Leiden University Scholary Publications
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Usutu Too?: Insights into vaccine development strategies for an emerging orthoflavivirus
Full text linkDespite major advances in infectious disease control, the world remains vulnerable to emerging mosquito-borne viruses, which are spreading ever more widely due to globalisation and climate change. This thesis focuses on Usutu virus (USUV), an emerging orthoflavivirus (the virus family containing dengue, Zika and yellow fever) which has become established across much of Europe in recent decades. USUV causes lethal disease in birds and, more rarely, neurological disease in humans.The thesis gives an introduction to orthoflavivirus biology, and reviews vaccine design, including innovative approaches and associated challenges. The creation of two infectious USUV cDNA clones is described. An immunocompromised mouse model is optimised, revealing that low viral doses can cause rapid lethal disease, and used to compare different lineages of USUV circulating in the Netherlands. Attenuated USUV mutants were designed based upon mutations known from related orthoflaviviruses – but for many of these mutations the attenuation phenotype was not conserved. Chimeric vaccines using the yellow fever 17D backbone were still lethal in mice, highlighting the challenges around design strategies and research models.The thesis concludes by discussing broader preparedness, the need for improved non-animal models, and the potential of pan-orthoflavivirus vaccines, alongside social, political, and biosecurity barriers to vaccine development.LUMC / Geneeskund
Navigating the unknown: nature-based solutions for coastal climate adaptation under deep uncertainty
No full textDecision-making on long-term coastal climate change adaptation faces deep uncertainty. Compared to traditional hard-engineered coastal defences, nature-based solutions (NbS) are promising multifunctional adaptation strategies under uncertainty. Yet, their adoption remains limited. This research identified how deep uncertainty affects planning and management of NbS for coastal adaptation. We performed unstructured and semi-structured interviews with Dutch experts on coastal NbS, adaptation and decision-making under deep uncertainty. We identified which topics of deep uncertainty affect decision-making, their interactions with NbS, and the implications for adopting NbS. These topics were categorised into three areas: conceptual system understanding, probabilities of outcomes and drivers, and outcome prioritisation. Decision-making primarily faces uncertainties regarding the rate of sea-level rise and political uncertainties on flood risk acceptance. Under these conditions, NbS are promising short-term interventions due to their adaptivity and multifunctionality. However, this potential is limited in the longer term, depending on increasingly uncertain factors. These include climate change impacts, NbS performance, conflicting functions, risk acceptance and the desired state of nature. Our results imply that the multifunctionality and adaptivity intrinsic to NbS are two sides of a coin. They enable robust short-term strategies but increase uncertainty and the risk of lock-in and sunk investments in the longer term. Navigating this trade-off in coastal adaptation requires the integration of political and technical scenario planning. Balancing uncertain multifunctionality against more predictable flood prevention and vulnerability reduction early on is essential for developing resilient long-term coastal management strategies.NWO17595The politics and administration of institutional changeEnvironmental Biolog
Precision and efficacy guided novel approaches to target dyslipidemia and atherosclerosis
Full text linkThis thesis explores innovative therapeutic strategies to more effectively treat obesity and its associated cardiometabolic diseases. Despite scientific and medical progress, obesity and related conditions such as type 2 diabetes and atherosclerotic cardiovascular disease continue to rise globally. Here, we focus on three promising strategies to combat these diseases: 1) targeting the right tissue, 2) multi-targeted approaches, and 3) refinement of intracellular signalling pathways.First, the work examines microRNAs, particularly miR-33a, as potential multi-targeting tools to improve cholesterol homeostasis and reduce atherosclerosis. The studies show how modulating miR-33a affects lipid metabolism through coordinated regulation of several key proteins. The importance of tissue specificity is highlighted by demonstrating that liver-targeted inhibition of ANGPTL4 lowers plasma lipids and attenuates atherosclerosis, without the adverse effects seen with systemic inhibition. The dissertation also investigates the neuroplasticity gene DCL, expressed in hypothalamic β-tanycytes, revealing its subtle yet significant role in whole-body energy balance and white adipose tissue browning. Finally, the thesis evaluates biased GLP-1 receptor agonism as a means to optimize downstream signalling and improve the metabolic effects of obesity pharmacotherapy.Together, these findings provide new insights into how precision targeting and pathway refinement can enhance the efficacy and tolerability of therapies for obesity-related diseases.LUMC / Geneeskund
Abstract representations underlie rhythm perception and production: evidence from a probabilistic model of temporal structure
Full text linkAdvanced Behavioural Research Method
Metabolic risk and cardiovascular disease: insights from large biobanks with genetic epidemiological approaches
Full text linkThe overall aim of this thesis was to gain additional in-depth insights into the metabolic risk assessment and management of cardiovascular disease (CVD), based on multiple omics data sources in large population studies and biobanks. The studies described in this thesis contributed to improved insight into the CVD in three main research areas: 1) the pathophysiological mechanisms of atherosclerosis (Part I), chapters 2 and 3 captured distinct metabolomic profiles associated with CVD and to characterize a potential novel therapeutic target; 2) the underlying genetics of CVD risk factors (Part II), chapter 4 examined the age-dependent genetic effects on metabolic risk factors of CVD, and chapter 5 investigated the effects of structural genetic variants on sleep disturbances, which is being increasingly considered an important cardiovascular risk factor; 3) the heterogeneity of CVD risk across populations with different metabolic characteristics (Part III), chapters 6, 7 and 8 addressed the role of metabolic syndrome, Lp(a) and subclinical hypothyroidism in CVD risk. This thesis highlights the potential of integrating genomics, metabolomics, and personalized approaches to enable more precise and individualized management of metabolic risk associated with CVD over the life course. LUMC / Geneeskund
From biofabrication to multi-organ platforms: engineering the human heart-kidney axis in vitro
Full text linkThis thesis presents an integrated in vitro approach to model the human heart–kidney axis, addressing a significant gap in understanding inter-organ communication relevant to cardiorenal syndrome (CRS). Human induced pluripotent stem cell (hiPSC)-derived organoids were used to create both cardiac microtissues and kidney organoids, enabling physiologically relevant and patient-specific experimentation. A microfluidic organ-on-chip platform was engineered to co-culture these tissues under static and perfused conditions, preserving structural and functional characteristics and allowing dynamic heart–kidney crosstalk to be investigated. Parallel work introduced a cost-effective bioprinting strategy to generate kidney organoids with improved reproducibility and scalability, overcoming limitations of manual fabrication and facilitating broader adoption of these models in biomedical research. The model enabled study of renal injury-induced cardiac dysfunction, revealing that nephrotoxic stress in kidney organoids triggered molecular and functional impairment in cardiac microtissues, consistent with CRS type 3 mechanisms. Together, these innovations demonstrate how combining stem cell technology, microfluidics, and biofabrication can recreate complex inter-organ physiology and support mechanistic insights into disease. The work highlights the translational potential of scalable, human-relevant multi-organ systems for drug screening, mechanistic studies, and future personalized medicine strategies.LUMC / Geneeskund
Elucidating the present and future of individuals with kidney disease: a multifaceted epidemiological approach
Full text link Individuals with kidney disease constitute a highly heterogeneous poulation. Besides the European Renal Association (ERA) recognising 281 distinct etiologies of kidney damage, these individuals also differ in psychosocial aspects of their disease. As such, there is high potential for person-centred approaches to improve kidney care. Person-centred care is reliant on an individual’s medical history, but may be further strengthened by information about their current care and individual prognosis. This information may be collected using pharmaco- and predictive epidemiological methods. Thus, this thesis aimed to apply pharmaco- and predictive epidemiological methods to elucidate current treatment patterns and individual prognosis in individuals with kidney disease. Additionally, given the essentially of sound methodology, the third aim of this thesis was to provide methodological guidance. Leiden University Medical Center; Dutch Kidney Foundation; Leiden University Fund; Minerva Scholarship FundLUMC / Geneeskund
Deep learning for vascular segmentation and tissue characterization in CT images
Full text linkThis thesis focuses on enhancing CTA image analysis and interpretation using the latest deep learning technologies. The overarching aim of this thesis is to overcome existing technical limitations in the automated analysis of CTA imaging data by developing advanced deep learning methods for two CTA application domains: coronary computed tomographic angiography (CCTA) and CTA of liver vasculature.LUMC / Geneeskund
Language policy and planning of Amazigh languages in Morocco: a study of the language ideology of the Royal Institute of Amazigh Culture (IRCAM)
Full text linkThis thesis examines how Amazigh (Berber) languages are planned in Morocco—the country with the largest Amazigh-speaking population—and investigates the considerations underlying these measures through the ideologies of the Royal Institute of Amazigh Culture (IRCAM). It traces the historical development of the Amazigh cultural movement from its Kabylian origins in the colonial period to its Moroccan expression, showing how language planning—through the creation of the Neo-Tifinagh script and the introduction of neologisms—became central to Amazigh nationalism.The study highlights the role of Mohamed Chafik, IRCAM’s founding rector, whose ideology redefined Amazighness as part of a unified Moroccan national identity. Through an analysis of IRCAM’s early initiatives—the adoption of the Neo-Tifinagh-IRCAM script and the Tifawin a Tamazight textbooks—it demonstrates how the pursuit of a homogeneous standard Moroccan Amazigh conflicts with the linguistic practices of the three main varieties in Morocco: Tarifiyt, Central Moroccan Amazigh, and Tashelhiyt.The thesis further examines how IRCAM rector Ahmed Boukous’s ideology of “revitalization” and “attrition” legitimizes this standardization, and how IRCAM’s selective application of the “polynomic approach” mediates between language ideology and linguistic practice. The China Scholarship Council (CSC); Leiden
University Scholarship (CSC No. 202007720086)Descriptive and Comparative Linguistic
Common constitutional traditions?: A comparative perspective on academic freedom in Europe
Full text linkNWOVI.Vidi.201.084The progression of EU law: Accommodating change and upholding value