International Migration, Integration and Social Cohesion online publications
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Complementing the factor H protein family:From assays to outcomes
Full text linkAs part of the European consortium SciFiMed (Screening for Inflammation to Initialize Personalized Medicine), this thesis addressed key challenges in studying the factor H (FH) protein family, with a particular focus on the FH-related (FHR) proteins. These challenges include longstanding controversies surrounding FHR protein function, the lack of consensus on their physiological concentrations, and the absence of standardized assays. In this thesis, we first developed highly specific reagents targeting individual FHR proteins and, together with SciFiMed partners, optimized and validated existing and novel immunoassays. This resulted in standardized, robust immunoassays enabling reliable and specific quantification of the entire FH protein family. These tools allowed us to resolve inconsistencies in reported protein concentrations and to further unravel the biological roles of the FHR proteins in physiological and complement-associated pathological contexts (cancer and age-related macular degeneration (AMD)). Next, using these assays, we further characterized the dynamics, kinetics and distribution of FHR-1 and FHR-2 dimers in a large cohort of healthy individuals and demonstrated how genetic variants influence their abundance. Moreover, we showed that the four most common CFH haplotypes in the European population give rise to distinct and classifiable protein expression profiles, establishing characteristic protein ratios between FH, FHL-1, and the FHRs. Finally, in a well-characterized cohort of patients with AMD, we showed a tissue-specific haplotype and disease-associated shift in protein concentrations, potentially explaining their strong association with this debilitating disease. Altogether, these findings highlight the significant role of the FHR proteins in fine-tuning complement regulation across different anatomical sites.</p
It takes a village to grow stronger:A socio-ecological model of resilience in refugees
Full text linkThe present dissertation explores the factors promoting refugees' resilience and complex relationship between these factors and resilience. This dissertation presents a breadth of methodology, using mixed-methods to study refugee resilience. Specifically, we started with an extensive and comprehensive systematic review to scope the literature on risk and protective factors of resilience in refugees. Then, we conducted qualitative interviews to explore refugees’ rich narratives of resilience, and finally, we ended with experimental studies to test causal relations and survey studies to model resilience and its associated factors. Findings from all of the studies conducted for this dissertation offer a multi-layered understanding of the nature of refugee resilience. Refugees’ resilience is determined by internal and external factors across four socio-ecological levels: individual, family, community, and society. This dissertation emphasizes that resilience is not merely an individual capacity, but a context-dependent process influenced by structural conditions and relational resources
Deep brain stimulation and cognition in managing motor fluctuations in Parkinson's disease
No full textParkinson’s disease (PD) is one of the fastest growing neurodegenerative disorders worldwide. Motor symptoms are initially managed with levodopa and adjunctive oral therapy, namely catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs), or monoamine oxidase B inhibitors (MAOB-Is). Part I of this thesis presents a systematic review with network meta-analysis of randomized controlled trials comparing the efficacy and safety of COMT-Is, DRAs and MAOB-Is as adjunctive oral therapy to levodopa in PD patients experiencing motor fluctuations. All adjunctive drug classes improved motor symptoms, activities of daily living, and quality of life, but DRAs, particularly pramipexole immediate release, were associated with the largest improvements. In Part II cognitive outcomes following subthalamic nucleus deep brain stimulation (STN DBS) in PD patients were examined. Overall, STN DBS appears to be a cognitively safe intervention, with cognitive outcomes comparable to continuous intrajejunal levodopa infusion and only a transient moderate decline in verbal fluency compared to best medical treatment (BMT). Furthermore, STN DBS induces a clinically meaningful motor improvement in PD patients with cognitive impairment, but the improvement may be smaller than in patients who are not cognitively affected. Lastly, smaller volume of the nucleus basalis of Meynert was associated with Parkinson’s disease dementia (PDD) at baseline, but not with cognitive decline six months after STN DBS. Part III aimed to facilitate future research in cognitively impaired PD patients by introducing the DBS-MODE trial, a randomized controlled study comparing DBS with BMT in PDD, and by providing practical recommendations for obtaining informed consent in PD patients with cognitive impairment.</p
The right to the truth in atrocity trials before municipal courts
Full text linkIn the past decades the right to the truth has gained increasing recognition in international human rights law. Grounded in the state’s duty to conduct an effective investigation into serious human rights violations and to ensure to victims the right to an effective remedy, the burgeoning right to the truth has a legal dimension. Taking as a baseline a definition of the right to the truth derived from international human rights jurisprudence this study has examined the place and the role of the right to the truth in municipal trials for atrocity crimes related to three general contexts. In many of the trials the study has found evidence of recognition of the right to the truth. Factual findings giving effect to the right to the truth as a substantive right have helped courts establish circumstances that have played a critical role in the commission of collective crimes. Recognition of the right to the truth as a procedural right has influenced the course of criminal investigations and trials and has supported greater compliance by the authorities with their duty to investigate and prosecute serious violations. Moreover, the findings of this study suggest that recognition of the right to the truth may have a positive impact on the norm expressive qualities of municipal atrocity trials. The study concludes by providing specific reasons why municipal courts adjudicating atrocity trials should give effect to the right to the truth
Animal hunts in late antiquity:Continuities and changes between the 4th and 6th century AD in the east of the Roman empire
Full text linkAnimal hunts (lat. venationes) were a popular form of mass entertainment in the Roman empire, from their origins in the republican period until Late Antiquity. Venationes continued to be presented even after gladiator fights, with which animal hunts were traditionally combined, disappeared from public life. They endured despite facing harsh and persistent opposition by Christian critics from the 2nd century AD onwards. The present thesis seeks to understand the reasons for the persistence and popularity of venationes in the late antique East from the beginning of the 4th century AD onward and for their eventual end in the mid-6th century AD. In previous scholarship, animal hunts have mostly been discussed in general works on Roman spectacles, in which they have often been sidelined next to gladiator fights and chariot racing. Additionally, evidence stemming from later periods and from outside Rome has received little attention. By centring animal hunts, this dissertation fills a lacuna in current research on Roman spectacles and highlights the unique circumstances and developments of venationes in Late Antiquity. The dissertation looks at a variety of sources to bring together local practices, inter-provincial networks, and imperial policies for a comprehensive understanding of the cultural and social significance of animal hunts for late antique society. By studying animal hunts as a historical instance of human-animal interaction, the dissertation acknowledges that animals are central to what venationes looked like, what venues were needed to accommodate them, what was necessary to organise them, and how the spectators and critics saw them
Poetik der Komplizenschaft:Zum kommunikativen Potenzial von Exilautobiographien der NS-Zeit
Full text linkZwischen 1933 und 1945 ergriffen zahlreiche Geflüchtete gegen das NS-Regime das Wort und versuchten anhand ihrer persönlichen Erfahrungen mit dem Dritten Reich eine Weltöffentlichkeit über dessen Verbrechen aufzuklären. Autobiographisches Schreiben wurde als Medium dazu genutzt, der totalitären Vereinnahmung von Identität(en) ein Gegennarrativ entgegenzustellen und Deutungsmacht zu beanspruchen, das durch Zensur und Repression auferlegte Schweigen zu durchbrechen, aber auch direkten Einfluss auf die alliierten Mächte auszuüben. Solche im Modus des Testimonialen operierende Autobiographien zeichnen sich durch eine starke Appellstruktur aus: sie versuchen ihr Publikum von ihrer Sicht der Dinge zu überzeugen und zu mobilisieren, fordern Anerkennung, Empathie, Vertrauen und Parteinahme ein und positionieren ihre Leser:innen auf diese Weise performativ als Kompliz:innen. In der Forschung wurden testimoniale Exilautobiographien zwischen 1933 und 1945 vor allem als zeithistorische und soziokulturelle Quellen behandelt, wobei ihre ästhetischen Qualitäten entweder ausgeblendet oder diese als formkonservativ und anspruchslos etikettiert wurden. Dabei wird das Genre einem an fiktionaler Literatur orientierten Werteraster unterworfen, welches seine sozialkommunikative Funktion und gattungsspezifische Eigenlogik unberücksichtigt lassen. Genau hier setzt der in dieser Arbeit entwickelte Analysebegriff der ‚Komplizenschaft‘ an, indem er das ästhetische Potenzial der testimonialen NS-Exilautobiographik in ihrer intersubjektiv-kommunikativen Dimension verortet. Die These ist, dass die prekären Produktions- und Rezeptionsbedingungen des Exils, die Positionierung der eigenen Lebensgeschichte als Gegendiskurs und spezifische rhetorische und narrative Techniken eine komplizitäre Lektürehaltung generieren, die konstitutiv für die Poetik dieser Texte ist. Zentral stehen drei Fallstudien: Catherine Kleins Escape from Berlin (1944), Sebastian Haffners Geschichte eines Deutschen (1939/2000) und Stefan Zweigs Die Welt von Gestern (1942)
The right to the truth in atrocity trials before municipal courts
No full textIn the past decades the right to the truth has gained increasing recognition in international human rights law. Grounded in the state’s duty to conduct an effective investigation into serious human rights violations and to ensure to victims the right to an effective remedy, the burgeoning right to the truth has a legal dimension. Taking as a baseline a definition of the right to the truth derived from international human rights jurisprudence this study has examined the place and the role of the right to the truth in municipal trials for atrocity crimes related to three general contexts. In many of the trials the study has found evidence of recognition of the right to the truth. Factual findings giving effect to the right to the truth as a substantive right have helped courts establish circumstances that have played a critical role in the commission of collective crimes. Recognition of the right to the truth as a procedural right has influenced the course of criminal investigations and trials and has supported greater compliance by the authorities with their duty to investigate and prosecute serious violations. Moreover, the findings of this study suggest that recognition of the right to the truth may have a positive impact on the norm expressive qualities of municipal atrocity trials. The study concludes by providing specific reasons why municipal courts adjudicating atrocity trials should give effect to the right to the truth
Deep brain stimulation and cognition in managing motor fluctuations in Parkinson's disease
Full text linkParkinson’s disease (PD) is one of the fastest growing neurodegenerative disorders worldwide. Motor symptoms are initially managed with levodopa and adjunctive oral therapy, namely catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs), or monoamine oxidase B inhibitors (MAOB-Is). Part I of this thesis presents a systematic review with network meta-analysis of randomized controlled trials comparing the efficacy and safety of COMT-Is, DRAs and MAOB-Is as adjunctive oral therapy to levodopa in PD patients experiencing motor fluctuations. All adjunctive drug classes improved motor symptoms, activities of daily living, and quality of life, but DRAs, particularly pramipexole immediate release, were associated with the largest improvements. In Part II cognitive outcomes following subthalamic nucleus deep brain stimulation (STN DBS) in PD patients were examined. Overall, STN DBS appears to be a cognitively safe intervention, with cognitive outcomes comparable to continuous intrajejunal levodopa infusion and only a transient moderate decline in verbal fluency compared to best medical treatment (BMT). Furthermore, STN DBS induces a clinically meaningful motor improvement in PD patients with cognitive impairment, but the improvement may be smaller than in patients who are not cognitively affected. Lastly, smaller volume of the nucleus basalis of Meynert was associated with Parkinson’s disease dementia (PDD) at baseline, but not with cognitive decline six months after STN DBS. Part III aimed to facilitate future research in cognitively impaired PD patients by introducing the DBS-MODE trial, a randomized controlled study comparing DBS with BMT in PDD, and by providing practical recommendations for obtaining informed consent in PD patients with cognitive impairment.</p
Replenishing dopamine in Parkinson’s disease:Tyrosine hydroxylase Ser40 phosphorylation and phosphodiesterase inhibition
Full text linkThis thesis focuses on the biosynthesis machinery of the neurotransmitter dopamine and its therapeutic potential in the treatment of Parkinson's disease, a degenerative disorder caused by a deficiency in dopamine. Although L-DOPA is the current treatment for Parkinson's disease, it can lead to adverse effects and eventually lose effectiveness. As an alternative approach to replenish dopamine levels, this thesis suggests regulating the activity of tyrosine hydroxylase, the rate-limiting enzyme involved in dopamine production. By stimulating tyrosine hydroxylase activity, dopamine production can be increased, activating dopamine cells in the brain. The activity of tyrosine hydroxylase is regulated by Ser40 phosphorylation, a chemical reaction in which a phosphate group is added to an amino acid in the enzyme. This thesis explores the mechanisms that influence Ser40 phosphorylation and how they can be manipulated to increase the dopamine biosynthesis machinery in the dopamine neurons that are affected in Parkinson’s disease, specifically. The research findings indicate that cyclic nucleotide-mediated signaling plays a vital role in promoting Ser40 phosphorylation. Furthermore, the thesis investigates the impact of inhibiting phosphodiesterases, which break down cyclic nucleotides, on Ser40 phosphorylation. The results demonstrate that phosphodiesterase inhibition can upregulate tyrosine hydroxylase Ser40 phosphorylation and, as such, can stimulate the dopamine biosynthesis machinery. Overall, these findings suggest that manipulating tyrosine hydroxylase activity through phosphodiesterase inhibition could be a promising strategy to replenish dopamine levels and improve the quality of life for Parkinson's disease patients
Discovery beyond the void:Energizing T cells in chronic lymphocytic leukemia
Full text linkIn the last decade, efficacy of treatment of chronic lymphocytic leukemia (CLL) has improved considerably. Highly effective targeted therapies such as ibrutinib and venetoclax have been developed and replaced chemoimmunotherapy as first-line treatment for CLL. However, these targeted therapies are not curative. CAR-T cell therapy for the treatment of hematological malignancies has curative potential, but CLL patients treated with CAR-T cells show poor responses. The current dogma is that exhaustion of T cells in CLL is to blame for CAR-T cell inefficacy. Since CAR-T cell therapy is a single dose therapy and has the potential to be curative, it is worthwhile to investigate and invent novel methods to increase its efficacy in CLL. Therefore this thesis focused on identifying the mechanism of T-cell exhaustion in CLL, whether this is reversible, and how we use this information to improve existing autologous based immunotherapies such as CAR-T cell therapy. In in this manuscript it is described that T cells in CLL patients are functionally and metabolically impaired. However, T cells in CLL are not terminally exhausted. In the final chapters of this thesis we present multiple methods to reverse T cell dysfunction in CLL, creating new possibilities to improve autologous based therapies in CLL