Oratie uitgesproken door Prof.dr. Ben S. Kuipers bij de aanvaarding van het ambt van hoogleraar Publiek Leiderschap aan de Universiteit Leiden op vrijdag 14 juni 2024
Lemkes, A.C.; Struijs, S.Y.; Littel, M.; Ekkers, W.D.; Berg, J.F. van den 2024
The human body consists of many different cell types. Cell types can be defined by the genes expressed, and unique cell-type-specific transcriptional mechanisms control these expressions. Single... Show moreThe human body consists of many different cell types. Cell types can be defined by the genes expressed, and unique cell-type-specific transcriptional mechanisms control these expressions. Single nucleotide polymorphisms (SNPs) in the DNA can be associated with diseases, but approximately 95% fall in the non-coding region. Usually, it is unknown whether these variants are causal, and which gene and cell type they affect.Advances in single-cell RNA-sequencing improved our understanding of heterogeneous tissues and led to the discovery of many new cell types. This new technology also presents computational challenges including consistent cell-type annotations. It is essential to annotate cells using classification instead of currently practiced clustering methods. To facilitate this transition, we benchmarked cell-type classification methods and developed computational methods to automatically build reference atlases using multiple already labeled single-cell datasets.Next, we establish a relationship between mutations and their effect on gene or isoform expression. We study sequence-to-expression models that can predict an alteration in expression when a mutation is observed. Given that gene expression mechanisms are cell-type specific, we introduce sequence-to-expression models based on single-cell data to make cell-type-specific predictions. We use these models to show that certain mutations are indeed changing expression, increasing our understanding of transcriptional regulation. Show less
Uveal melanoma, as opposed to cutaneous melanoma, is a tumor which is predominantly located in the center of the eye. Given its potential aggressive nature with fatal consequences, it is important... Show moreUveal melanoma, as opposed to cutaneous melanoma, is a tumor which is predominantly located in the center of the eye. Given its potential aggressive nature with fatal consequences, it is important to start treatment in a timely manner. Currently, treatment consists of decreasing the size of the tumor by means of radiation therapy or surgery, but by mapping the genetic makeup of uveal melanoma, personalized treatment potentially becomes possible. In this thesis we tried to solve a piece of this genetic puzzle by focusing on genetic and cellular differences within and between different uveal melanoma. By means of an innovative new technique, digital PCR, we aimed to visualize this so-called heterogeneity. We demonstrate that we can accurately assess which genetic aberrations are present in uveal melanoma. Moreover, we show in what percentage of cells these aberrations are present. Additionally, we illustrate which cell types play an important role in uveal melanoma development. This way, we characterized a substantial amount of different uveal melanoma based on their heterogeneity profile. Lastly, we display whether and how uveal melanomas with a specific heterogeneity profile are susceptible to treatment. Show less
Cardiac arrhythmias are a common cause of sudden death worldwide. However, despite decades of thorough investigation the underlying biophysical mechanisms of cardiac arrhythmias are still... Show moreCardiac arrhythmias are a common cause of sudden death worldwide. However, despite decades of thorough investigation the underlying biophysical mechanisms of cardiac arrhythmias are still insufficiently understood due to incomplete theories and the lack of precise spatiotemporal control in experiments. In the last decade, the problem of insufficient spatiotemporal control has started to be tackled by means of a new technique, called optogenetics. This technique employs expression of light-activated proteins, which are activated or deactivated in time and space by switching on/off light (in the near-ultraviolet to near-infrared wavelength range) in specific patterns thus realizing fully biological spatiotemporal control. However, with a few notable exceptions, cardiac optogenetic studies have only confirmed previously known mechanisms and yielded no or little novel mechanistic insights. In this thesis, to fill this gap, we combined nonlinear dynamics theory, numerical simulations and optogenetic experiments with unique spatiotemporal control to theoretically predict and demonstrate novel arrhythmogenic phenomena in cardiac tissue. Thanks to the robustness of the optogenetics methods and generality of the applied theories and computations, this thesis uncovered novel mechanisms for the biophysics of cardiac tissue that are applicable to the functioning of excitable systems in general. Show less
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
This research focuses on creating composite biomarkers that can classify diagnoses, estimate symptom severity, and detect treatment effects using data from wearable sensors and smartphone... Show moreThis research focuses on creating composite biomarkers that can classify diagnoses, estimate symptom severity, and detect treatment effects using data from wearable sensors and smartphone applications. The thesis consists of an introduction to machine learning techniques and their use in developing biomarkers for the central nervous system; a narrative review of the relevant literature; and detailed studies on the application of these techniques in various health conditions. Specifically, the research includes observational and cross-sectional studies on facioscapulohumeral muscular dystrophy (FSHD) and major depressive disorder (MDD), demonstrating how smartphone and wearable sensor data can be used to monitor disease severity and progression. Additionally, the research identified the use of a tablet-based finger tapping task to monitor the real-time effects of antiparkinson's drugs on Parkinson's symptom severity. Key findings highlight the potential of mHealth biomarkers to provide continuous, real-time monitoring of patients, which can enhance the accuracy of clinical assessments and potentially reduce the burden on patients and healthcare systems. The thesis also addresses the challenges of variability in mHealth device data and emphasizes the need for robust validation and standardization to ensure the reliability of these biomarkers in clinical settings. 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
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
