The outbreaks of AIDS and COVID-19 showed clearly how infectious viruses can influence people’s lives. Investigating the changes in the host metabolism may provide a paradigm shift to consider... Show moreThe outbreaks of AIDS and COVID-19 showed clearly how infectious viruses can influence people’s lives. Investigating the changes in the host metabolism may provide a paradigm shift to consider immune-metabolic interactions as therapeutic targets. The aim of this thesis is to examine the interplay between the immune system and metabolism during viral infections, such as HIV and coronavirus. These investigations will utilize metabolomic and lipidomic mass spectrometry techniques to gain a comprehensive understanding of the metabolic changes that occur during viral infections. To enhance the coverage of the lipidome, a new method will be developed. Show less
Cancer immunotherapy has experienced remarkable advances in the last decades. Striking clinical responses have been achieved for several solid cancers, particularly cancer types with a high... Show moreCancer immunotherapy has experienced remarkable advances in the last decades. Striking clinical responses have been achieved for several solid cancers, particularly cancer types with a high mutation burden, which placed tumour-mutated antigens (neoantigens) centre stage as targets of tumour immunity and cancer immunotherapy. Neoantigens can be presented in complex with HLA molecules on the tumour cell surface, where T cells with the correct specificity can recognize the neoantigen as ‘non-self’ which will trigger killing of the tumour cell by the T cell. In theory, cancers with a low/moderate mutation burden that present neoantigens in complex with HLA class molecules could still be eligible for T cell-mediated immunotherapy. This thesis, describes the finding that neoantigen-specific T cells are present in mismatch-repair proficient (MMR-p) colorectal cancer patients, a low mutation burden cancer type. Moreover, CD39 and CD103 were found as cell surface markers that pinpoint the T cell population that contains the neoantigen-specific T cells. In addition, subsequent metastasis of a melanoma patient cohort were studied and revealed that also at advanced, late-stage disease, neoantigen-directed T cell therapy is, in theory, still applicable. Taken together, the studies reveal potential for the development of neoantigen-directed cancer immunotherapy for a broader patient population. Show less
The endothelium is a crucial component of the vascular system, and its proper function is vital for microcirculatory function and by extension cardiovascular health. Hence, endothelial dysfunction... Show moreThe endothelium is a crucial component of the vascular system, and its proper function is vital for microcirculatory function and by extension cardiovascular health. Hence, endothelial dysfunction is involved in a majority of cardiovascular disease and poses a high societal burden. Endothelial nitric oxide bioavailability is essential for a healthy microcirculation. The first half of this thesis investigates the reliability of imaging techniques that non-invasively assess the microcirculation and nitric oxide bioavailability, including laser speckle contrast imaging, Doppler flowmetry, dark field microscopy, skin fluorescence imaging and near infrared spectroscopy. In addition, the vascular effects of a mixed meal and a far-infrared light emitting patch, as measured with the imaging methods, are assessed. Finally, differences in microcirculatory function in people with mitochondrial disorders and healthy volunteers are explored. In the second half of the thesis, first-in-human and proof-of-mechanism studies with a soluble guanylyl cyclase stimulator and a phosphodiesterase inhibitor are described, drugs thought to enact some of their effects through modulation of vascular function downstream of nitric oxide. The thesis concludes with a critical appraisal of the investigated imaging modalities and their potential for inclusion in future clinical trials with drugs aiming to affect the microcirculation. Show less
In the current global context, there is a pressing need to address sustainable energy supplies to safeguard our Planet and its ecosystems. The choices made by human society have a significant... Show moreIn the current global context, there is a pressing need to address sustainable energy supplies to safeguard our Planet and its ecosystems. The choices made by human society have a significant impact on genetic evolution and climate. To ensure a better future for all, it is crucial to exercise foresight, foster collaboration across various sectors, and reach agreements based on fair and ethical principles. Science plays a pivotal role in advancing energy conversion, offering the potential for significant scientific breakthroughs that contribute to the protection and respect of our World. Specifically, the development of solar-to-fuel devices holds promise for achieving this transition to green energy. This Ph.D. dissertation centers on the development and functionalization of 2D membranes and materials, which constitute integral components of these conversion devices. The optimization of functionalized 2D materials necessitates a comprehensive computational design approach. This involves the adoption of a multiscale computational framework for the thorough design of these materials and the precise prediction and understanding of molecular processes, encompassing molecular self-assembly, ion transport, and catalytic surface reactions. Show less
We show that Kirchhoff ’s law of conservation holds for non-commutative graph flows if and only if the graph is planar. We generalize the theory of (Euclidean) lattices to infinite dimension and... Show moreWe show that Kirchhoff ’s law of conservation holds for non-commutative graph flows if and only if the graph is planar. We generalize the theory of (Euclidean) lattices to infinite dimension and consider the ring of algebraic integers as such a lattice. We compute some invariants using capacity theory and obtain a partial solution to the (algorithmic) closest vector problem. We generalize the results on (universally) graded rings by Lenstra and Silverberg. We study the special case of group rings, and show that under similar assumptions rings can be uniquely decomposed into a group ring in a maximal way. We give a functorial algorithm to compute roots of fractional ideals of orders in number rings. Show less
Indian agriculture is widely believed to be in crisis. There is broad consensus among scholar, policymakers and activists that economic hardships and the changing climate have made sustaining a... Show moreIndian agriculture is widely believed to be in crisis. There is broad consensus among scholar, policymakers and activists that economic hardships and the changing climate have made sustaining a livelihood through farming increasingly untenable. There is a strong sense that something has to be done to help farmers deal with the crisis, and in recent years agricultural insurance has been presented as a possible fix for rural distress. This dissertation studies how a new agricultural insurance scheme called PMFBY becomes part of everyday social interactions and experiences. Insurance companies often assert that quantified procedures can accurately - and fairly - calculate the extent of agricultural risk, attach a price tag to it and protect against it. Can quantification really be the antidote to crisis? To answer this question I explore how insurance numbers translate to the everyday experiences of rural people in central Maharashtra. I find that, when seen from the perspective of those encountering them in their daily lives, the numbers are anything but straightforward. The effects of quantification were often arbitrary, and despite promises of transparency, they had a tendency to obscure rather than clarify. In short, the numbers turned out to be inconsistent and ambiguous. The dissertation describes how people attempt to make sense of this ambiguity through their moral understandings. It focusses on the (often heated) discussions, the collective pondering such discussions led to, the personal dilemmas it posed as well as the dreams and aspirations numbers became entwined with. I explore how such quandaries unfold and argue that a focus on the morality of quantification brings to light the social life of numbers beyond their 'objective' factuality. Show less
Targeted therapy using EGFR inhibitors cetuximab and panitumumab has anti-tumor efficacy in colorectal cancer, though only in patients without a KRAS mutation in their tumor. This thesis aims to... Show moreTargeted therapy using EGFR inhibitors cetuximab and panitumumab has anti-tumor efficacy in colorectal cancer, though only in patients without a KRAS mutation in their tumor. This thesis aims to give insight on several aspects of EGFR inhibitors en RAS mutations in colorectal cancer. It reviews aspects of mutational analysis, aims to find ways to restore sensitivity to EGFR inhibitors in patients with KRAS mutated colorectal cancer and discusses the distinctive skin toxicity of cetuximab en pantiumumab. Show less
Healthcare is under pressure: an ageing population, healthcare-staff shortage, quality (healthcare outcomes) must increase and costs must be reduced.Yet, what are the outcomes of healthcare?For... Show moreHealthcare is under pressure: an ageing population, healthcare-staff shortage, quality (healthcare outcomes) must increase and costs must be reduced.Yet, what are the outcomes of healthcare?For some conditions, quality of care is measured for every patient. Unfortunately, this is not the case for prostate cancer and lumbar disk herniation in the Netherlands. We used claims data to evaluate healthcare outcomes and volume-outcome relationships.Examples of our results:Prostate cancer:• More than 30% of patients is incontinent 1 year after radical prostatectomy• Large differences between hospitals (19%-85%)• Risk of incontinence is 52% lower at highest-volume hospitalsLumbar disk herniation:• One year after hernia surgery, 23% of patients have one or more undesirable outcomes (e.g. re-operation, use of opioids).• Wide variation in number of operations and outcomes per hospitalOur recommendations:• Reconsider the disproportionately strict interpretation of the GDPR (AVG) for healthcare research• Unlock the huge potential of healthcare research based on existing data • Make routine measurement of healthcare outcomes a national standard, for prostate cancer even on a per surgeon level• Centralization of care should be combined with outcome measurement• Hospitals should share healthcare outcomes with patients• Our results urge doctors, health insurers, patient organizations and policymakers to take action Show less
Two types of financial incentives can help improve healthy lifestyles: carrots (a reward where one can gain something) and sticks (a deposit contract where one can lose something). In a deposit... Show moreTwo types of financial incentives can help improve healthy lifestyles: carrots (a reward where one can gain something) and sticks (a deposit contract where one can lose something). In a deposit contract, participants deposit own money and can lose or earn it back depending on lifestyle changes. We studied the potential of deposit contracts to stimulate a healthy lifestyle.A smartphone app was developed together with the Swiss university ETH Zurich to conduct experimental research into the effects of deposit contracts. In addition, we collaborated with the American company WayBetter to observe the effects of commercially available deposit contracts. Finally, the opinion of people with cardiovascular disease and healthcare professionals regarding financial incentives and deposit contracts for lifestyle change was investigated.The results show that deposit contracts can have strong effects on exercise behavior (daily step counts) in the short term. The results also show that voluntary participation in deposit contracts is limited, but can be increased by doubling the amount deposited and by allowing participants to determine the amount themselves. Finally, healthcare providers think it is a good idea to use financial incentives, but people with cardiovascular disease themselves are skeptical about the use of deposit contracts. Show less
The first aim of this thesis was to evaluate the Late Effects Comprehensive Care & Follow-up (LEEF) program after pediatric stem cell transplantation for nonmalignant diseases at the LUMC, and... Show moreThe first aim of this thesis was to evaluate the Late Effects Comprehensive Care & Follow-up (LEEF) program after pediatric stem cell transplantation for nonmalignant diseases at the LUMC, and includes the assessment of various late effects and health-related quality of life. The second aim was to implement and evaluate aspects of VBHC at the LEEF program. This thesis describes lessons learned from the VBHC implementation in the Late Effects Comprehensive Care & Follow-up (LEEF) program and suggests possible future directions for VBHC implementation in similar comprehensive care programs. In this thesis, patient-reported outcomes (PROs) have demonstrated their value in research, such as long-term quality of life studies, but they have also proven to be valuable when used in clinical practice. The evaluation of PROs for both research purposes and clinical use can be expanded within the broader care path of pediatric stem cell transplantation. Furthermore, when discussing long-term HSCT outcomes, it is not solely about survival rates, but PROs are integral to capturing these long-term outcomes. Show less
Oxygen supplementation is a cornerstone of supportive medical treatment for critically ill patients. We studied self-reported attitudes towards oxygen therapy and actual clinical practice of ICU... Show moreOxygen supplementation is a cornerstone of supportive medical treatment for critically ill patients. We studied self-reported attitudes towards oxygen therapy and actual clinical practice of ICU clinicians. We found that clinicians are concerned with oxygen induced lung injury and will change mechanical ventilation settings accordingly. However, we performed a large, randomized trial assessing whether a conservative oxygenation strategy resulted in reduced mortality compared to a liberal oxygenation strategy and found there was no significant difference in mortality between the two groups. This thesis has brought to light an important problem of studying ICU patients regarding the consent procedure. We had to exclude patients because no consent had been obtained, losing valuable data and risking selection bias. Afterwards we asked patients how they experienced participating in the trial and most were not aware of their participation but did agree with their participation. This challenges the feasibility of informed consent in critically ill patients. Moreover, we researched disturbances in the homeostasis of sodium and found that an increase in serum sodium was associated with mortality, even in patients with normonatremia and moderate hyponatremia. This challenges the assumption that correcting hyponatremia would lead to lower mortality. Show less
Most of current public-key cryptography is considered insecure against attacks from sufficiently powerful quantum computers. Post-quantum cryptography studies methods to secure information... Show moreMost of current public-key cryptography is considered insecure against attacks from sufficiently powerful quantum computers. Post-quantum cryptography studies methods to secure information resistant against such attacks. One proposal is isogeny-based cryptography, which bases its security on computational hardness assumptions related to maps between elliptic curves. We analyze the security of isogeny-based cryptographic schemes, in particular those based on class group actions. We find special cases in which the underlying computational hardness assumptions can be broken, sometimes even by classical computers. Furthermore, we study a method, known as radical isogenies, to accelerate the execution of isogeny-based protocols. Finally, we introduce multivariate generalizations of Hilbert class polynomials, which may yield computational benefits compared to their univariate counterparts. Show less
Polymyxins are clinically used antibiotics, discovered in mid-20th century. Once abandoned due to excessive nephrotoxicity, they are now used increasingly to address infections caused by multi-drug... Show morePolymyxins are clinically used antibiotics, discovered in mid-20th century. Once abandoned due to excessive nephrotoxicity, they are now used increasingly to address infections caused by multi-drug resistant Gram-negative bacteria.In this thesis, we describe the development and synthesis of analogues of polymyxin, aimed at reducing its associated nephrotoxicity. Analogues were made by semisynthesis, with modifications introduced mostly in the exocyclic portion of the molecule. Especially the introduction of a disulfide bond within the linked lipid helped in reducing the toxicity of the molecules, as evidenced by testing on proximal tubule epithelial cells. For most potent analogues, the antimicrobial activity was completely retained.In addition, this thesis describes studies on the mechanism of action of polymyxin, mostly based on the full stereoisomer of polymyxin B4. This analogue lacks antimicrobial activity, indicating its original stereochemistry to be of utmost importance for its use as an antibiotic.Hybrids based on polymyxin B derivatives are described, addressing non-conventional targets. A hybrid with vancomycin (typically active on Gram-positive bacteria only) shows activity on Gram-negative bacteria. A polymyxin-based hybrid coupled to a peptide with a beta-hairpin motif addresses Gram-negative bacteria, presumably by binding to outer membrane protein BamA. Show less
This thesis explores the 4 pillars of Primary Healthcare (PC), the innovations that have been implemented to improve them, and the role digital technologies may have had as part of these... Show moreThis thesis explores the 4 pillars of Primary Healthcare (PC), the innovations that have been implemented to improve them, and the role digital technologies may have had as part of these innovations, with a focus on their impact in the management of chronic conditions. This thesis seeks to identify the optimal way to incorporate digital technologies in PC and how they could improve the PC consultation, in particular, and the PC field in general. It is composed of three parts: the first revises the concept of PC and explores interventions to improve it; the second part, delves into the role digital technologies have had in improving PC and looks at how apps may impact the treatment of chronic conditions. And the third, explores the digital competencies required for PC professionals to use these technologies. Show less
Understanding how galaxies form, interact, and evolve comes largely from comparing theory predictions with observational data. Numerical simulations of galaxies provide the most accurate approach... Show moreUnderstanding how galaxies form, interact, and evolve comes largely from comparing theory predictions with observational data. Numerical simulations of galaxies provide the most accurate approach to testing the theory, as they follow the non-linear evolution of gas and dark matter in great detail and incorporate numerous baryonic processes, among which are energy feedback from supernovae (SNe) and Active Galactic Nuclei (AGN). In this thesis, we show the results of the development of the new model COLIBRE for cosmological simulations of galaxy formation that include a cold interstellar medium. First, we present a new SN feedback recipe developed for COLIBRE, whereby SN energy is injected into the gas in thermal and kinetic forms, and the total energy and momentum of the system of gas and stars are exactly conserved. Second, we conduct a detailed comparison of different ways in which SN energy is distributed in the gas environment around young stellar populations. Third, by using our simulation setup originally developed to test COLIBRE’s SN feedback, we show that the radioactive isotope Fe60 that has been detected on Earth is likely of SN origin. Finally, we present the calibration of the SN and AGN feedback of the COLIBRE model using machine learning. Show less
This book is about three West African sign languages with different time-depths, community sizes and patterns of social interactions. Adamorobe Sign Language (AdaSL), Ghana, is an old village sign... Show moreThis book is about three West African sign languages with different time-depths, community sizes and patterns of social interactions. Adamorobe Sign Language (AdaSL), Ghana, is an old village sign language used by 33 deaf people. Langue des Signes de Bouakako (LaSiBo), Côte d'Ivoire, is a new village sign language, used by six deaf people. Língua Gestual Guineense, Guinea-Bissau, is an emerging school-based sign language used by around 500 deaf people.In the three sign languages, 45 narratives of personal experiences were analysed to better understand how the time depth, the community size and the socialisation frequency influenced the three sign languages. Four different descriptive analyses of the narratives were carried out. Study 1 analysed the structure of the narratives, following Labov & Waletzky's model (1967) and Freytag's dramatic pyramid (1894). Studies 2, 3 and 4 focus on specific narrative devices that work to make narratives more convincing, as part of Labov's (1972) "evaluation" component. These devices refer to the moments when storytellers give dramatic prominence to narratives through the incorporation of characters, such as the use of different signing perspectives (Study 2), the use of role shifting between characters and constructed dialogues (Study 3) and the use of different types of descriptions of the animal (Study 4).These studies show that AdaSL and male LGG signers use devices that reflect a greater ability to capture the audience's attention, while LaSiBo and female LGG signers tend to show similar patterns in using simpler or reduced devices.This study shows that the frequency of social interaction between deaf peers is the most crucial factor in language change over time. Show less
The research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of... Show moreThe research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of platinum and palladium compounds utilizing the [Pt(bapbpy)]2+ scaffold. The study identifies intercalation as the primary mechanism of action for these complexes. Furthermore, it provides a detailed structure-activity relationship analysis, highlighting the critical role of the complex's protonation state in influencing its biological activity and efficacy. Subsequently, the study delves into photoactivated chemotherapy (PACT) using ruthenium (II) complexes, where light activation of ruthenium complexes enables targeted drug delivery to tumor cells, thereby reducing adverse effects. This research emphasizes the development of ruthenium-based compounds that can photorelease a DNA repair inhibitor, specifically targeting the RAD51 protein, essential for Homologous Recombination (HR). By disrupting the DNA repair mechanisms in cancer cells, this approach seeks to enhance the cytotoxicity of the therapy and address drug resistance. Show less
The development of class cleavages in Chile in the 20th century has been notable for its similarity to European cases, which gave rise to important socialist left-wing parties. However, the Chilean... Show moreThe development of class cleavages in Chile in the 20th century has been notable for its similarity to European cases, which gave rise to important socialist left-wing parties. However, the Chilean left was characterised by its revolutionary socialist project channelled through the legal and democratic means of the time, known as the Chilean road to socialism. This thesis seeks to explain the formation of this project through a historical analysis of the development of socialism as a political expression of the class cleavage in Chile between 1891 and 1938. To this end, the study focuses on the ideological dimension of cleavages, with emphasis on three specific aspects of ideological groups: their strategic configurations, their organisational forms, and their political adaptability. The thesis reconstructs the ideological trajectory of the various socialist currents of the period, whose strategies and organizations encompassed a wide range of both institutional and extra-institutional projects. Through this analysis, it identifies the ideological patterns that facilitated or hindered certain socialist groupings from successfully channelling their respective political projects and eventually integrating themselves into the Chilean party system. Show less
The terrorist attacks of September 11th, 2001 represent a seminal event in American history, catalyzing a 20-year period in which counterterrorism was the top priority for US national security. Yet... Show moreThe terrorist attacks of September 11th, 2001 represent a seminal event in American history, catalyzing a 20-year period in which counterterrorism was the top priority for US national security. Yet, our understanding of US counterterrorism policy and the factors driving its evolution remains varied and unclear.In this dissertation, two dimensions of policy perspective and mode of thinking are integrated into a framework called the Policy Profile Code (PPC), a model that helps us understand the options policymakers have when confronted with crisis. Through the PPC, we metaphorically named the profiles of a policymaker: The Commander, The Prosecutor, The Negotiator, and The Doctor. When applying the PPC to each US presidential administration (Bush, Obama, and Trump) across the 20-year period following 9/11, we find overall change in US counterterrorism policy that included an evolution from The Commander, to The Prosecutor, to The Negotiator. We also find The Doctor policy profile was not adopted during this period. Show less
