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Complementing the factor H protein family:From assays to outcomes
No full textAs 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
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
Private dispute resolution and the right to an effective remedy in transnational business and human rights
No full textThis thesis examines how private dispute resolution (PDR), namely negotiation, mediation, and arbitration, contributes to and/or impairs the realisation of the right to an effective remedy in cases of transnational business-related human rights abuses. Rightsholders often face barriers to access judicial remedies due to jurisdictional challenges, evidentiary obstacles, and economic constraints. In this context, PDR has been promoted by the UN Guiding Principles on Business and Human Rights (UNGPs), as a complementary route to remedy. Yet its diffusion has outpaced the analysis of its effects in relation to international human rights law (IHRL). Using a legal doctrinal methodology grounded in IHRL, the thesis analyses 20 mechanisms employing PDR as a means of remedy and develops three case studies, the Porgera Individual Claims Programme, the Renova Foundation’s Mediation Programme, and the Bangladesh Accord arbitrations. It analyses their procedural design and remedial outcomes against the content of the right to an effective remedy. The findings indicate PDR’s dual character: it can contribute to the realisation of this right when it is independently administered, accessible, participatory, protective against retaliation, and capable of delivering diverse forms of reparation. However, more commonly, it impairs the right’s realisation through restrictive eligibility, burdensome proof requirements, company-influenced administration, standardised compensation packages, and legal waivers that limit access to courts. The thesis concludes that PDR should not substitute judicial remedies and that its legitimacy depends on public governance, including oversight and regulation, that secures compatibility with IHRL and reaffirms States’ role as guarantors of remedy
Second cancers, cardiovascular disease and quality of life after treatment for large B-cell lymphoma and Hodgkin lymphoma
No full textAdvances in treatment of diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL) have significantly increased survival, but have also introduced risks of late effects. The studies in this thesis examined the risk of second malignant neoplasms, cardiovascular diseases and fatigue, neuropathy, psychological distress and health-related quality of life among long-term survivors of lymphoma.The first part of this thesis evaluates risks of second cancers. In female five-year HL survivors, we demonstrate for the first time that doxorubicin exposure at adolescent and adult ages increases breast cancer risk, independent of chest radiotherapy or age at treatment. In DLBCL five-year survivors we showed increased risks of solid and hematologic malignancies, particularly after higher cumulative doses of cyclophosphamide or doxorubicin.The second part focuses on cardiovascular diseases. In a five-year DLBCL survivor cohort, risks of heart failure and cerebrovascular accident were increased compared with the general population for over twenty years; particularly in survivors treated with higher doses of doxorubicin and radiotherapy. The CLARITY cross-sectional study provides detailed echocardiographic and biomarker measurements, demonstrating a high prevalence of subclinical left ventricular dysfunction in five-year survivors compared with a sibling comparison group. We also review emerging evidence on immune checkpoint inhibitor-associated atherosclerosis.The third part describes that persistent symptoms are frequently reported up to 13 years after diagnosis, substantially affecting health-related quality of life compared with a normative population.Together, the findings underscore the need for tailored survivorship care, including personalized screening for second cancers and cardiovascular disease, and strategies to address chronic symptoms and improve quality of life among lymphoma survivors
Replenishing dopamine in Parkinson’s disease:Tyrosine hydroxylase Ser40 phosphorylation and phosphodiesterase inhibition
No full textThis 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
No full textIn 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
Reimagine, redesign and transform:Enhancing generation and exploration in creative problem finding processes in visual arts education
No full textDeze dissertatie beoogt een bijdrage te leveren aan de kennis over hoe het onderwijs de originaliteit van beeldende producten van leerlingen kan verhogen en aan de verdere ontwikkeling van nieuwe onderwijsprogramma's in beeldende vormgeving en culturele en kunstzinnige vorming (ckv) en het vaststellen van de effectiviteit daarvan. Het bevorderen van de creativiteit en originaliteit van leerlingen zijn belangrijke doelstellingen van beeldende vormgeving en ckv in het voortgezet onderwijs. De kernvraag in de dissertatie is daarom: 'Hoe kunnen docenten bij beeldende vormgeving en ckv hun leerlingen ondersteunen bij het ontwikkelen van hun creativiteit en originaliteit?'. Divergent denken is cruciaal bij het maken van creatieve beeldende producten en het is een indicator van creativiteit. In het eerste deel van deze dissertatie worden de effecten van twee versies van een instructieontwerp gerapporteerd. Deze lessen moesten het divergente denken bevorderen, door expliciete (strategie)instructie van metacognitie. Dat is geen gebruikelijke aanpak in lessen beeldende vormgeving en ckv. De resultaten tonen aan dat deze onderwijsprogramma's het divergente denken van leerlingen inderdaad bevorderden. In deel twee werden drie processen bestudeerd die de verschillen in de originaliteit van beeldende producten zouden kunnen verklaren. De resultaten lieten zien dat visueel genereren en visueel exploreren de verschillen konden verklaren in de originaliteit van de beeldende producten. Drie soorten exploreren - associëren, combineren en abstraheren - leverden een significante bijdrage aan de beeldende ontwerpen. Daarnaast bleek over het algemeen dat naarmate de afstand van de activiteiten (tot een stimulus) groter was, des te hoger de originaliteit van de beeldende ontwerpen was
It takes a village to grow stronger:A socio-ecological model of resilience in refugees
No full textThe 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
Comparative CRISPR-based systems for HIV gene editing
No full textHIV-1 persists as integrated proviral DNA within long-lived cellular reservoirs, preventing eradication despite effective antiretroviral therapy. CRISPR-based genome editing offers a promising strategy to disrupt the proviral genome. This dissertation systematically evaluates several programmable CRISPR systems, including Cas12b, CjCas9, SaCas9, and ultracompact TnpB/Fanzor nucleases. It also investigates lipid nanoparticle (LNP) delivery strategies to advance curative HIV-1 editing approaches.Cas12b, CjCas9, and SaCas9 each demonstrated potent antiviral activity, with single guide RNA (gRNA) strategies sufficient to fully inactivate HIV-1 in T cells. Among these systems, SaCas9 displayed the strongest inhibition, eliminating all detectable wild-type proviruses using a single gRNA. Dual-gRNA approaches further enhanced editing efficiency. Cas12b and CjCas9 primarily induced INDELs (insertions and deletions), with limited proviral DNA excision. Notably, excision efficiencies varied among SaCas9 gRNA pairs. Analysis of the binding and cleavage kinetics of the Cas nuclease-gRNA complex revealed that efficient excision requires rapid, synchronized cleavage at both targets. The Gag3 + Pol5 pair achieved near-complete excision (97%), whereas kinetically mismatched pairs produced individual mutations at both target sites.TnpB and Fanzor were evaluated for their ability to inactivate HIV. However, their low antiviral activity indicates that substantial RNA and protein engineering will be necessary to enhance their HIV-inactivating potential. LNP-based delivery platforms were developed, including a selective organ targeting (SORT) formulation that achieved >90% mRNA expression across multiple cell types. Additionally, anti-CD4 DARPin-conjugated LNPs were explored. Overall, these findings represent a step forward in HIV-1 gene-editing strategies, while highlighting that further work is required to achieve clinical application
Keeping time:Neuroendocrine rhythms, bone, and glucose metabolism
No full textThis thesis investigates how disruption and/or restoration of human biological rhythms affects glucose metabolism, sleep, and bone metabolism. In Part I, we focused on circadian rhythm disruptions in healthy adolescents, patients with pituitary adenoma and patients with type 2 diabetes. In a combined case-control study and randomized crossover trial in adolescents, we demonstrate that both blue-light-blocking glasses and refraining from screen use in the evening improve daytime symptoms of insufficient sleep and advance sleep onset time. In a prospective cohort study in patients with pituitary adenoma with optic chiasm compression, transsphenoidal adenoma resection did not affect the post-illumination pupil responses and sleep-wake rhythms in the first 12 months after surgery. In a case-control study, we show altered functional rhythms of the central brain clock in people with insulin resistance and type 2 diabetes compared to people with normal insulin sensitivity.In Part II, we focused on the topic of menopause. In a cross-sectional survey, we show that two-thirds of women with type 1 diabetes perceive changes in their glucose regulation after menopause (i.e. the final menstrual period), and that changes in perceived glucose regulation are associated with the severity of reported menopausal symptoms. In a systematic review and meta-analysis, we demonstrate that postmenopausal hormone replacement therapy reduces HbA1c and fasting glucose in women with type 2 diabetes. In a randomized controlled trial in healthy postmenopausal women, restoring monthly rhythms of 17-β-estradiol resulted in higher bone formation over time compared to continuous 17-β-estradiol, while exerting neutral effects on cardiometabolic risk factors