Research indicates that interactions with law enforcement, determinative of access to justice is far from positive for racial minorities and women and is often characterized by suspicion,... Show moreResearch indicates that interactions with law enforcement, determinative of access to justice is far from positive for racial minorities and women and is often characterized by suspicion, unfriendliness and dismissal of complaints. This conduct is not easily captured by prohibitive regulation although it can amount to discrimination proscribed by equality laws. Training, monitoring and codes of conduct have had limited effect. This book, therefore, explores another approach to legally compliant behaviour, a lens which focuses on the internalization of norms underlying laws and regulations, through persuasive technology. Drawing from the nudge theory, as well as Lessig's articulation of the influence of norms and architecture on behaviour, this book takes an interdisciplinary approach, rooted in a broader view of the law's impact on human cognition and decision making and technology's impact on behaviour. The inter-disciplinary lens combines an understanding of the cognitive and organizational factors driving discrimination with behaviour change theories such as the social identity theory, and technological artefacts like conversational agents that can influence behaviour, to proffer an alternative solution. This work constitutes the first steps towards addressing discriminatory behaviour by leveraging the ubiquity and versatility of technology to regulate behaviour in accordance with the law and its intentions. Show less
This thesis describes innovative interventions that aim to improve clinical workplace learning in a clerkship internal medicine. Clinical workplace learning is challenging in many aspects. It takes... Show moreThis thesis describes innovative interventions that aim to improve clinical workplace learning in a clerkship internal medicine. Clinical workplace learning is challenging in many aspects. It takes place through participation in actual patient care and is dependent on collaboration with other healthcare professionals. The workplace may consist of physical, online and virtual learning environments, The interventions in this thesis targeted these three elements by the development and analysis of 1). interprofessional learning activities in a Clinical Teaching Unit (CTU), 2) a Small Private Online Course (SPOC) using theoretical and practical educational principles to stimulate motivation and collaborative learning, and 3). remote learning in a virtual environment using head-mounted cameras at bedside. The findings imply that implementation of a CTU not only facilitates the integration of patient care and education but also the integration of different professions working together. The SPOC is a useful and accessible addition to the clinical learning environment, however online collaboration remains challenging. Virtual learning with cameras on site could offer sustainable opportunities for interprofessional, crossinstitutional or even international learning with real patient encounters. Show less
Healthy aging is one of the prime goals in today's society and atherosclerosis is among the greatest causes of morbidity in elderly. Cardiovascular disease patients receiving treatment are often of... Show moreHealthy aging is one of the prime goals in today's society and atherosclerosis is among the greatest causes of morbidity in elderly. Cardiovascular disease patients receiving treatment are often of advanced aged and have an aged immune system, which limits translating experimental findings to the patient. It is therefore essential to take aging into consideration when investigating immune cells and their responses in atherosclerosis studies. This thesis describes research exploring the impact of aging on the immunological landscape in atherosclerotic cardiovascular disease using single-cell profiling. Through the use of a highly translational aging mouse model of atherosclerosis, we characterized inflammation in the plaques of young versus old mice. We discovered new cell types (T and B cells) not present in young mice with atherosclerosis. These cells secrete a variety of inflammatory factors that may contribute to the disease process and exacerbate arteriosclerosis. While the aged B cell is more prevalent in female mice, the aged T cell is more abundant in male mice. We then also found these aged cells in the blood and plaques of cardiovascular disease patients. These aged cell types could be interesting targets for future treatments against progression of atherosclerotic cardiovascular disease. Show less
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
Pseudomonas Aeruginosa is a Gram-negative bacterium which can form biofilms, increasing its resistance against antibiotics and the host immune system. Polysaccharides are an integral part of this... Show morePseudomonas Aeruginosa is a Gram-negative bacterium which can form biofilms, increasing its resistance against antibiotics and the host immune system. Polysaccharides are an integral part of this biofilm, one of these polysaccharides is called Psl. PslG is a glycosidase, able to cleave this polysaccharide, Psl, into smaller fragments. This decreases the antibiotic resistance of P. Aeruginosa. Interestingly PslG is produced by P. Aeruginosa itself, where it is found on the synthesis gene of Psl. The exact effects of PslG remain partly unknown. Moreover, only hypotheses have been made as to why P. Aeruginosa expresses such an enzyme. Here we have developed a set of activity-based probes based on Psl to discover the mode of action of PslG. Subsequently, a set of inhibitors have been designed based on the Psl motive and the mechanism of action of PslG. PslG was then co-crystallized with the inhibitors in order to study their binding interactions. Show less
This thesis explores the role of lipid mediators (LM) in osteoarthritis (OA), examining their profiles in patients and how therapeutic interventions influence these profiles. The first part reviews... Show moreThis thesis explores the role of lipid mediators (LM) in osteoarthritis (OA), examining their profiles in patients and how therapeutic interventions influence these profiles. The first part reviews the therapeutic potential of LM, particularly in non-weight-bearing joints, validated through the Hand OA Prednisolone Efficacy (HOPE) study. The second part focuses on LM regulation during the inflammatory response, identifying their role in innate and adaptive immunity, particularly in monocyte-derived macrophages. The third part investigates the mechanisms by which pro-inflammatory and pro-resolving LMs function, using 17-HDHA and oleic acid as models to study their effects on cellular behavior and inflammation resolution. 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 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
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
Hydrogen fuel cells are expected to be pivotal in the energetic transition towards renewable energy sources such as solar and wind power. However, their industrial scalability is severely hindered... Show moreHydrogen fuel cells are expected to be pivotal in the energetic transition towards renewable energy sources such as solar and wind power. However, their industrial scalability is severely hindered by the high cost and degradation rate of platinum catalysts, one of their key components. Addressing this challenge necessitates developing better catalysts, which requires a better fundamental understanding of their reactivity and degradation mechanism. In this thesis, we investigate the (in)stability of model platinum surfaces submerged in liquid and under applied voltage, thus simulating the operational conditions of fuel cells. For this we use a home-build Electrochemical Scanning Tunneling Microscope (EC-STM), which allows us to observe, in real time, the surface structure at the atomic scale. Our findings elucidate the origin of the platinum surface roughening that takes place upon voltage cycling. Moreover, we demonstrate that closely-spaced atomic steps are prone to bunch together, resulting in steps with multi-atomic height. This structural change has a significant effect on the catalyst reactivity, as we explain in detail. Overall, this dissertation contributes to a deeper fundamental understanding of the surface processes that drive platinum surface restructuring as well as their implications for reactivity. Show less
There is accumulating evidence for an increase in severe global drought events. In particular, Europe experienced several severe droughts in 2003, 2015, and 2018 (unprecedented in the past 2,110... Show moreThere is accumulating evidence for an increase in severe global drought events. In particular, Europe experienced several severe droughts in 2003, 2015, and 2018 (unprecedented in the past 2,110 years). Such droughts have caused serious and far-reaching impacts on terrestrial ecosystems. As droughts are predicted to become more prolonged and intense across wide regions in the coming decades, the risks to the human system as a result of the disturbed ecosystems worldwide will increase. To mitigate these risks, it is critical to prioritize the most vulnerable ecosystems and intervene on time. Thus, the understanding of ecosystem responses and their vulnerability to intensive drought needs to be developed. This thesis reveals European-wide ecosystem vulnerability based on ecosystem responses. With more frequent and severe droughts in the future, a wide range of ecosystems will become more vulnerable and may even collapse due to high mortality. This thesis provides several suggestions for timely early warning and intervention possibilities for vulnerable ecosystems. Moreover, this thesis demonstrates the potential of remote sensing in monitoring ecosystem responses. Combining remote sensing for early and comprehensive monitoring of ecosystems will provide new possibilities and critical information for future drought prevention and management. Show less
In light of climate change, it is crucial to determine whether plant species can adapt to future climates to avoid extinction. Plants adapt to various conditions by altering their functional traits... Show moreIn light of climate change, it is crucial to determine whether plant species can adapt to future climates to avoid extinction. Plants adapt to various conditions by altering their functional traits, such as leaf size or photosynthetic rate. Some traits appear linked and vary together between species, suggesting resource management strategies of plants. Traits can also vary within species, known as intraspecific trait variation (ITV), and its extent varies between species. Our understanding of how and why these traits vary within species is limited.This dissertation uses newly compiled global databases of species' ITV and genetic adaptation rates. We investigate whether trait-trait relationships between species also occur within species, confirming these as true plant strategies. We then explore the drivers of components of ITV: phenotypic plasticity, allowing plants to change in response to the environment, and genetic adaptation, involving inherited changes. Each offers different benefits for species adapting to changing conditions. By combining them, we can better understand plant species' adaptive capacity. Finally, we evaluate whether plants with different growth forms and from different biomes differ in their adaptive capacity to climate change.Our results provide new insights into plant strategies and have important implications for vegetation modelling and conservation efforts. Show less
This thesis explores the role of what has traditionally been considered as neural “noise”, specifically BOLD signal variability and aperiodic neural activity, in human cognitive functions,... Show moreThis thesis explores the role of what has traditionally been considered as neural “noise”, specifically BOLD signal variability and aperiodic neural activity, in human cognitive functions, particularly in metacontrol. The metacontrol model assumes that individuals vary in their cognitive styles between "persistence" and "flexibility." Persistence emphasizes focused goal pursuit, while flexibility allows for easy task switching and consideration of diverse possibilities. Through three empirical studies, this thesis investigates the relationship between two specific forms of neural "noise" – BOLD signal variability and aperiodic neural activity – and metacontrol biases (i.e., persistence vs. flexibility). Chapter 2 emphasizes the importance of resting-state BOLD signal variability in understanding individualized cognitive control styles. Chapter 3 highlights the importance of the aperiodic component of the EEG power spectrum in reflecting demand-specific metacontrol states. Notably, Chapter 4 illuminates the functional significance of aperiodic activity in creative thinking. Overall, the research presented in this thesis highlights the importance of resting-state BOLD signal variability and aperiodic activity in the EEG power spectrum for understanding the neural underpinnings of cognitive functions. Show less
To cope with environmental changes, humans need to adjust their cognitive control states to meet different challenges. Two important cognitive control states are cognitive persistence and cognitive... Show moreTo cope with environmental changes, humans need to adjust their cognitive control states to meet different challenges. Two important cognitive control states are cognitive persistence and cognitive flexibility. Persistence is a state of maintaining stable attention, while flexibility is a state where attention can switch freely. These two states are antagonistic to each other; one cannot switch attention flexibly while being focused, and one cannot focus on a single stimulus while switching attention flexibly. Our understanding of the neural mechanisms underlying these cognitive control states is still limited. Therefore, in this dissertation, we used two brain science research techniques, EEG and fMRI, to study brain activities associated with these two states. To induce these states, the dissertation employed two creative thinking tasks, namely convergent thinking and divergent thinking, and two meditation techniques, focused attention meditation and open monitoring meditation. The results discuss EEG and fMRI indicators related to these states, providing preliminary evidence for research in this field. Show less
This dissertation aims to explore how university students use mobile technology for their self-directed language learning and investigate factors influencing their self-directed learning with... Show moreThis dissertation aims to explore how university students use mobile technology for their self-directed language learning and investigate factors influencing their self-directed learning with mobile technology. It contributed to theoretical and practical knowledge of self-directed language learning using mobile technology outside the classroom in higher education. The research aims of the dissertation were twofold. First, it was aimed at increasing our understanding of the learning experience of learners’ self-directed learning process while preparing for IELTS (International English Language Testing System). Second, it was aimed at suggesting implications for improving the effectiveness of self-directed learning, with implications for learners, educators, and IT practitioners. Four studies were performed focused on (1) an overview of the learning strategies that learners used in their self-directed learning assisted by mobile technology; (2) self-directed learners’ learning process while preparing for the IELTS on their own; (3) language learners’ behavioral intention towards and actual use of mobile technology in self-directed learning; and (4) language learners’ engagement, satisfaction, and persistence in the context of informal, self-directed language learning using mobile technology. In sum, the conclusions of the four studies will inform self-directed learners, educators, and software developers on how to effectively enhance self-directed learning with mobile technology. Show less
As part of the Indo-European language family, the Indo-Iranian branch traces its origins back to the Indo-European homeland on the Pontic-Caspian steppe 5000 years ago. But how did it spread from... Show moreAs part of the Indo-European language family, the Indo-Iranian branch traces its origins back to the Indo-European homeland on the Pontic-Caspian steppe 5000 years ago. But how did it spread from there to Asia? The aim of this thesis is to uncover the early prehistory of Indo-Iranian by investigating its relationship to the Balto-Slavic languages of Eastern Europe, which have been hypothesized to form a subgroup with Indo-Iranian: Indo-Slavic. By comparing the linguistic data with evidence from archaeology and genetics, this thesis traces the migration path of prehistoric Indo-Iranian speakers from the Pontic-Caspian steppe, via the rivers and forests of Eastern Europe, across the Ural Mountains, and southwards to the steppes of Central Asia. Show less
