International Migration, Integration and Social Cohesion online publications
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Quadruplex structures in mobile DNA:Next-level regulation of transposable elements in the human genome
Get PDFQuadruplex structures, non-canonical DNA configurations, are central to the evolution and regulation of mobile genetic elements, such as transposable elements (TEs). These elements drive genetic diversity and adaptability, playing a significant role in neurogenomics by influencing neural complexity and plasticity. The objective of this thesis was to increase our understanding of the influence of TEs and their G4 structures on human gene expression, particularly in brain evolution, development, and health.Epigenetic mechanisms, particularly DNA methylation, are critical in modulating TE activity. KRAB-ZNF proteins work alongside these mechanisms to control TE activity, safeguarding genomic stability. This regulation is crucial in shaping 3D-DNA architecture, as the interplay of active and repressed chromatin regions influences spatial genome organization during critical stages of development. Genome-wide methylation assays in human embryonic stem cells and cortical organoids revealed that certain young TE subclasses lose repression through hypomethylation, becoming reactivated during early brain development.In addition, primate-specific TEs, particularly the G4-dense SVA elements, exhibit significant potential for forming G4 structures. Genome-wide tools and in vivo G4-specific antibody mapping have indicated that younger TE subtypes have a higher G4 potential, though G4 formation is tightly controlled and cell type-specific. Additionally, the interaction between SVA and ZNF91 highlights molecular mechanisms underlying intronic SVA insertions, contributing to disorders such as X-linked dystonia parkinsonism (XDP), where an SVA insertion in TAF1 disrupts transcription.This work advances understanding of human cortical development and demonstrates that many young TEs contribute secondary DNA structures to gene regulatory networks
Patient prognostication and long-term survival in resected pancreatic ductal adenocarcinoma
Get PDFThe field of pancreatic cancer has undergone multiple evolutions and revolutions. The current landscape involves increased utilization of multiagent chemotherapies in the neoadjuvant setting, higher rate of resections of borderline and locally advanced disease, and more patients achieving long-term survival. Prognostication is critical to patient management and understanding long-term survival can provide important clinical insights. Historically, multiple prognostic factors have been identified in resected pancreatic cancer. However, neoadjuvant therapy could impact their prognostic relevance. It is critical to update current prognostic tools, so they remain applicable to current practice. Part II of this thesis demonstrates that the prognostic implication of historically established factors is altered after neoadjuvant therapy. Novel prognostic models that are applicable to both chemo-naïve and neoadjuvant therapy patients were developed for clinical use. In Part III, examination of long-term survivors demonstrated that historically established factors have a time-varying effect on survival, their presence does not preclude long-term survival, and currently our prediction remains modest. In Part IV it is demonstrated that biomarkers including circulating tumor cells and circulating tumor DNA show promise in improving prognostication and prediction of long-term survival. Lastly, Part V details the establishment of the PANC-PALS Consortium which is aimed at developing a global network of experts in the field to allow for large scale collaborative research efforts. In the cycle of evolutions and revolutions in the field hopefully work in this thesis will facilitate the next revolution that ushers in the era of biomarker-based precision medicine and improved patient outcomes in pancreatic cancer
To execute, rewrite, and debug:On the construction and deconstruction of computation
Get PDFCurrent discourses on computational media display a fascination with the linguistic, numeric, algorithmic, and material aspects of technology, from which several new domains of study have emerged in the past several years, including Software Studies, Digital Humanities, and Media Archeology, to name but a few. One can argue that these by now well-established programmatic ventures are symptomatic of a profound transformation taking place within the core epistemological apparatus of the Humanities: the fact that technology, rather than being a mere surrogate for the human body or the human mind, displaces and neutralises the sensible and the thinkable as it confronts age-old ways of sense making. This dissertation addresses this problematic by looking at the various epistemological ruptures and sutures that have transformed how we conceive of sense making from the late 19th century onwards. The dissertation’s main object is computation and its diverse historical moments, conceptual articulations, and artefacts. It directly addresses questions of language (logos) and its sense-effects in relation to mathematics, logic, proof theory, software execution and debugging, as well as works of modern literature. These questions are read and problematised through three types of idioms: onto-logic—asking the question “what is”—, logo-logic—asking the question “according to which rules”—, and finally deonto-logic—asking the question “what ought to be.” In turn, the question of sense is approached through a constructivist logic of action whose aim is to attend to the event and force of execution which necessarily exceeds any of its ensuing results
Rebels, renegades, and Robin Hoods:The social-hierarchical dynamics surrounding norm violators
Get PDFWhen studying the social-hierarchical dynamics surrounding norm violators it is important to consider both perceptions of power as well as people’s willingness to actually grant power to a norm violator. People often submit to others who appear powerful, therefore norm violators may inspire submission through their powerful appearance. However, perceptions of power do not necessarily translate into the voluntary granting of power. Instead, observers may put the norm violator back in place, as we observed in Chapter 2 when sanctions removed the apparent power that the norm violator initially seemed to have. Therefore, when studying the social-hierarchical dynamics surrounding norm violators, it is important to also consider people’s willingness to grant power to norm violators. The findings of Chapters 3 and 4 suggest that people who bluntly break norms are not granted power (e.g., in the form of obtaining a leadership position). However, norm benders and parochial norm abiders may be readily granted power if there is a cause for their disregard for the norm – be it in the form of situational demands (competition calls for a dominant leader) or in the form of situational constraints (it is not possible to abide by group norms without violating community norms)
The rise and fall of mesodiencephalic dopaminergic neurons:Molecular programming by transcription factors Engrailed 1, Pitx3, and Nkx2.9 during the development of mesodiencephalic neurons
Get PDFThe mid- and hindbrain harbor two essential monoaminergic neuronal populations: the mesodiencephalic dopaminergic (mdDA) neurons in the midbrain and the serotonergic (5HT) neurons in the hindbrain. Both systems innervate multiple regions in the forebrain and are involved in the guidance of our mood, motility and motivation guided behavior. The population of mdDA neurons can be divided in the substantia nigra (SNc) and the ventral tegmental area (VTA). An important difference between these dopaminergic nuclei is revealed during the evolution of Parkinson's Disease (PD). The mdDA neurons of the SNc are progressively lost, whereas the mdDA neurons of the VTA are (mostly) spared. The subsequent loss of dopaminergic signaling in the striatum results in tremors, rigidity and depression in patients suffering from PD.We investigate the origin story of the mdDA neuron in order to understand the mdDA system in the healthy, adult brain as well as in the adult brain during pathological conditions. We examined the molecular pathway of transcription factors Engrailed 1, Pitx3 and Nkx2.9, that are required to code mdDA neurons. Furthermore, we aimed to unravel the molecular coding that define the molecular and functional differences between SN and VTA neurons. Together this work contributes to the general knowledge of the developing mdDA neurons and the sensitivity to programmed cells death that characterizes the SN subset of mdDA neurons
Lifting the corporate veil: The responsibility of international organizations and their member states
No full textThis thesis aims to contribute to closing the responsibility gap in international law, which is characterized by a lack of remedies against international organizations and their member states. International courts and tribunals typically do not have jurisdiction to adjudicate claims against international organizations, which also enjoy far-reaching immunity before domestic courts. Member states are not held responsible for the acts of an international organization due to its separate international legal personality. Part I on ‘The Corporate Veil’ discusses the relationship between international organizations, their member states and third parties based on the concept of the corporate veil. In their internal relations with their member states, international organizations are agents of their members, which grant the organization autonomy through a constitutional framework. In their external relations with third parties, those internal relations are cloaked by a corporate veil, and the principal-agent relationship may be reversed. Part II applies the concept of the corporate veil to the determination of ‘Wrongfulness’ in the law of international responsibility. Based on the mutual agency relationships between international organizations and their members, it examines different rules and principles, as elaborated by the pertinent codification projects, that relate to situations of lifting and piercing the corporate veil of an international organization. Part III on ‘Responsibility’ considers the procedural and substantive remedies available to injured parties. The recognition that international organizations and their members regularly incur shared responsibility, based on their mutual agency relationships, is an important factor in understanding and increasing the remedial avenues for injured parties
Modulators of metabolism:Pathways to insulin resistance
Get PDFThe prevalence of obesity has increased worldwide the last several decades. Obesity is associated with complications such as type 2 diabetes, hypertension, and dyslipidemia, and as a result, obesity is associated with increased mortality. One of the major underlying mechanisms by which obesity leads to its complications is the development of insulin resistance, i.e. the diminished biological response to insulin. The only treatment modality that has been proven effective in the long term is bariatric surgery. In this thesis, we aimed to investigate some of the pathways and mechanisms that contribute to obesity-induced insulin resistance. In addition, we studied the effect of bariatric surgery-induced weight loss on some of these parameters as well as which clinical parameters predict the metabolic success of this type of surgery in the long term
Categories on the move:Governing refugees in transnational admission programmes to Germany
Get PDFIn light of record numbers of displaced people worldwide, surrounded by a rhetoric of crisis and limited resources, European states are redrawing boundaries of access and belonging. A timely example are recently introduced European resettlement and humanitarian admission programmes, admitting limited numbers of ‘particularly vulnerable’ refugees from countries of refuge. Categorisation practices are central in this process. In official policies and in daily frontline work, policy categories prioritise, include and exclude along the intersecting lines of inter alia nationality, gender, age or education. Thereby, they create inequalities and shape perceptions of who is most deserving of access or care, and who is considered undeserving or a risk. Taking Germany’s humanitarian admission programmes from Lebanon and Turkey as an example, the thesis follows categorisation practices throughout the complete transnational admission chain: from policy formulation in Germany, via refugee selection and pre-departure in countries of refuge, to refugee reception in German provinces and municipalities. Grounded in a triangulated methodology, including document analysis, interviews, and participant observations, the thesis reveals how categorisations get translated and transform from one institutional context to another, who gets prioritised at different steps in the process, and how actors normatively justify or contest categorisations and resulting inequalities. Fusing insights from Interpretive Policy Analysis, International Political Sociology and feminist theories of intersectionality, the thesis advances a dynamic and processual understanding of categorising, inclusion and exclusion. Moreover, it contributes to theorising the normative grammars actors deploy to justify categorisation practices and the inequalities they produce
Chronic visceral acid sphingomyelinase deficiency:Paving the way to biomarker development
No full textAcid sphingomyelinase deficiency (ASMD) is rare lysosomal storage disease in which sphingomyelin accumulates due to deficiency of the enzyme acid sphingomyelinase. ASMD covers a broad clinical spectrum with varying degrees of severity of which the chronic visceral subtype is the least severe. The most common manifestations of chronic visceral ASMD are hepatosplenomegaly and decreased diffusion capacity. Treatment in the form of enzyme replacement therapy (ERT) has recently become available. The aim of this thesis was to evaluate the current insights regarding imaging and biochemical markers of visceral ASMD manifestations, to use these insights to formulate recommendations for initiation of ERT and to investigate potential new markers for visceral manifestations of ASMD
Revolverende fondsen als overheidsfinancieringsinstrument:De beginselen van de democratische rechtsstaat getoetst
No full textDe overheid verstrekt op allerlei manieren geld om maatschappelijk relevante projecten van burgers en ondernemingen van de grond te krijgen. Een van die manieren is via een revolverend fonds. Anders dan bij een klassieke subsidie verstrekt een revolverend fonds leningen, garanties en deelnemingen, met als doel dat er geld terugvloeit naar het fonds. Idealiter kan hierdoor hetzelfde overheidsgeld meerdere keren worden ingezet: het geld revolveert.In dit proefschrift wordt onderzocht hoe de overheid revolverende fondsen juridisch vormgeeft en welke gevolgen deze vormgeving heeft voor de borging van de beginselen van de democratische rechtsstaat. Er worden hierbij concrete aanbevelingen geformuleerd voor de wetgever, het openbaar bestuur, revolverende fondsen en de rechter over hoe de beginselen van de democratische rechtsstaat optimaal kunnen worden beschermd bij de inzet van revolverende fondsen. Het proefschrift is daarmee waardevol voor iedereen die zich bezighoudt met de democratische rechtsstaat, het semipubliek ondernemingsrecht en het bestuursrecht, in het bijzonder het subsidierecht