1940s, this thesis studies such a moment of change from a perspective that is alternative to and critical of the ‘modernization’ and ‘dependency’ paradigms. It focuses on the People’s House, an institution the Turkish state established in the 1930 and 40 with the direct aim to introduce the reforms to the population. More specifically, it is a case study of two provincial People’s Houses, their clientele and their activities. Finally, it focuses on three policies of the People’s Houses, i.e. women and villager related activities, and new forms of socialization in contrast to the old coffeehouse type of socialization. This study treats the resistance and accommodation to these p olicies by local social actors as productive for the shaping of new social identities, collective and personal, but also as indicative of the limits of a state that is otherwise considered the sole instigator of social change in the literature of the Turkish Republic. Show less
This dissertation presents a grammar of Khwarshi, a Nakh-Daghestanian language. The grammar is based on material collected by the author during fieldwork. The dissertation gives an overview of the... Show moreThis dissertation presents a grammar of Khwarshi, a Nakh-Daghestanian language. The grammar is based on material collected by the author during fieldwork. The dissertation gives an overview of the main aspects of the phonology, morphology, and syntax of the language. At the phonological level, a description of the system of vowels and consonants is given as well as of the secondary articulations: nasalization, palatalization, and pharyngealization. Khwarshi has several interesting morphological features including an elaborate system of up to 43 spatial cases, five noun genders which mark agreement between the Absolutive noun phrase and the verb, adjective, adverb, or postposition with the help of the gender affixes. Khwarshi is an ergative language with basic SOV word order and widespread use of non-finite verb forms. In the chapter on syntax, the main types of subordinate clauses such as relative, complement, and adverbial clauses are treated. Show less
Because of the disappointing progress that has been made in the last decades in survival in patients with head and neck cancer, existing therapy needs to be improved and/or new treatment needs to... Show moreBecause of the disappointing progress that has been made in the last decades in survival in patients with head and neck cancer, existing therapy needs to be improved and/or new treatment needs to be introduced. This thesis describes a new promising treatment, apoptin gene therapy. The scope of this study was to investigate the applicability of apoptin in head and neck squamous cell carcinoma (HNSCC). First, we assessed its potential in-vitro. Next, a suitable animal model was established, which was used for in-vivo experiments with apoptin. In chapter 2 we describe the results of apoptin treatment in a HNSCC cell line with a mutated p53 and the effect of over-expression of Bcl-xL on the outcome. Chapter 3 describes the synergistic effect of apoptin and irradiation in HNSCC both in radiation sensitive and in more radioresistant HNSCC cell lines. The applicability of an immune competent animal model for in-vivo research is described in chapter 4. The time needed to establish a useful oral squamous cell carcinoma in mice is assessed and immunological comparisons are made with human counterparts. In chapter 5 the tumorigenesis of the same carcinogenic immune competent model is investigated and characteristics are analyzed. The efficacy of the apoptin therapy in-vivo is described in chapter 6. This is done by looking into the effect of intratumoral injection of a constructed adenovirus expressing the apoptin protein. Finally, the data are critically discussed in chapter 7 in view of apoptin as a potential new anti-cancer therapy. Show less
This study contains a text edition of the Kidung Tantri Kĕdiri, a Middle-Javanese text from the Indonesian island of Bali. This text is an adaptation of the Old Javanese prose text Tantri Kāmandaka... Show moreThis study contains a text edition of the Kidung Tantri Kĕdiri, a Middle-Javanese text from the Indonesian island of Bali. This text is an adaptation of the Old Javanese prose text Tantri Kāmandaka, and as such it belongs to the world literature. The Tantri Kāmandaka is an Old Javanese version of the Pañcatantra. The text is translated into Modern Indonesian. Furthermore this book contains some discussions about the manuscripts and a comparison between this and the original in prose. Other aspects of the work are discussed as well. Show less
he creation of European Union agencies is arguably one of the most prominent institutional innovations at the EU level in recent history. Especially since the early 1990s, the EU and its member... Show morehe creation of European Union agencies is arguably one of the most prominent institutional innovations at the EU level in recent history. Especially since the early 1990s, the EU and its member states delegated a wide range of (semi-)regulatory, monitoring, and coordination tasks to a quickly growing number of agencies. Most existing research focuses on the creation of these agencies. As a result, we do not know much about how agencies develop after their creation. EU agencies are formally independent, but do they also behave autonomously in practice? How does actual autonomy vary across EU agencies and how does this affect the role these agencies play in the multi-level system of European governance? This study addresses these questions theoretically and empirically by comparing six EU agencies – the European Medicines Agency (EMEA), the European Food Safety Authority (EFSA), the European Environm ent Agency (EEA), the European Monitoring Centre for Racism and Xenophobia (EUMC), Europol and Eurojust. It shows how some of these agencies develop into relatively autonomous entities by acquiring a distinct organisational character and by generating support from actors in their environment, whereas other agencies do so to a much lesser extent or not at all. Show less
Parkinson__s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain... Show moreParkinson__s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain barrier (BBB) is a key player in the relationship between plasma and brain pharmacokinetics, the influences of disease states on BBB functionality in the various stages of the disease is important in order to judge on drug effects. This warrants a systems pharmacology approach to the development of novel drug treatments of Parkinson__s disease. Animal models of disease are an essential asset in this research. The research described in this thesis shows that the intracerebral rotenone rat model is a chronic and progressive animal model for Parkinson__s disease, displaying alpha-synuclein immunoreactivity and aggregation in several cases. The model has also shown that no changes were found in passive BBB permeability, nor in BBB transport modes of L-DOPA. However, a diseased condition was present as indicated by the clear effect of rotenone on the levels and elimination rates of DOPAC and HVA in brain that provided information on decreased dopamine concentrations at the diseased brain side. Altogether, it can be concluded that the intracerebral rotenone rat model is an animal model which is suitable as a tool in systems pharmacology research on Parkinson__s disease. Show less
