Carbohydrates, or sugars, are the most diverse and most abundant biomolecules known. However, the isolation of carbohydrate samples in sufficient amounts and purity is often impractical or even... Show moreCarbohydrates, or sugars, are the most diverse and most abundant biomolecules known. However, the isolation of carbohydrate samples in sufficient amounts and purity is often impractical or even impossible, so the chemical synthesis of glycosides becomes relevant. The glycosylation reaction, in which a glycosidic linkage is constructed from two glycosyl building blocks to form more complex (oligo)saccharides, is a central reaction in this endeavor. The most common approach to chemically create glycosidic bonds is a nucleophilic substitution reaction between a glycosyl acceptor containing a nucleophilic alcohol, and a glycosyl electrophile (donor) carrying an anomeric leaving group. When this anomeric leaving group is activated by a promotor, this leads to an equilibrium of reactive intermediates. The stability and reactivity of these species strongly determine which intermediate acts as the dominant reactive intermediate. Covalent reactive intermediates provide more SN2-like reactions, while more dissociated intermediates give rise to SN1-like reactions. Although both SN2- and SN1-like reactions can give rise to both the α and β anomer, the stereoselectivity of these reactions is greatly determined by the nature of the reactive intermediates and the incoming nucleophile. The research described in this thesis aims to characterize reactive intermediates that dictate the stereoselectivity of glycosylation reactions. Show less
The first steps are made in personalised cancer vaccination strategies, which aim to induce a more specific immune response with fewer side effects. The activation of cytotoxic T cells is crucial... Show moreThe first steps are made in personalised cancer vaccination strategies, which aim to induce a more specific immune response with fewer side effects. The activation of cytotoxic T cells is crucial for an effective immune response. In this thesis, the cellular processes behind antigen cross-presentation (signal 1) are further researched. For this, we make use of the bioorthogonal ‘click-to-release’ strategy to shield glycolipid and peptide antigens. A strategically placed, small chemical group, trans-cyclooctene (TCO), is used to minimise interference on processing, however, effectively blocks T cell activation. The chemical protecting group can be selectively removed by introducing a tetrazine, serving as a deprotection compound. The tetrazine clicks onto the protecting TCO group, inducing the release of the entire tetrazine-TCO complex. This click-to-release approach allows for precise regulation of T cell activation. Consequently, T cell activation assays can be used to research antigen cross-presentation, in both a spatially and temporally manner. Show less
This article deals with the interpretation of Hipparchus and the question to which extent its advocacy of φιλοκέρδεια or the love of gain should be read ironically. It argues that this... Show moreThis article deals with the interpretation of Hipparchus and the question to which extent its advocacy of φιλοκέρδεια or the love of gain should be read ironically. It argues that this pseudoPlatonic dialogue can be best understood in the context of a broader fourth-century philosophical debate on the pursuit of (economic) self-interest. First, I show how the Hipparchus comments on and develops thoughts from Plato’s Republic. Then, I demonstrate how the re-evaluation of the love of gain compares to Xenophon’s treatment of φιλοκέρδεια, κέρδος, and πλεονεξία in the Oeconomicus and Cyropaedia, which also respond to the Republic, and show how both authors provocatively re-evaluate these negative notions of gain or self-interest into neutral ones. These comparisons inform a layered reading, in which the apparent irony helps readers to reflect on the proposed re-evaluation of commerce. Show less
The studies in this thesis jointly led to an evidence-based, expert-based and experience-based conceptualization of the challenging rehabilitation environment in five clusters. This... Show moreThe studies in this thesis jointly led to an evidence-based, expert-based and experience-based conceptualization of the challenging rehabilitation environment in five clusters. This conceptualization has been incorporated into the CREATE-tool, a team-self assessment tool that can be used to implement and evaluate the challenging rehabilitation environment in geriatric rehabilitation departments.This CREATE-tool is able to identify areas for improvement for the challenging rehabilitation environment at ward level and professionals are satisfied with the use of the tool. Show less
Financial scarcity, marked by insufficient resources, challenges individuals and households to meet basic needs and negatively impacts emotions, thoughts, behavior, well-being, and health. This... Show moreFinancial scarcity, marked by insufficient resources, challenges individuals and households to meet basic needs and negatively impacts emotions, thoughts, behavior, well-being, and health. This leads to financial stress, characterized by a perceived lack of resources, control, and increased worry. Social welfare systems can alleviate financial stress by providing necessary resources to low-income households, but widespread non-take-up of social welfare limits its effectiveness.This dissertation aims to deepen the understanding of the dynamic relationship between financial stress and mental well-being, identify economic predictors of financial stress, and explore the determinants of non-take-up of social welfare as a tool for alleviating financial stress. The first part examines the relationship between financial stress and mental health, highlighting the dynamic interaction between these factors during the COVID-19 pandemic. Adopting an integrative approach, the study also investigates the influence of various economic conditions—income, debts, savings, income volatility, and employment—on financial stress.The second part focuses on the non-take-up of social welfare. It addresses gaps in the literature through a systematic review, qualitative interviews, empirical testing of an integrated model for take-up of benefits, and an experimental design. Findings reveal the complexity of factors influencing non-take-up, including administrative burden, fear of reclaims, and perceived eligibility. The impact of reclaims on non-take-up is examined, highlighting the specific deterrent effect of reclaims on welfare participation.The dissertation concludes with recommendations for future research and policy design, emphasizing the need for simpler, more accessible social welfare systems to reduce financial stress and improve overall well-being among financially vulnerable households. Show less
This thesis has the aim to identify challenges and to optimize management and care of older patients with multimorbidity and cancer. The first part focuses on identifying challenges in the current... Show moreThis thesis has the aim to identify challenges and to optimize management and care of older patients with multimorbidity and cancer. The first part focuses on identifying challenges in the current way of organising care from perspective of patients, informal caregivers and the healthcare professionals. Furthermore, it advocates for policy makers to aid in changing care in this population. The second part looks at patient priorities and the involvement of the older patient in decision-making. It identifies the importance of quality of life and further investigates the exact meaning of quality of life. Additionally, it tests a method (the OPT-c) to elicit patient priorities for various health outcomes. The third part then specifies how chronic health conditions could be incorporated and monitored in cancer care. It starts with a study on which chronic health conditions are relevant in decision making and care and how to incorporate them. An additional study then identifies 19 core symptoms to monitor in older patients with multimorbidity and cancer. The results of the previously mentioned chapters are combined in part four, which consists of the description of the new patient-centred care pathway for the older patient with multimorbidity including cancer. Show less
Over the past decade, the abundance of high-throughput omics approaches coupled with the use of machine learning techniques, has made it possible to investigate the full molecular complexity of... Show moreOver the past decade, the abundance of high-throughput omics approaches coupled with the use of machine learning techniques, has made it possible to investigate the full molecular complexity of health and aging. The primary forcus of this thesis was to study and improve biological aging prediction. To achieve this we developed, evaluated, and deployed state-of-the-art models predicting different aspects of human health risks by employing multiple omics measurement, with a particular attention given to 1H-NMR metabolomics. Availability, affordability, interpretability, and robustness of the 1H-NMR metabolomics platform by Nightingale Health makes it a powerful tool with implications in the risk prediction of common diseases. We explored this research line in epidemiological settings within the BBMRI-nl consortium, which incorporates 28 cohorts with various specific characteristics. Hence, we took advantage of the wide range of health statuses when examining the extensive BBMRI datasets, investigated specific subgroups such as elderly or night-working individuals respectively recruited for the Leiden Longevity Study (LLS) and LIFELINES, and even explored the potential complementarity and interaction of different omics (e.g., 1H-NMR metabolomics, DNA methylome) available within the subset known as BIOS Consortium. Show less
This thesis explored the molecular pharmacological mechanisms of targeting CB2R via investigation of novel drug discovery concepts such as target binding kinetics, allosteric modulation and biased... Show moreThis thesis explored the molecular pharmacological mechanisms of targeting CB2R via investigation of novel drug discovery concepts such as target binding kinetics, allosteric modulation and biased signaling. Central to the investigation of CB2R pharmacology was developing new assays and providing an overall kinetic view, aimed at bringing fresh insights that could be further integrated into the field of GPCR research. To this end, the development and application of state-of-the-art and novel cellular and biochemical assays contributed to a better understanding of agonist-mediated CB2R activation and signaling, which can advance drug discovery efforts for treatments of diseases that involve CB2R.It’s about time that novel concepts for GPCRs are incorporated into early drug discovery programs, where a kinetic view is applied to provide a better translational perspective. Show less
Nanoparticles can be used as delivery systems for both small molecules and macromolecules such as proteins, peptides or oligonucleotides. This thesis focuses on the use of liposomes, nanometric... Show moreNanoparticles can be used as delivery systems for both small molecules and macromolecules such as proteins, peptides or oligonucleotides. This thesis focuses on the use of liposomes, nanometric vesicles formed by a lipid bilayer enclosing an aqueous core. Liposomes are highly versatile delivery systems. Fine tuning their physicochemical properties such as size, shape, rigidity or surface charge allows the control of the liposome's biological effect. Among the different applications for liposomes, antigen delivery is especially interesting. Liposomes can protect antigens from degradation, and they can direct the antigen delivery to specialised cells such as antigen-presenting cells (APCs), key for the induction of immune responses. APCs will present antigens to T cells to generate an immune response. The way in which these cells present the antigen will determine the type of immune response generated, either a pro-inflammatory response necessary to fight viral and bacterial infections or a tolerogenic response useful to temper down inflammation, for example in the context of cardiovascular diseases like atherosclerosis. Therefore, these formulations can be used as vaccines against inflammatory diseases and as prophylactic vaccines against infectious diseases. In this thesis, we examine key aspects of liposome formulations including the elucidation of target antigens to be used in a tolerogenic vaccine against atherosclerosis, the manufacture of these formulations using microfluidics, the use of vitaminD3 as a tolerogenic adjuvant and the role of liposome rigidity in the tolerogenic effect of these nanoparticles. Furthermore, we explore the use of liposomes to induce protective anti-viral immunity against influenza. Show less
Although classical DC (cDC), which are derived from myeloid progenitors,are specialized in antigen processing and (cross)presentation. However, theyalone are sometimes not enough to prime efficient... Show moreAlthough classical DC (cDC), which are derived from myeloid progenitors,are specialized in antigen processing and (cross)presentation. However, theyalone are sometimes not enough to prime efficient CD8+ T-cell responses. Theconcept of DC licensing by CD4+ T-cell “help” for anti-tumor CTL responses wasdiscovered in 1990s. Since then, ample mouse studies have been conducted aimingto discover the mechanism of the “help” signals. In this thesis, I delved intothe molecular mechanisms of CD4+ T-cell “help” as a critical signal that cansuccessfully activate human cDC1 and describe the clinical significance of cDC1licensing in human cancers. I also explored the role of type I interferon(IFN-I) signaling as part of cDC1 licensing machinery, and identified tumor-infiltratingKi67+CXCL13+CD4+ T-cells as IFN-I producers in the context of help delivery tocDC1 in the tumor. With the intention to employ the knowledge of DC biology incancer treatments, I also explored the potential of DC targeting immunotherapies.Lastly, as an integral component of my exploration into DC biology, Iinvestigated how myeloid progenitors respond to both external and internalstress. Show less
The aim of the research described in this thesis was to use structure-based design to optimise multiple properties of aryl sulfoxide monoacylglycerol lipase inhibitors as anti-inflammatory analgesics.
The aim of this thesis is to develop automatic methods for quantifying the severity of SSc disease from CT images through direct and indirect routes. The indirect route involves lung, lobe, and... Show moreThe aim of this thesis is to develop automatic methods for quantifying the severity of SSc disease from CT images through direct and indirect routes. The indirect route involves lung, lobe, and vessel segmentation (Chapter 2) and PFT estimation from segmented vessels (Chapter 5). The direct route focuses on directly estimating PFT (Chapter 4) and scoring ILD from CT (Chapter 3). Chapter 2 introduces a deep-learning network for lobe segmentation using a multi-task semi-supervised model and an alternating training strategy, evaluated on an external CT dataset. A Python package for calculating segmentation metrics is developed (see Chapter 8 Supplementary material). Chapter 3 presents a deep learning framework for automating SSc-ILD scoring, using a cascade of two neural networks to select craniocaudal positions and estimate pattern ratios, with synthetic data augmentation and a heat map method for output explanation. Chapter 4 proposes a deep-learning framework for automatic PFT estimation from CT scans, exploring the influence of segmented lungs and vessels, and introducing regression attention maps (RAM) to highlight contributing regions. Chapter 5 extends Chapter 4's work by enhancing PFT estimation performance with point cloud (PNN-Vessel) and graph neural networks (GNN-Vessel) based on vessel centerlines, and combining different networks for optimal results. Show less
This dissertation is an attempt at interrogating the relationship between world empire and universal ideology in Late Antiquity. It argues that universalism is a recurring, and almost inevitable,... Show moreThis dissertation is an attempt at interrogating the relationship between world empire and universal ideology in Late Antiquity. It argues that universalism is a recurring, and almost inevitable, condition of any aspiration for global domination, a pattern that emerged in early Christianity and still animates political ideologies of today such as liberal democracy and socialism. It also argues that the nature of such global ambitions requires the universal ideology they espouse to be supersessionist, which invariably results in an ideological, and occasionally physical, clash with other systems of thought. Furthermore, it posits that such beliefs most commonly manifest themselves in eschatological and apocalyptic thinking, for the obvious reason that in commenting about the end of the world and the fate of humanity, it is impossible to avoid talking about the other. As its case-studies, it deals with nascent Islam, its emergence as a non-supersessionist movement and its transition to supersessionism as an imperial religion, as well as apocalyptic Judaism and Christianity. Show less
Wat offline niet mag ook online niet. De Nederlandse en Uniewetgever drukken steeds vaker uit dat het normenkader op onlineplatforms gelijk is aan de offlinewereld. Hoewel de Nederlandse wetgever... Show moreWat offline niet mag ook online niet. De Nederlandse en Uniewetgever drukken steeds vaker uit dat het normenkader op onlineplatforms gelijk is aan de offlinewereld. Hoewel de Nederlandse wetgever in het geval van doxing heeft gekozen voor een strafbaarstelling wordt desinformatie binnen de EU enkel online gereguleerd. Ook de digitaledienstenverordening volgt een exceptionalistische benadering waarbij, bijvoorbeeld, tussen onlineplatforms en zeer grote onlineplatforms wordt gedifferentieerd. Deze bijdrage bespreekt deze exceptionalistische benadering en laat zien dat het in het belang van de vrijheid van meningsuiting (zowel online als offline) kan zijn om te differentiëren tussen online en offline normstellingen. Show less
Kivelä, L.M.M.; Fried, E.I.; Does, A.J.W. van der; Antypa, N. 2024
The overarching goal of this thesis is to set the foundations, but also make the first essential steps towards establishing a comprehensive, mesoscopic, hydrodynamic theory of epithelial tissues.... Show moreThe overarching goal of this thesis is to set the foundations, but also make the first essential steps towards establishing a comprehensive, mesoscopic, hydrodynamic theory of epithelial tissues. The stage is set by an exhaustive study of topological defects in passive p-atic liquid crystals, singularities in the orientation field, that allow us to bridge our continuum theory with the discrete epithelial cellular network. After questioning the very existence of active liquid crystals, we confirm they form a new, distinct universality class of orientationally ordered systems, of which tissues are a typical case. We then proceed to identify the precise nature of their orientational order. Although complex and long debated, we show that tissues exhibit only 6-fold (hexatic) and 2-fold (nematic) orientational order, at small and large scales respectively. Before concluding, we establish a predictive, quantitative duality between topological defect dynamics and cell intercalation. Cell intercalation is the origin of collective cell migration, an essential mechanism of epithelial tissues, necessary for functions such as morphogenesis, wound healing, and even cancer progression. Our results are supported by a combination of experiments, analytics, and numerical simulations. The analytic and computational toolkit we utilize comprises concepts, mathematics, and models from hydrodynamics, theory of elasticity, statistical physics, and topology. Finally, we close with some thoughts on the emergence in living systems, revolving around our central theme of epithelial tissues. Show less
Gender separatist utopian literature portrays communities that are populated with only women while men live elsewhere or at times as slaves. This separatism brings about issues of sociopolitical... Show moreGender separatist utopian literature portrays communities that are populated with only women while men live elsewhere or at times as slaves. This separatism brings about issues of sociopolitical and emotional conflict between women and men. This subgenre carries great potential for the interrogation of the supposed biologically inherent differences between women and men, and also among women in the same gender groups. I concentrated on the narrative cycle of hope, destruction, and rebirth present in many literary examples from this subgenre. The cycle starts out with the complete destruction of the current state of affairs in their respective worlds in order to achieve a state of tabula rasa. In this research project, I examined a wide variety of gender separatist feminist utopian texts, spanning from the work of Christine de Pizan from the 1400s -absent in most of the overviews of this genre dominated by men- up until the work of Leigh Richards in 2004 (a pseudonym for Laurie R. King). Keeping the scope of my corpus as wide as I could helped me gain a literary overview of the subgenre, with a clear focus on the last decades of the 20th century. My dissertation engages with questions regarding whether the connection between this narrative cycle and utopian disillusionment can lead to a perceived failure of the utopian ideal, whether feminist utopianism can be located in feminist dystopian narratives of destruction, how this cycle can interact with the common traditions of utopian literature, feminist utopian literature, and feminist theory, and how women's subjectivity in these works of literature relates to the problem of history, how the 'female subject' sees her role in relation to her sociopolitical context, and how the mechanism of hope, destruction and optimism interact in this subgenre. Show less
