The aim of this thesis is to develop noise robust electrical properties tomography (EPT) reconstruction methods that are free from tissue transition artifacts to support clinical applications for... Show moreThe aim of this thesis is to develop noise robust electrical properties tomography (EPT) reconstruction methods that are free from tissue transition artifacts to support clinical applications for complex tissue structures such as the brain. In particular the contrast-source inversion approach is pursued. This focus of this thesis is on the reconstruction of the electrical properties from the transmit field of radiofrequency coils most frequently available in magnetic resonance imaging. Show less
Parental socialization refers to the process through which parents transmit values and beliefs to their children. During this process, children learn to understand the world and shape their social... Show moreParental socialization refers to the process through which parents transmit values and beliefs to their children. During this process, children learn to understand the world and shape their social functioning. The impact of parental socialization can vary across different cultures. My research focuses on family interactions within Chinese cultures, emphasizing the importance of cultural nuances when examining the role of parental behaviors in children's social development. The study utilized samples of Chinese children and their parents, employing various research methods, including observations, interviews, and questionnaires. The findings indicated that Chinese mothers' psychological control had a relatively minor negative effect on children's emotion regulation and social anxiety. Additionally, the research revealed racism and colorism among Chinese children, which were associated with mothers' color-evasive socialization behaviors. Chinese mothers did not avoid talking about racial appearance and cultural background, which contrasts with studies in White Western populations where most White mothers showed color evasion. Chinese mothers’ acknowledgement of shared culture predicted children’s positive attitudes towards their own racial ingroup with a darker skin tone. My research underscores the unique features of Chinese culture that play a pivotal role in shaping the nature and consequences of parental socialization on children's social functioning. It highlights that Western theories related to parenting and color-evasive socialization may need adaptation when applied to non-Western cultural contexts. Show less
Metabolomics has the potential to play a pivotal role in understanding disease onset and progression, and ultimately personalized treatments. One of its major challenges is its large-scale... Show moreMetabolomics has the potential to play a pivotal role in understanding disease onset and progression, and ultimately personalized treatments. One of its major challenges is its large-scale implementation, which is necessary to deal with the high variability of the metabolome. In this work we have developed tools for automated sample handling and preparation for metabolomics analysis, and bioanalysis in general. The tools are versatile, suitable for high-throughput, and able to deal with sensitive and biomass-limited samples. Sample transfer through segmented-flow can accommodate a wide range of samples and volumes, and can work seamlessly with many downstream processing or analysis. Two sample preparation tools based on droplets; one universal preconcentration tools using controlled evaporation, and one based on simultaneous extraction and enrichment, also provide a versatile interface and can be used to bridge gaps between processing steps. The working principles of these sample handling and preparation tools are universal and can be adapted for specific applications. Show less
This research concerns the role of metabolic sensor AMPK, which is activated during low energy levels, and known to suppress the activation of some immune cells. I studied how AMPK regulates the... Show moreThis research concerns the role of metabolic sensor AMPK, which is activated during low energy levels, and known to suppress the activation of some immune cells. I studied how AMPK regulates the function of dendritic cells (DCs), immune cells that are key regulators of the adaptive immune response. Key findings include that drug-induced AMPK activation in DCs results in metabolic rewiring that leads to immunosuppressive DCs. Furthermore, we show that the AMPK signaling axis in DCs is important for protection against obesity-induced inflammation, while AMPK in DCs inhibits the anti-tumor immune response and thereby promoting tumor growth. Therefore, AMPK activation in DCs may be a promising strategy for the generation of therapeutic tolerogenic DCs, while AMPK inhibition may be beneficial for DC-based cancer therapies. Together, these findings contribute to a better understanding of AMPK as regulator of immunity and tolerance in dendritic cells. Show less
Utilizing the polymeric platform of polypept(o)ides, this thesis describes synthesis and investigation of novel triblock copolymers to obtain carrier systems with multiple compartments for... Show moreUtilizing the polymeric platform of polypept(o)ides, this thesis describes synthesis and investigation of novel triblock copolymers to obtain carrier systems with multiple compartments for efficient siRNA delivery. Although the individual microstructure of nanoparticles differs depending on the polymeric building blocks, desired application and cargo, the final nanoparticles always combine a polysarcosine (pSar) shell with a polypeptide core, providing the ability of siRNA complexation by a polycationic segment. In addition, a third block enabled either covalent cross-linking, hydrophobic / π- π-stacking mediated stabilization or co-encapsulation of small hydrophobic drugs. Broadening the structural variety of such polypept(o)ides, a novel synthetic procedure was introduced to access AA'B- and ABC-type miktoarm star polymers.Investigations have been dedicated to the design of novel polymeric structures based on polypept(o)ides, to improve the delivery of siRNA by Polyion Complex Micelles (PICMs), provide access to different polymeric architectures, and to establish novel synthetic methods for the synthesis of these materials. Covering aspects from the synthesis of novel polymeric species up to advanced drug delivery strategies for siRNA in vivo, developments throughout this thesis extent the accessibility of the polypept(o)ide platform for nucleic acid delivery, highlight their potential in nanomedicine and further elaborate delivery strategies for next-generation nanomedical applications. Show less
The thesis assess the robustness of 4D flow MRI for analyzing aortic hemodynamics and valvular flow, as well as exploring the clinical potential of this technique in patients with aortic and... Show moreThe thesis assess the robustness of 4D flow MRI for analyzing aortic hemodynamics and valvular flow, as well as exploring the clinical potential of this technique in patients with aortic and valvular disease. The first part of the thesis evaluates the reproducibility of segmenting the aortic lumen and calculating various hemodynamic parameters, demonstrating that these processes can be performed accurately and consistently. The second part examines the natural course of aortic hemodynamics during aging, concluding that hemodynamic parameters remain relatively stable. Furthermore, different hemodynamic phenotypes are identified in patients with aortic root and ascending aortic dilatation, possibly explaining the presence of dilatation. Show less
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
