Heart failure is a major health care problem with high mortality. Although advances have been made in treatment of patients suffering from heart failure with reduced ejection fraction, this is not... Show moreHeart failure is a major health care problem with high mortality. Although advances have been made in treatment of patients suffering from heart failure with reduced ejection fraction, this is not true for patients suffering from heart failure with preserved ejection fraction. The mechanism underlying heart failure with preserved ejection fraction is still unclear. Recent evidence suggests that factors circulating in blood might have an effect on the microvessels, including those in the heart. To diagnose and treat microvascular diseases, we aim to explore the association of circulating plasma factors with microvascular integrity. As current human 2D models with cultured endothelial cells lack sufficient complexity to assess the function of microvascular endothelial-pericyte interactions, research on microvascular loss largely depends on animal models. To mimic the microarchitecture and functions of the human blood vessel in a more efficient way for drug discovery, we developed the microvessel-on-a-chip. This system allowed us to screen microvascular destabilization factors in blood and study the efficacy of potential drugs for microvascular diseases. In conclusion, our platform may serve as a unique tool for microvascular destabilization studies as well as for the development of novel therapeutic strategies to combat microvascular complications. Show less
In order to gain a better insight into the basis of the rapid jasmonic acid (JA)-mediated stress response, an integrated approach using a targeted high-resolution mass spectrometry-based (HRMS)... Show moreIn order to gain a better insight into the basis of the rapid jasmonic acid (JA)-mediated stress response, an integrated approach using a targeted high-resolution mass spectrometry-based (HRMS) platform, was conducted to monitor the metabolism of JA using the model system of cell suspension cultures of Catharanthus roseus. Components in the JA-pathway involved in the primary metabolism such as the fatty acid (FA)-precursor C18:3; terpenoid indole alkaloids (TIA) belonging to the secondary metabolism and JA derivatives involved in its catabolism were examined. The effects of JA on FA and TIA in cell suspension cultures of C. roseus were time dependent and are thus considered late events in the JA-stress response. Feeding cells with d5-dnOPDA led to the accumulation of d5-JA and d5-JA-Ile in cells, proving that cells are constitutively ready to incorporate and transform dnOPDA into JA-Ile catalyzed by JA-amino synthetase 1 (JAR1). Moreover, d5-JA was excreted to the growth medium possibly by JA/JA-Ile TRANSPORTER 1 (JAT1). Signal attenuation of JA included the accumulation in cells of 12-hydroxyjasmonic acid (12-HOJA), 12-hydroxyjasmonoyl-L-isoleucine (12-HOJA-Ile) and 12-carboxyjasmonoyl-L-isoleucine (12-HOOCJA-Ile) and 12-O-glucosyl-jasmonic acid (12-O-Glc-JA), as well as 9,10-dihydrojasmonic acid (DHJA) in growth medium. Show less
The main focus of the thesis is the discovery and development of novel inhibitors of bacterial metallo-β-lactamases (MBLs). Chapter 1 provides an overview of FDA-approved β-lactamase inhibitors as... Show moreThe main focus of the thesis is the discovery and development of novel inhibitors of bacterial metallo-β-lactamases (MBLs). Chapter 1 provides an overview of FDA-approved β-lactamase inhibitors as well as those currently being evaluated in clinical trials. Chapters 2 and 3 describe our evaluation of small-molecule aminocarboxylic acids either commercially available or prepared via chemoenzymatic approaches for their activity against clinically important MBLs. We found that nitrilotriacetic acid and its phosphonic acid isostere, as well as ethylenediamine-N,N′-disuccinic acid (EDDS), are potent inhibitors of New-Delhi metallo-beta-lactamase (NDM-1). Focusing on another class of MBL inhibitors, chapter 4 describes our study of selected thiol-containing compounds. Among them, thiomandelic acid showed the most potent and broad-spectrum synergistic activity when combined with meropenem against MBL-producing gram-negative bacteria. Stability studies, however, showed that thiomandelic acid is oxidized to its corresponding disulfide with the half-life of ca. 5 h. To address the stability and selectivity issue associated with thiols, in chapter 5 we describe a prodrug approach where we synthesized and evaluated a series of thiol conjugates of cephalosporins. Some of these cephalosporin conjugates exhibit potent inhibition of IMP class of MBLs. Finally, chapter 6 describes our biochemical evaluation of a newly identified class A carbapenemase. Show less
This dissertation investigates memorisation strategies that were employed in the fields of painting and calligraphy in imperial China, with a focus on the Ming (1368-1644) and Qing (1644-1911)... Show moreThis dissertation investigates memorisation strategies that were employed in the fields of painting and calligraphy in imperial China, with a focus on the Ming (1368-1644) and Qing (1644-1911) dynasties. Its core questions are: How do memory aids reflect the society that produced them? What role did they play in the transmission and codification of practical knowledge in the field of arts?With the expansion of the printing industry during the Ming dynasty, knowledge of artistic practices came to be valued not only by craftsmen, but also by editors, publishers and highly educated authors. By analyzing both publication context and practices of remembering recorded in works from the Ming and Qing, this study provides insight into the dynamic changes of social values attributed to crafts. It takes a socio-historical approach to analyse memory aids in textual and visual formats recorded in manuals, including formulae (jue 訣) and charts. It provides six case studies to discuss under which circumstances memory aids were composed and how they were received over time, laying a foundation for understanding how practical skills were taught and how new canons of artistic knowledge were constantly being negotiated. Show less
In the liminal area of southern Latium and northern Campania Rome founded three neighbouring colonies with different citizenship status in the 4th-3rd c. BC. The dissertation re-examines the... Show moreIn the liminal area of southern Latium and northern Campania Rome founded three neighbouring colonies with different citizenship status in the 4th-3rd c. BC. The dissertation re-examines the historical and archaeological sources within this micro-region and focuses on local-regional characteristics and pre-Roman structures that influenced the colonies. Thereby, this research argues for a local colonial material culture and discusses the impact of cultural and economic factors on the colonial foundations. These support their multi-layered integration into supra-regional trade and production networks as well as spatial and individual connectivity in late Republican times. In contrary to traditional conceptions limited to citizenship status and military purpose, this research emphasizes the heterogenous socio-political, economic, religious, and cultural developments of the colonies. Show less
Rheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this... Show moreRheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this thesis we studied involvement of the forefoot. Throughout this thesis we found that synovitis in the rheumatoid foot affects more than just the joints. In an anatomic study we revealed that the tendon-sheaths in the forefoot also possess a synovial layer. Inflammation of this, detected by MRI that is referred to as tenosynovitis, was an important aspect of RA involvement in the forefoot. In addition, intermetatarsal bursae also detected by MRI are also often inflamed due to disease-involvement. These extra-articular involvements of the synovium that are found in RA importantly contribute to joint swelling and walking disability, and are therefore clinically relevant. Therefore we believe that it is essential for the clinician to pay attention to the forefeet of patients with RA to have a complete idea of disease activity Show less
The goal of this thesis was to provide guidance for the neuro-oncologist’s daily clinical practice with respect to tailoring antiepileptic drug (AED) treatment and improving the radiological... Show moreThe goal of this thesis was to provide guidance for the neuro-oncologist’s daily clinical practice with respect to tailoring antiepileptic drug (AED) treatment and improving the radiological assessment of tumor response and progression in patients with gliomas and brain metastases. Part I of this thesis focused on the impact of AEDs on clinical outcome, such as survival, and the consequence of AED withdrawal on seizure recurrence and radiological outcome. Part II focused on the impact of antitumor treatment on clinical and radiological outcome, especially regarding the assessment of (pseudo)progression. Show less
Despite the fact that gold nanoparticles (GNPs) are one of the most studied nanoparticles, there is still a necessity for new approaches allowing for effective protective coating to enable wider... Show moreDespite the fact that gold nanoparticles (GNPs) are one of the most studied nanoparticles, there is still a necessity for new approaches allowing for effective protective coating to enable wider use of GNPs in biomedical applications. This dissertation is focusing on the use of self-assembling peptide amphiphiles as stabilizers for spherical GNPs and gold nanorods (GNRs). Peptide amphiphiles stabilize GNPs and GNRs through formation of a self-assembled monolayer on their surface. These gold-peptide amphiphile conjugates are stable under (and beyond) physiologically relevant conditions, do not induce cytotoxicity, and can be readily modified with ligands of interest. To demonstrate the potential of these conjugates, they were used to study T-cell mediated immune responses as function of GNP size and shape. It was shown that GNRs deliver more antigen to the lysosomes and induce better T-helper responses, while larger particles were more effective at mediating antigen delivery to the cytosol, thus inducing better cytotoxic responses. Show less
Margaret of Burgundy (1374-1441) is known mainly for two reasons. Firstly, her marriage in 1385 to William of Bavaria, eldest son of the Count of Hainault, Holland and Zeeland, laid the foundation... Show moreMargaret of Burgundy (1374-1441) is known mainly for two reasons. Firstly, her marriage in 1385 to William of Bavaria, eldest son of the Count of Hainault, Holland and Zeeland, laid the foundation for the transfer of power in these principalities to the Burgundian dynasty some 50 years later. Secondly, she supported her only child Jacqueline of Bavaria, who fought many battles in order to prevent this. The combination of these two roles points to a conflict of interest. By supporting her daughter as the rightful Bavarian heir, Margaret inevitably came into conflict with members of her own dynasty of origin, the Valois Burgundians. The overarching question in the research presented in this thesis is what tilted the scales for Margaret as a political player in different phases of her life: was it her loyalty to the Burgundian or to the Bavarian dynasty, her connection with the Hook party in Holland, or was she driven mainly by self-interest, as is sometimes suggested? Related to this is the question whether her means were substantial enough to allow her to play her own game. In this biographical study, a chronological and a thematic approach have been combined. The loyalty question serves as guideline for the first part, in which the story of Margaret’s life is told chronologically within the broader context of political developments. The thematic second part is dedicated to her financial position as a widow, her court, and her religious and literary patronage. Show less
This is a decolonial study about Ñuu Savi (Mixtec) pictorial manuscripts (codices), Mexico. The aim is the understanding of their cultural values through a holistic and diachronic way, studying... Show moreThis is a decolonial study about Ñuu Savi (Mixtec) pictorial manuscripts (codices), Mexico. The aim is the understanding of their cultural values through a holistic and diachronic way, studying living and historical-cultural heritage of Mixtec People, based on the re-integration of cultural memory and cultural continuity, linking the past and the present through the Mixtec language (or Sahan Savi) and from its own perspective. The final aim is the re-appropriation of this knowledge by the Ñuu Savi communities themselves. Show less
Streptomyces are filamentous bacteria that produce more than two-thirds of known antibiotics. Due to their multicellular lifestyle as well as their prolific production of secondary metabolites, Str...Show moreStreptomyces are filamentous bacteria that produce more than two-thirds of known antibiotics. Due to their multicellular lifestyle as well as their prolific production of secondary metabolites, Streptomyces are of unique fundamental and applied importance. However, Streptomyces have unstable genomes, an attribute that can cause genomic rearrangements and dramatically alter their phenotype. Previous studies have failed to explain this phenomenon. In this dissertation, we investigate the evolutionary functions and mechanisms of genomic instability in Streptomyces coelicolor. We first find that a subpopulation of cells generated through large genomic rearrangements becomes specialized to produce antibiotics. This results in a division of labor which benefits the entire colony, while the yield and diversity of antibiotics are maximized, despite significant fitness costs to this altruistic subpopulation. Next, we show that these altruistic mutants continue to lose fitness due to the irreversible accumulation of large deletions and deleterious mutations, coupled to an increased mutation rate. Finally, we explore the molecular consequences of large genomic rearrangements for development and antibiotic production using detailed proteomics and metabolomics analyses, which highlight key pathways that are impacted by these genomic events. Overall, this dissertation provides new insights of genomic instability in Streptomyces. Show less
The challenge of achieving fast quantification in metabolomics is the presence of severe matrix effects during the MS analysis of complex samples. Complex samples also result in challenges during... Show moreThe challenge of achieving fast quantification in metabolomics is the presence of severe matrix effects during the MS analysis of complex samples. Complex samples also result in challenges during metabolite identification as complex MS/MS spectra and peak overlap in 1H NMR complicate structure elucidation. The goal of this thesis is to tackle these challenges by the development and application of innovative fractionation approaches and state-of-the-art MS and NMR analyses. Show less
In this thesis we investigated the ability of two-photon multifocal microscopy for single-molecule microscopy in live cells and organisms. Two-photon excitation combined with multifocal scanning... Show moreIn this thesis we investigated the ability of two-photon multifocal microscopy for single-molecule microscopy in live cells and organisms. Two-photon excitation combined with multifocal scanning has the potential to achieve, high (temporal) resolution imaging at a low background. Splitting the laser beam into multiple beamlets reduced laser power to all but eliminate photobleaching. The low background combined with the fast scan speeds and absence of photobleaching allowed us to measure single-particles and single-molecules in live zebrafish embryo's for long time periods. To the best of our knowledge, it is the first time that single-molecule molecules have been observed in a wide-field two-photon microscope. Show less
The next generation of high-contrast imaging instruments on space-based observatories requires sophisticated wavefront sensing and control in addition to a high-performance coronagraph. This thesis... Show moreThe next generation of high-contrast imaging instruments on space-based observatories requires sophisticated wavefront sensing and control in addition to a high-performance coronagraph. This thesis aims to further our knowledge of coronagraphs and their integration into high-contrast imaging instruments. Chapter 2 presents a new algorithm for global optimization of the apodizing phase plate coronagraph. Chapters 3 and 4 present the theory, design and laboratory results of the SCAR coronagraph, which uses a phase plate and single-mode fibers. Chapter 5 presents the development of HCIPy, a software package in Python for high-contrast imaging. Chapters 7 and 8 present the theory, design and laboratory results of the PAPLC coronagraph, which uses a phase plate, knife-edge focal-plane mask and Lyot stop, and an integrated high-order wavefront sensor. These new coronagraphy and wavefront sensing concepts pave the way for improved high-contrast imaging instruments, both from ground-based and space-based observatories. Show less
This thesis describes two studies on the efficacy and safety of vaccinations in patients stable autoimmune myasthenia gravis, one with tetanus revaccination and one with influenza vaccination. Of... Show moreThis thesis describes two studies on the efficacy and safety of vaccinations in patients stable autoimmune myasthenia gravis, one with tetanus revaccination and one with influenza vaccination. Of both vaccinations, the humoral response and clinical parameters of the disease are described. For tetanus revaccination, also the cellular response is described. Furthermore, the validation of a disease specific quality of life questionnaire is described. Show less
Dissolving microneedles are a subgroup of microneedle types that completely dissolve within the skin. During this dissolving process the vaccine, stored in the needle matrix, is released into the... Show moreDissolving microneedles are a subgroup of microneedle types that completely dissolve within the skin. During this dissolving process the vaccine, stored in the needle matrix, is released into the skin. Dissolving microneedles are made of a water-soluble, inert and safe material, such as hyaluronic acid. The microneedles have been used to vaccinate via the skin, which is a very immune competent organ that holds great potential for vaccine delivery. The minimally invasive and easy nature of the injections can reduce the risk of infections and alleviate the need for trained personnel. Furthermore, they eliminate all sharp waste as the needles dissolve during drug delivery.The goals of this project has been to improve the immunogenicity of vaccines through skin delivery, allowing for increased understanding of skin immunology and the development of pain free and safe vaccine delivery systems. Show less
Inflammatory Bowel Diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic immunological digestive diseases with a progressive character and associated with significant... Show moreInflammatory Bowel Diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic immunological digestive diseases with a progressive character and associated with significant healthcare costs. Different solutions have been proposed such as innovation in care monitoring or implementation of electronic health (eHealth). IBD is one of many chronic diseases that could benefit from eHealth, adding smartphone applications to the toolbox for care management has the potential improve disease understanding, enhance medication adherence, improve patient-physician communications, and for earlier interventions by medical professionals when problems arise. Furthermore, the accessibility to Big Data and increased computational resources have paved the way for Artificial Intelligence (AI) to provide potential solutions for the management of prototypical complex diseases with advanced heterogeneity and alternating disease states, like IBD. In this thesis we assessed the current economic and psychosocial impact of IBD by assessing its effect on indirect costs, productivity and caregiving. Furthermore, we observed if we can proactively identify IBD patients’ needs using eHealth and Artificial Intelligence. Lastly, we analyze the impact of monitoring IBD patients using eHealth interventions in order to facilitate the delivery of high-value care. Show less
It has now been well established that shocks and turbulent motions in the intra-cluster medium (ICM) generated through cluster mergers can produce large-scale synchrotron emission. However, the... Show moreIt has now been well established that shocks and turbulent motions in the intra-cluster medium (ICM) generated through cluster mergers can produce large-scale synchrotron emission. However, the underlying particle acceleration mechanisms responsible for the origin of these faint diffuse radio sources are not well understood. With the advent of new generation low-frequency radio telescopes and better calibration techniques it has now become possible to unveil low-frequency radio sky with unprecedented depth and sensitivity, that is full of potential for new discoveries. The first part of this dissertation presents the study to better understand the nature of revived fossil (radio) plasma sources in galaxy cluster and establish them as a distinct class of radio sources. The complexity of objects, observed with these new instruments are just tip of the iceberg of the population, and will challenge the traditional taxonomy of diffuse radio sources. The last part of the dissertation focuses on deriving the deepest radio source-counts at 150 MHz. This is one of the several cosmological tests to check feasibility of new cosmological models and a sanity check for the data reduction. The derived source-counts are also compared with the other existing determinations, as well as with state-of-the-art evolutionary models. Show less
This dissertation includes four different experimental field studies. In each study, we focussed on a different, societally relevant problem within the realm of financial decision-making in the... Show moreThis dissertation includes four different experimental field studies. In each study, we focussed on a different, societally relevant problem within the realm of financial decision-making in the Netherlands. In Chapter 2 we investigate whether we could increase saving behaviour, by giving participants feedback about their progress towards their savings goal. In Chapter 2 we encouraged people to adhere to their appointment at a debt advice service by sending them reminders via SMS. In Chapter 4 we investigated whether adjusting the websites of a Dutch moneylender in a way that makes the total costs of a loan more salient, affects customers’ loan decisions. In Chapter 5, we investigated whether interventions that provided students with personalized information about the future costs of their loan would encourage students to recalibrate their monthly loan amount.The studies that are presented in this dissertation, show the value of using behavioural insights in increasing sound financial decision-making. But if we really want to change behaviour for the better, we should explore new ways in which insights from behavioural science could be embedded in policies, processes or systems, because with every choice architecture that is being established, behaviour is steered into a certain direction. Show less
