The ideas underlying this thesis are that lipidomics may improve the diagnosis of liver metabolic diseases, and can provide further insights into the underlying pathophysiology of these diseases.... Show moreThe ideas underlying this thesis are that lipidomics may improve the diagnosis of liver metabolic diseases, and can provide further insights into the underlying pathophysiology of these diseases. However to achieve this, the measurement of lipids should be further improved by enabling comprehensive coverage, accurate identification and quantitation. Therefore, in this thesis, new analytical methodologies using LC-MS for the accurate detection and quantitation of lipids are developed. These methods are then applied to MCADD samples to identify lipid biomarkers, which are further correlated with gene expression analysis to understand the underlying biochemical pathways. Show less
This thesis studies the geometry of representation varieties and character stacks. These are spaces parametrizing the representations of a finitely generated group, typically the fundamental group... Show moreThis thesis studies the geometry of representation varieties and character stacks. These are spaces parametrizing the representations of a finitely generated group, typically the fundamental group of a compact manifold, into an algebraic group G. We provide a number of methods to study these spaces through their invariants, focussing on the invariant that takes values in the Grothendieck ring of varieties. We show how both the arithmetic method, which studies the character stacks of compact orientable surfaces through counting points over finite fields, and the geometric method, which studies these character stacks using stratifications, can be expressed in terms of topological quantum field theories. We compute explicitly the invariants in specific cases, such as for G = SL2 and for G equal to the groups of upper triangular matrices. Motivated by these applications, we develop a number of new computational tools. Finally, we study the representation varieties and character stacks of the free groups and of the free abelian groups, of finite rank. We introduce a notion of motivic representation stability for stability in the Grothendieck ring of varieties, and show that these character stacks stabilize in this sense for G equal to the general linear groups. Show less
Gynaecological carcinomas (ovarian, endometrial, cervical, vaginal, vulvar and breast) are among the ones leading to the highest cancer-related deaths worldwide. The presence of germline pathogenic... Show moreGynaecological carcinomas (ovarian, endometrial, cervical, vaginal, vulvar and breast) are among the ones leading to the highest cancer-related deaths worldwide. The presence of germline pathogenic variants in the breast cancer susceptibility genes BRCA1 and BRCA2 is associated with an increased risk for breast and ovarian cancer as well as other cancers. The BRCA proteins play a crucial role in the homologous recombination (HR) pathway, which is the only DNA damage repair pathway that can repair DNA double-strand breaks error-free. The repair of DNA damage by HR is crucial to maintain genomic integrity. Patients whose tumors are HR-Deficient (HRD) are particularly sensitive to platinum-based chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). BRCA1/2 deficiency, but also (epi)genetic defects in other HR-related genes or other unknown factors can lead to HRD. However, BRCA1/2 deficiency, and not HRD, is still the leading prerequisite to be eligible for PARPi therapy. In this thesis, two functional RAD51-based HRD tests (RECAP and RAD51-FFPE test), were developed and validated using gynaecological carcinomas. These functional HRD tests were benchmarked with BRCA1/2 deficiency and with other DNA-based HRD tests measuring genomic scars and mutational signatures. In addition, the prevalence of functional HRD was explored among a variety of gynaecological carcinomas. Show less
In this Ph.D. thesis we study the interaction of low energy electrons with thin materials, namely layered materials (graphene, hexagonal boron nitride, molybdenum disulfide) and organic films. At... Show moreIn this Ph.D. thesis we study the interaction of low energy electrons with thin materials, namely layered materials (graphene, hexagonal boron nitride, molybdenum disulfide) and organic films. At these low energies the quantum mechanical wavelength of the electron wave function is in the order of a few Angstroms, thus comparable to the interlayer distance in layered materials. This leads to resonances in the electron reflection/transmission spectrum, comparable to the interference of light when it is reflected from a thin film. We use low energy electron microscopy (LEEM) and electron Volt transmission electron microscopy (eV-TEM) to determine the energy dependent electron mean free path (MFP) and identify resonant transmission/reflection states related to the unoccupied band structure. Furthermore, we use photoemission electron microscopy (PEEM) to image low energy electrons from a gold surface covered with a film of chiral organic molecules. We image the photoexcited electrons and compare the intensity of photoemission caused by different (circular) polarizations of light. Show less
De ziekte van Parkinson treft wereldwijd miljoenen mensen. Naarmate de ziekte vordert, ervaren patiënten motorische en niet-motorische symptoomschommelingen die hun kwaliteit van leven aanzienlijk... Show moreDe ziekte van Parkinson treft wereldwijd miljoenen mensen. Naarmate de ziekte vordert, ervaren patiënten motorische en niet-motorische symptoomschommelingen die hun kwaliteit van leven aanzienlijk beïnvloedt. Ze wisselen tussen perioden van een goede respons op medicatie (ON) en perioden van onvoldoende respons (OFF). Hoewel plotselinge OFF-perioden goed behandeld kunnen worden met apomorfine subcutane injecties, is er behoefte aan gebruiksvriendelijkere toedieningsmanieren. Dit proefschrift onderzocht twee nieuwe toedieningsvormen: een inhalator met apomorfine en een spray die apmorfine-oplossing aanbrengt aan de binnenkant van de wangen. Inhalatie zorgde voor snelle opname van apomorfine in het bloed (binnen 1-2 minuten) en verbeterde Parkinson symptomen (binnen 10 minuten). Ook de apomorfine spray bereikte klinisch relevante concentraties in het bloed. Maximale concentraties werden bereikt na 32-53 minuten (verschillend per dosering). Een vervolgstudie moet nog onderzoeken hoe snel dit tot verbetering van Parkinson symptomen leidt.Om het effect van nieuwe snelwerkende medicatie te onderzoeken, zijn objectieve, kwantitatieve en snelle metingen nodig. Vooral voor de behandeling van OFF-perioden is het bepalen van aanvang van effect essentieel om te kijken of een medicijn geschikt is voor deze indicatie. Momenteel wordt vaak de MDS-UPDRS III schaal gebruikt om de effectiviteit van medicijnen te beoordelen, maar deze meting vereist een getrainde beoordelaar, duurt relatief lang (ca. 15 minuten) en vertoont variatie tussen en binnen beoordelaars. Dit proefschrift toonde aan dat wijsvingertikken en duim-wijsvingertikken korte, beoordelaar-onafhankelijke metingen zijn die het effect van (snelwerkende) dopaminerge Parkinson medicatie kunnen aantonen met een vergelijkbare effectgrootte als de MDS-UPDRS III. Machine learning identificeerde een optimale combinatie van wijsvingertik parameters die zelfs beter is in het aantonen van medicatie effecten dan de MDS-UPDRS III. Show less
Spectroscopic studies on fluorescent single molecules in organic condensed matter does not only provide information about the molecule itself, but also its near environment. By suppression of... Show moreSpectroscopic studies on fluorescent single molecules in organic condensed matter does not only provide information about the molecule itself, but also its near environment. By suppression of phonon-induced broadening of spectral lines through cooling to low temperatures, small changes in the spectral lines’ position can be observed in response to weak variations in local fields. These variations can for instance be caused by rearrangements of charges or minute changes in the crystal lattice around the molecule. Therefore, molecules are sensitive sensors to what happens at the nanoscale. This is exemplified by coupling to an external electric field, inducing a Stark shift of the molecule’s spectral lines, as shown in Chapter 4. Other dynamics, related to the crystal around the molecule, are resolved in the fluorescence of molecules on the surface of two-dimensional hexagonal boron nitride, shown in Chapter 5. In Chapter 2, 3 and 6, perylene molecules are studied in a new host crystal with the aim of detecting a ‘forbidden’ transition to the triplet state from the ground state, a transition required for building a single-molecule optical switch. Show less
In this thesis we study curves. In the first half, we study moduli spaces of curves and Gromov-Witten invariants, certain kinds of curves counts. We employ logarithmic geometry for this. Some major... Show moreIn this thesis we study curves. In the first half, we study moduli spaces of curves and Gromov-Witten invariants, certain kinds of curves counts. We employ logarithmic geometry for this. Some major results include the polynomiality of the double ramification cycle and recursive relations for the log double ramification cycle.In the second half we study rational points on curves, in particular Chabauty's method for finding the rational points and extensions of it. Major results include that the geometric (quadratic) Chabauty method is theoretically stronger than the original (quadratic) Chabauty method, and that local heights for quadratic Chabauty are explicitly computable. Show less
The research developed in this doctoral dissertation contributes to Sasanian studies in particular, and to ancient Iranian studies more generally, in three main ways. First, it offers a critical... Show moreThe research developed in this doctoral dissertation contributes to Sasanian studies in particular, and to ancient Iranian studies more generally, in three main ways. First, it offers a critical study of the history of research surrounding the decipherment of the Middle Persian script, to define the contribution of Sasanian epigraphy to the broader historiographical debates concerning the study of Late Antiquity. Then, through the palaeographic analysis of the earliest pre-Sasanian and Sasanian Middle Persian written vestiges, it highlights the existence of a lively scribal tradition that was local to Persis in the Seleucid and Parthian periods. Finally, it investigates a possible model for the study of Sasanian inscriptions which takes into account the references made in these monumental texts to (now lost) manuscript documents, as well as to key features of their natural and built environment; this helps bring into sharp focus the often overlooked legal, administrative and religious functions of Sasanian rock-cut texts. Show less
The marine shipping industry is one of the strongest emitters of nitrogen oxides (NOx), a pollutant detrimental to ecology and human health. Over the last 20 years, the pollution produced by power... Show moreThe marine shipping industry is one of the strongest emitters of nitrogen oxides (NOx), a pollutant detrimental to ecology and human health. Over the last 20 years, the pollution produced by power plants, the industry sector, and cars has been decreasing. In contrast, the pollution impact of maritime transport continues to increase. This generates a big societal pressure, resulting in regulations proposed by the International Maritime Organization (IMO). These regulations impose restrictions on emission levels from ships. While various methods are used to assess the emission from ships in ports and off-coastal areas, monitoring over the open sea has been infeasible. The game-changer is the TROPOMI instrument on board the Sentinel 5 Precursor Satellite – studies show that NO2 plumes from some individual seagoing ships can be distinguished on TROPOMI images. The objective of this thesis is to pave the way toward the application of the TROPOMI instrument for the monitoring of compliance of seagoing ships. This is achieved through the fusion of machine learning, feature engineering, and data integration. Each chapter builds upon the findings of its predecessor, as a whole, representing state-of-the-art knowledge in the application of TROPOMI data for the monitoring of NO2 emissions from individual seagoing ships. Show less
What physics controls the properties of quantum matter, such as how electrons flow inside high-temperature superconductors? This question has captivated the physics community and industry for... Show moreWhat physics controls the properties of quantum matter, such as how electrons flow inside high-temperature superconductors? This question has captivated the physics community and industry for decades, in part due to the great technological potential such materials have, but also because they have resisted all traditional methods of understanding. It calls for a complete change in paradigm. An unexpected venue for progress was found in the study of gravity. By studying special gravitational solutions such as black holes and stars made of electrons, it turns out to be possible to shed some light on the physics and transport properties of quantum matter. This analysis relies on the use of high-performance computations to obtain these gravitational solutions, but the payoff is access to uncharted areas of physics. So far, such methods have successfully brought some insight into the flow of energy in such systems, but the flow of electric charge or the quantum information patterns remain shrouded in mystery. The findings of this thesis address key parts of these questions, particularly in the context of black holes as models of exotic quantum metals. Show less
To test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural... Show moreTo test the hypothesis that early-life adversity accelerates the pace of biological aging, we analyzed data from the Dutch Hunger Winter Families Study (DHWFS, N = 951). DHWFS is a natural-experiment birth-cohort study of survivors of in-utero exposure to famine conditions caused by the German occupation of the Western Netherlands in Winter 1944 to 1945, matched controls, and their siblings. We conducted DNA methylation analysis of blood samples collected when the survivors were aged 58 to quantify biological aging using the DunedinPACE, GrimAge, and PhenoAge epigenetic clocks. Famine survivors had faster DunedinPACE, as compared with controls. This effect was strongest among women. Results were similar for GrimAge, although effect-sizes were smaller. We observed no differences in PhenoAge between survivors and controls. Famine effects were not accounted for by blood-cell composition and were similar for individuals exposed early and later in gestation. Findings suggest in-utero undernutrition may accelerate biological aging in later life. Show less
More than 5,000 exoplanets have been found over the past couple of decades. These exoplanets show a tremendous diversity, ranging from scorching hot Jupiters, common super-Earths, to widely... Show moreMore than 5,000 exoplanets have been found over the past couple of decades. These exoplanets show a tremendous diversity, ranging from scorching hot Jupiters, common super-Earths, to widely separated super-Jupiters on the planet/brown dwarf boundary. We have now moved into the era of exoplanet atmospheric characterisation. Two crucial techniques for characterizing these exoplanets from the ground are high-contrast imaging and high-resolution spectroscopy. In the first part of the thesis, existing facilities are used to characterize the atmospheres of two of the most accessible types of planets: An ultra-hot Jupiter (WASP-76b) and a young supter-Jupiter (beta Pictoris b). The second part of the thesis develops instrumental concepts that are required to push exoplanet characterization towards smaller and closer-in planets. It shows how we can choose between spectral resolution, bandwidth, and field-of-view in developing an instrument for exoplanet detection, and how one can design an nearly optimal wavefront sensor for adaptive optics. Finally, it is demonstrated how machine learning techniques can help us improve the performance of these adaptive optics systems such that we can reach deeper contrasts for exoplanet imaging and characterization. Show less
In this thesis, topics relating to the optimization of high-throughput pipelines used for imaging are discussed. In particular, different levels of implementation, i.e., conceptual, software, and... Show moreIn this thesis, topics relating to the optimization of high-throughput pipelines used for imaging are discussed. In particular, different levels of implementation, i.e., conceptual, software, and hardware, are discussed and the thesis outlines how advances on each level need to be made to make gains in computationally demanding imaging applications. Chapter 2 concerns the implementation of real-time segmentation of X-ray computed tomography (CT). Chapter 3 concerns the end-to-end optimization of various CT workflows by using auto-differentiation frameworks. Chapter 4 concerns a novel pruning method for neural network to significantly increase the speed of convolutional neural networks (CNNs). Chapter 5 comprises a benchmark study of optimization algorithms for tuning GPU kernels, and introduces a novel graph-based approach to quantify search space difficulty. Chapter 6 introduces a novel model to improve the energy efficiency of GPUs. Show less
The aim of this thesis was to gain a better understanding of the deleterious effects of Neonatal Brachial Plexus Palsy (NBPP) on central development by analyzing sensory and motor function.The... Show moreThe aim of this thesis was to gain a better understanding of the deleterious effects of Neonatal Brachial Plexus Palsy (NBPP) on central development by analyzing sensory and motor function.The explanation for problems with hand function was not clear in children who had an upper NBPP where only the C5 and C6 spinal nerves are affected, which predominantly innervate the shoulder and elbow flexion. The main findings of this thesis: Children with an upper NBPP have a diminished sensibility of the thumb and index finger which correlates with diminished dexterity. The ability to localize stimuli to the thumb, index, third and fourth fingers is disturbed in children with an upper NBPP. Most children with an upper NBPP are not aware of the diminished sensibility in their affected hand. Also Grip force of the hand is reduced in children with an upper NBPP lesion. NBPP is a peripheral nervous lesion, which affects the development of the central nervous system as well. The age at which children with NBPP can walk independently is delayed, which does not depend on the severity of the lesion. Treatment of children with a NBPP had to focus on the total development of the child. Show less
The mid-sixteenth century was a time of rapidly intensifying interest in the study of living nature. Networks of experts described a rapidly growing number of species, complementing descriptions... Show moreThe mid-sixteenth century was a time of rapidly intensifying interest in the study of living nature. Networks of experts described a rapidly growing number of species, complementing descriptions with ad vivum depictions. Since the increase in the number of known species soon called for an organisation of this information, to keep this accessible and navigable, naturalists experimented with classifications and the presentation of information in text and image. This dissertation explores questions about the management of knowledge and information specifically in the context of natural history, looking at a subfield of zoology, the study of fishes and other aquatic animals, as an example, taking as a point of departure the works published by the naturalist Conrad Gessner (1516-1565). Gessner aimed to incorporate into his works an overview of the state of knowledge. As a result his work presents an ideal case study from which to approach questions such as: What happens when a field of knowledge experiences a sudden influx of information? How is information made accessible, how do researchers keep the overview of an increasing quantity of information? How is rudimentary and incomplete information processed and presented, how does it affect established interpretations and methods of working? Show less
