This thesis is part of NanoNextNL, a micro and nanotechnology innovation consortium of the Government of the Netherlands and 130 partners from academia and industry. More information on www... Show moreThis thesis is part of NanoNextNL, a micro and nanotechnology innovation consortium of the Government of the Netherlands and 130 partners from academia and industry. More information on www.nanonextnl.nl. Show less
Synthetic long peptides (SLPs) derived from cancer antigens hold great promise as well-defined antigens for immunotherapy of cancer. However, the formulation of SLPs for in vivo administration... Show moreSynthetic long peptides (SLPs) derived from cancer antigens hold great promise as well-defined antigens for immunotherapy of cancer. However, the formulation of SLPs for in vivo administration still needs to be improved. So far, SLPs have been formulated in Montanide-based water-in-oil emulsions in (pre-)clinical trials. However, the use of Montanide as an adjuvant has some important limitations, such as: non-biodegradability; significant local side effects; poor control of release rate; lack of specific dentritic cell (DC)-activating capacity; and the presence of organic solvents (needed to dissolve the peptides prior to mixing with the adjuvant) in the final formulation. Therefore, alternative formulations containing an effective delivery system for peptide-based cancer vaccines are highly needed. Among the numerous vaccine delivery systems, poly(lactic-co-glycolic acid) (PLGA) biodegradable particulate delivery systems are particularly interesting because they are biocompatible; can protect soluble antigens from degradation and rapid clearance once administered; allow for co-encapsulation of (multiple) antigens and adjuvants; and mimic the size and structure of a pathogen, being more efficiently taken up by DCs than soluble antigen. This thesis describes fundamental studies on the design and applicability in a preclinical setting of PLGA-based particulate formulations for the delivery of SLP-based cancer vaccines. Show less
During this research project we studied circulating cells in the blood of people with cardiovascular disease, we investigated if these cells could be used as biomarkers for future cardiovascular... Show moreDuring this research project we studied circulating cells in the blood of people with cardiovascular disease, we investigated if these cells could be used as biomarkers for future cardiovascular incidents. We specifically looked at circulating immune cells such as monocytes, T cells and neutrophils. It was shown that both specific subsets of monocytes as well as neutrophils could be used to predict cardiovascular events in patients with cardiovascular disease. Surprisingly it was shown that different cell subsets were predictive for cardiovascular events in men and women. Investigating the difference between men and women further we show that the acute immune response in during cardiovascular disease is different between men and women. While the response in males was skewed towards a monocyte response, in women the acute response was skewed towards a T cell response. The research presented in this thesis shows that our knowledge of the gender specific immune response in cardiovascular disease is limited and further research is necessary. Show less
The main object of this study is the MIPES Indonesia, which I collected during my previous research that was funded by the British Library in London. The present research is primarily aimed at... Show moreThe main object of this study is the MIPES Indonesia, which I collected during my previous research that was funded by the British Library in London. The present research is primarily aimed at elaborating the tradition of writing and copying manuscripts by students of pesantrens in East Java Province and their relation to the learning tradition as practiced during the nineteenth and twentieth centuries. In order to reconstruct this tradition, I propose four research questions that are to be elucidated throughout this dissertation:1. What is the history of two collections of Islamic manuscripts from Indonesia: the collection of the Library of the University of Leiden and of the MIPES Indonesia, which is the main object of this study?2. Which codicological features can we reconstruct from the digital facsimile of the entire MIPES Indonesia Collection?3. How can we publish an inventory of the whole MIPES collection?4. How does the learning tradition of Islam in Indonesian pesantren influence a reader’s response to a manuscript?5. What can we propose regarding a tentative typology from the appearance of vocalization, interlinear translation and marginal notes in these manuscripts? Show less
Toxicological insults are met by cellular adaptive stress response pathway activation. We find that activation of adaptive stress responses occur well before the typical ultimate outcome of... Show moreToxicological insults are met by cellular adaptive stress response pathway activation. We find that activation of adaptive stress responses occur well before the typical ultimate outcome of chemical cell injury. To increase our understanding of chemically-induced adaptive stress response pathway activation and its contribution to safety assessment we believe that a time-resolved, sensitive and multiplex readout of chemical-induced toxicological relevant cellular stress responses will be essential. For that purpose, we developed a platform containing a panel of distinct adaptive stress response reporter cell lines. These are used for automated high content live cell imaging and quantitative multi-parameter image analysis to elucidate critical adaptive stress response pathway activation that can contribute to human chemical safety assessment. To conserve the endogenous gene regulatory programs, we tag selected reporter target genes with GFP using BAC-transgenomics approaches. In this thesis we demonstrate the functionality of individual BAC-GFP pathway in toxicity reporter cell lines. The application of these reporters in chemical safety assessment in relation to drug-induced liver injury is discussed in detail. We anticipate that ultimately a phenotypic adaptive stress response profiling platform will allow a high throughput and time-resolved classification of chemical-induced stress responses assisting in the safety assessment of chemicals. Show less
In this thesis computational modeling is used to help unravel the mechanisms of key steps in angiogenesis, the formation of new capillaries from existing blood vessels. The first step in... Show moreIn this thesis computational modeling is used to help unravel the mechanisms of key steps in angiogenesis, the formation of new capillaries from existing blood vessels. The first step in angiogenesis is the invasion of new branches into the surrounding tissue by degradation of extracellular matrix proteins, e.g. fibrin. A first model describes how invading sprouts use the so called plasminogen system, which dissolves fibrin matrices. A next model asks how endothelial cells can dynamically switch position during angiogenesis. Based on experimental observations, several authors suggest that dynamic cell shuffling is under strict, genetic control. Our simulations show, however, that shuffling can emerge as a side effect of sprouting. Once a sprout is formed, it needs to hollow to allow blood flow. The mechanisms responsible for this hollowing, or lumen formation, are debated: vacuoles may punch a hole through the cell, or cells might repulse one another. In our simulations, both these hypotheses can work synergistically in lumen formation, suggesting that both hypotheses might work together. In a final chapter, we introduce a workflow to simultaneously test the impact of changes in the value of multiple parameters on the outcome of the type of models used in this thesis. Show less
Chapter 1 presents a general introduction to the factors involved in crop domestication and the specific role of transcription factors in this process. Chapter 2 describes the functional analysis... Show moreChapter 1 presents a general introduction to the factors involved in crop domestication and the specific role of transcription factors in this process. Chapter 2 describes the functional analysis of a Dof-type transcription factor, named OsDof24, from rice.chapter 3 describes the role of OsDof25 in the regulation of OsC4PPDK. Interactions between OsDof25 and OsC4PPDK were confirmed in experiments involving EMSA, yeast one-hybrid analysis and transient expression in rice protoplasts. The regulatory role of OsDof25 in OsC4PPDK expression was confirmed using OsDof25 misexpression plants. The results suggested that OsDof25 is a trans-activator of the OsC4PPDK gene in rice. Chapter 4 describes the effects of OsDof24 and OsDof25 on the content of rice seeds storage proteins. First the interaction between both OsDof24 and OsDof25 with the GluB-1 promoter was investigated by a set of in vitro and in vivo experiments. Results showed that both OsDof24 and OsDof25 can affect seed storage protein content probably by activating the transcription of the GluB-1 promoter. Finally, in Chapter 5, a general discussion of the results from Chapters 2, 3 and 4 is presented. Show less
The thesis is focused on the investigation of the electron transfer mechanisms leading to solar fuel production and to the identification of engineering principles that can be used to design... Show moreThe thesis is focused on the investigation of the electron transfer mechanisms leading to solar fuel production and to the identification of engineering principles that can be used to design materials able to improve charge separation. Molecular systems composed of three or more subunits arranged in a Donor-Antenna-Acceptor design are required to achieve efficient photoinduced charge separation. It is shown how structural changes in the systems design can be used to systematically optimize the energy gradients and electronic coupling between the molecular subunits, necessary to achieve controlled unidirectional charge transfer. To gain insight into the mechanisms governing the charge transfer processes within a molecular system, the process of photoinduced heterogeneous electron injection is investigated through nonadiabatic dynamics simulations. Coherent electron-nuclear vibrational effects are found to drive the electron transfer process by promoting the coherent superposition of the exciton and the charge transfer quantum state. A photoanode for solar water splitting comprising the functions of light-harvesting, charge separation and catalysis is also investigated. It is observed that, following a fast heterogeneous electron injection, the system catalytic activity is driven by a proton-coupled electron transfer mechanism in which the role of the solvent is crucial. Show less
For more than 65 years, scientists have been fascinated by the idea to miniaturize electrical circuits toward the smallest length scales. One particular way is inspired by nature itself,... Show moreFor more than 65 years, scientists have been fascinated by the idea to miniaturize electrical circuits toward the smallest length scales. One particular way is inspired by nature itself, specifically to assemble electrical components and switches from atoms and molecules. The molecules typically used have dimensions of the scale of a few nanometers (1 nanometer = 0,000000001 meter). The scientific research area that represents the study of electrical currents through molecules is called "molecular charge transport" or "molecular electronics". In this thesis, I have performed fundamental research on charge transport through various molecules. Specifically, I have investigated a special type of molecule that has the ability to change its spin state. To test these functional molecules, I have used a more robust type of molecular device that enables me to bridge the size gap mentioned above. This thesis has led to two important new insights. First, the properties of a switchable molecular device can be strongly enhanced artificially by making use of a charge transport mechanism called multiple inelastic cotunneling. Second, we show that the spin transition phenomenon can take place in a molecular-nanoparticle ensemble. Show less
We live in a magnetic universe with magnetic fields spanning an enormous range of spatial and temporal scales. In particular, magnetic fields at the scale of a galaxy are known as galactic magnetic... Show moreWe live in a magnetic universe with magnetic fields spanning an enormous range of spatial and temporal scales. In particular, magnetic fields at the scale of a galaxy are known as galactic magnetic fields and are the focus of this PhD thesis. These galactic magnetic fields are very important since they affect the dynamics of the interstellar gas as well as the gas distribution. The presence of these magnetic fields induces a certain type of radiation to occur at radio frequencies known as synchrotron radiation. The observed polarization properties of this synchrotron radiation then serves to record the imprint of these magnetic fields. The goal of this thesis has been to infer the structure of the magnetic field across various spatial scales in our own Galaxy as well as the strength and structure of the magnetic field in other galaxies using radiopolarimetric observations. Show less
This thesis, from a comparative perspective, examines the worldview and its interplay to the frontier and military policies in early periods of the two ancient empires on Eurasian: Rome and Han... Show moreThis thesis, from a comparative perspective, examines the worldview and its interplay to the frontier and military policies in early periods of the two ancient empires on Eurasian: Rome and Han China. The first part (chapter 1 and chapter 2) concerns the formation and transformation of the world views of Rome and Qin-Han China in their respectively lengthy trajectories of empire-building. It is followed by part two (chapter 3 and chapter 4) in which I shift my focus from ideology to practical issues in attempt to observe how the distinctive world views held by the elite class of Rome and China were manifested and interacted with the actual policy-making and territorial conquests. The last part of the dissertation (chapter 5 and chapter 6) concentrates on the roles of emperors. By highlighting the distinctive roles that the Roman and Chinese emperors had played, it allows audience to have a better understanding in the similarities, and especially the crucial differences concerning the perception of the world and actual policies discussed above. Also, I hope this tentative comparative study sheds some lights on the reflection of the concept of empire in current scholarship of ancient history. Show less
Aim of this thesis was to provide evidence for the clinical implication of biomarkers in blood and urine, as well as genetic markers, for the prediction of the severity and course of febrile UTI.... Show moreAim of this thesis was to provide evidence for the clinical implication of biomarkers in blood and urine, as well as genetic markers, for the prediction of the severity and course of febrile UTI. Furthermore, this thesis focused on optimization of antimicrobial treatment of febrile UTI. The main results are: 1. Recent hospitalization, indwelling urinary catheter and especially individual fluoroquinolone (FQ) use are independent risk factors for a FQ-resistant Escherichia coli febrile UTI. 2. Women with febrile UTI, including postmenopausal women and those with comorbidities, can be safely and successfully treated with a 7-day course of oral ciprofloxacin. In men, however, treatment duration should be at least 14 days. 3. Diabetes mellitus does not affect the clinical presentation and course of febrile UTI; concurrent illnesses and higher age of the diabetic population attribute to a more complicated course. 4. MR-proADM more accurately predicts a complicated course of disease than currently available inflammatory biomarkers. Importantly, biomarkers derived directly from host defense mechanisms are not suitable to distinguish between febrile UTI patients with and without bacteremia. 5. MP-TF activity is related to disease severity and bacteraemia in febrile E. coli UTI and may contribute to the prothrombotic state in gram-negative sepsis. Show less
Special populations are groups of patients that may respond differently to drug treatment due to a variety of factors, such as age or disease. Therefore, in drug development dedicated clinical... Show moreSpecial populations are groups of patients that may respond differently to drug treatment due to a variety of factors, such as age or disease. Therefore, in drug development dedicated clinical studies are often required to determine the optimal dose for these (vulnerable) patient groups. Such studies are complicated by ethical and practical barriers that can hinder the objective of the study when not well designed. To optimise the design of such studies, the application of model-based approaches is essential. In this thesis, we aimed to develop a semi-physiological framework that constitutes a scientific basis for optimisation of study designs in special populations. First, we examined the accuracy of existing approaches in paediatric patients. For the "allometric scaling plus maturation function" approach, the accuracy was shown low especially in young children. An alternative approach was found in the physiological well-stirred-model of hepatic clearance. On this basis, the semi-physiological PK models were developed by interfacing descriptive compartmental pharmacokinetic models with the well-stirred-model of hepatic clearance, and a mechanistic description of plasma-protein binding. The performance of these models was evaluated using two paradigm-drugs (solifenacin and tamsulosin) and was shown successful for the prediction of the pharmacokinetics in paediatric, hepatic-impaired and renal-impaired patients. Show less
This PhD dissertation covers the dynamics of floodplain fisheries in the Waza Logone floodplain (Far North region, Cameroon) and conflicts between fishers. The main objective is to understand the... Show moreThis PhD dissertation covers the dynamics of floodplain fisheries in the Waza Logone floodplain (Far North region, Cameroon) and conflicts between fishers. The main objective is to understand the dynamics of the fisheries sector in the Waza Logone floodplain and specifically the level of fishing effort, diversity of fishing gear and conflicts between fishermen. It__s aims to (i) assess the current situation of the fishing effort and catches in the Waza Logone floodplain, (ii) evaluate the sustainability of fisheries practices, and (iii) provide a means to better understand the factors influencing conflicts and conflict resolution between fishers in the Waza Logone floodplain. Methodology consisted mainly of a rural appraisal technique and included an open workshop with 18 traditional and municipal authorities, leaders of international and national NGOs, an interview survey in 91 villages and a daily survey on fishermen, canoes and fishing materials, between August 2008 and June 2009 in 13 fishing spots. In addition, fishing channels along the Logomatya River, the Lorome Mazera River and around the Abana natural mares were counted, after which thirteen (13) of them were selected for a more detailed survey. It also included an institutional analysis on conflict management and fisheries policy in Cameroon and the Central and West African region. Show less
DNA-hosted silver clusters (Ag:DNAs) have attracted a lot of attention due to their small size (~20 atoms), wide range of applications in chemistry and biology, and sequence-dependent optical... Show moreDNA-hosted silver clusters (Ag:DNAs) have attracted a lot of attention due to their small size (~20 atoms), wide range of applications in chemistry and biology, and sequence-dependent optical tunability. Most of the previous studies are focused on the ensemble of emitters in solution. However, little is known about the optical properties of individual emitters, which is a crucial step towards understanding of their real nature, otherwise lost in ensemble averaging. We show that the excitation and emission spectra of individual emitters are broad even at 1.7 K (FWHM ~25 nm). Also, polarization measurements indicate that the excitation is not strongly dependent on the polarization of excitation light, whereas the emission is highly linearly polarized. Furthermore, from time-resolved measurements, we can conclude that the emission of single emitters can be fitted with single exponential decay curve, whereas the emitters organized with nanometer precision on the DNA scaffolds show double–exponential decay. This indicates the interaction between densely packed Ag:DNAs. Finally, we show that the DNA tubes can be used as a nano-contact glue between the colloidal particles functionalized with short DNA strands. Show less
In part 1 of the thesis quantitative proteomics was used to determine changes in abundance and phosphorylation status of host proteins during infection with the human pathogen chikungunya virus ... Show moreIn part 1 of the thesis quantitative proteomics was used to determine changes in abundance and phosphorylation status of host proteins during infection with the human pathogen chikungunya virus (CHIKV). Several proteins were identified that may be specifically downregulated during CHIKV infection to create a suitable environment for viral replication. eEF2 was identified as a factor that becomes strongly phosphorylated during infection with several viruses which may be a mechanism to stall translation in response to viral infection. In part 2 of the thesis the discovery of a novel and unusual -2/-1 programmed ribosomal frameshifting (PRF) mechanism is described that is used during translation of the nonstructural open reading frame of the economically important porcine reproductive and respiratory syndrome virus (PRRSV). This mechanism relies on a slippery site and stimulatory RNA signal in the PRRSV genome and is stimulated by the viral protein nsp1beta and host poly (C) binding proteins 1 and 2. Frameshifting results in the synthesis of two previously unidentified proteins, nsp2 TF (-2 PRF) and nsp2N (-1 PRF). Virus mutants that can no longer make the frameshift products are attenuated and may be used for vaccine development. Show less
An increasing number of fetal diseases are being detected prior to birth due to major improvements in prenatal ultrasound examinations and the wide implementation of screening programs. For various... Show moreAn increasing number of fetal diseases are being detected prior to birth due to major improvements in prenatal ultrasound examinations and the wide implementation of screening programs. For various diseases, fetal therapy may be a life-saving option or an alternative to postnatal treatment, to prevent permanent organ damage. A major breakthrough in fetal therapy was the introduction of intrauterine blood transfusion for severe fetal anemia in the early 1960s. Since then, fetal therapy has gradually evolved resulting in a dramatic increase in overall survival in several fetal diseases. In the Netherlands, fetal surgical interventions are concentrated in one center, the LUMC, a tertiary medical center which serves as the national referral center for fetal therapy. Although an increasing number of children are being born alive after fetal therapy, reliable data on the long-term neurodevelopmental outcome remain scarce. Follow-up studies are of paramount importance to increase our knowledge on the quality of long-term survival and to identify potential risk factors for adverse outcome. In this thesis, studies on the long-term neurodevelopmental outcome after fetal therapy for various fetal diseases are presented including intrauterine transfusion for fetal anemia, fetoscopic laser surgery for twin-twin transfusion syndrome and selective reduction in complicated monochorionic pregnancies. Show less
Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) can play a key role in understanding neurobiological mechanisms of diseases that affect the human brain. The specific changes that occur... Show moreDiffusion-weighted magnetic resonance spectroscopy (DW-MRS) can play a key role in understanding neurobiological mechanisms of diseases that affect the human brain. The specific changes that occur within neurons can be reflected as changes in the diffusivity of tNAA, whereas the changes in glial cells can cause pronounced changes in the diffusivities of tCr and tCho. This information combined with that obtained from diffusion tensor imaging (DTI) and other MRI tools can help elucidate various disease processes in the future. The main purposes of this thesis are (i) to investigate neuroanatomy in vivo with DW-MRS, (ii) to develop methodology to enable future clinical applications of the technique in human brain in vivo, and (iii) to characterize the microstructural deficit in neuropsychiatric systemic lupus erythematous (NPSLE) with DW-MRS and other microstructural tools such as DTI and magnetization transfer imaging. The studies presented in this thesis show the robustness and clinical relevance of microstructural information obtained via DW-MRS. The contributions of this thesis such as the optimized acquisition protocols for single volume DW-MRS, the robust DW-CSI and DW-MRS post-processing pipelines that comprise information from DTI, will all facilitate the applications of DW-MRS both for basic neuroscience research and clinical research studies. Show less
The legend of St. Aūr contained in the Naqlūn homily deals with the foundation history of the church of the archangel Gabriel at the monastery of Naqlūn in the province of Fayyum in Egypt. The... Show moreThe legend of St. Aūr contained in the Naqlūn homily deals with the foundation history of the church of the archangel Gabriel at the monastery of Naqlūn in the province of Fayyum in Egypt. The origins of this still existing monastery date back to the fifth century. After its composition in the eleventh century, the text remained in use till the present and spread all over Egypt and Ethiopia. Apart from the central date, 26 Ba’ūna, the text contains a number of other dates which reflect the liturgical calendar in use at Naqlūn. Moreover, four other homiletic texts and a hymn were identified, each related to the monastery of Naqlūn in a different way, forming evidence of the rich literary tradition that developed at this site from the eleventh century onwards. The texts recall into memory the great saints from earlier periods, such as St. Antony, the father of monasticism, and Samuel of Qalamūn, and link Naqlūn with several other monastic sites in the neighbourhood, giving Naqlūn a place in the history of Egyptian monasticism. The Middle Arabic language of all five texts, its style and its contents, are characteristic of Copto-Arabic hagiographic literature of the Middle Ages. Show less
This dissertation comprises an empirical study and a meta-analytical study on autonomic nervous system (ANS) functioning and attachment representations in maltreating parents. For the empirical... Show moreThis dissertation comprises an empirical study and a meta-analytical study on autonomic nervous system (ANS) functioning and attachment representations in maltreating parents. For the empirical study we recruited a sample of 45 mothers with substantiated abuse and neglect and 45 non-maltreating control mothers. Mothers listened to infant cry sounds of varying pitches while their heart rate, vagal tone, pre-ejection period, skin conductance, and salivary α-amylase were measured. Maltreating mothers showed a blunted ANS response to the cry sounds, as well as a lack of coherence between ANS components, compared to the non-maltreating group. During a second appointment we conducted the Adult Attachment Interview. More maltreating mothers had an Unresolved/disoriented (U/d) attachment representation and maltreating mothers showed lower coherence of mind. In turn, U/d attachment was associated with a decrease in skin conductance during an attachment-related computer paradigm, while coherence of mind was associated with higher skin conductance during the paradigm. A meta-analysis of 11 studies (N = 524)showed that (risk for) child maltreatment was associated with higher levels of baseline ANS activity, while a second meta-analysis (k = 11, N = 503) showed no differences in ANS stress reactivity between maltreating parents/at-risk adults and non-maltreating/low-risk comparison groups. Show less
