In some condensed matter systems, such as the surface of a 3D topological insulator, the electrons are effectively massless and we must necessarily use the massless Dirac equation to describe them... Show moreIn some condensed matter systems, such as the surface of a 3D topological insulator, the electrons are effectively massless and we must necessarily use the massless Dirac equation to describe them.A very convenient way to numerically solve this equation is to discretise them. However, the Nielsen-Ninomiya theorem proves that if we try to do it naively, extra unphysical massless fermion species appear, giving rise to a number of undesired artefacts. This is known as fermion doubling, and the main focus of this thesis is to tackle this problem via the discretisation method of tangent fermions.Chapters 2,3 and 4 are devoted to developing various aspects of this method. Chapters 5 and 6 are not directly related to the method of tangent fermions but still describe processes that arise in materials with a Dirac-like dispersion relation. In chapter 5, we study the effect a non-zero net supercurrent parallel to the edges of a topological superconductor. We find that the supercurrent can induce a "chirality inversion'' of the Majorana edge modes.In the last chapter, we simulate the injection of "edge-vortices'' into a topological superconductor. These are a type of quasiparticles that can theoretically be used to realise a quantum computer. Show less
This dissertation aims to explore how university students use mobile technology for their self-directed language learning and investigate factors influencing their self-directed learning with... Show moreThis dissertation aims to explore how university students use mobile technology for their self-directed language learning and investigate factors influencing their self-directed learning with mobile technology. It contributed to theoretical and practical knowledge of self-directed language learning using mobile technology outside the classroom in higher education. The research aims of the dissertation were twofold. First, it was aimed at increasing our understanding of the learning experience of learners’ self-directed learning process while preparing for IELTS (International English Language Testing System). Second, it was aimed at suggesting implications for improving the effectiveness of self-directed learning, with implications for learners, educators, and IT practitioners. Four studies were performed focused on (1) an overview of the learning strategies that learners used in their self-directed learning assisted by mobile technology; (2) self-directed learners’ learning process while preparing for the IELTS on their own; (3) language learners’ behavioral intention towards and actual use of mobile technology in self-directed learning; and (4) language learners’ engagement, satisfaction, and persistence in the context of informal, self-directed language learning using mobile technology. In sum, the conclusions of the four studies will inform self-directed learners, educators, and software developers on how to effectively enhance self-directed learning with mobile technology. Show less
Background Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations. Methods A phantom with tubes of known diameters... Show moreBackground Computed tomography (CT) is the usual modality for diagnosing stroke, but conventional CT angiography reconstructions have limitations. Methods A phantom with tubes of known diameters and wall thickness was scanned for wall detectability, wall thickness, and contrast-to-noise ratio (CNR) on conventional and spectral black-blood (SBB) images. The clinical study included 34 stroke patients. Diagnostic certainty and conspicuity of normal/abnormal intracranial vessels using SBB were compared to conventional. Sensitivity/specifcity/accuracy of SBB and conventional were compared for plaque detectability. CNR of the wall/lumen and quantitative comparison of remodeling index, plaque burden, and eccentricity were obtained for SBB imaging and high-resolution magnetic resonance imaging (hrMRI). Results The phantom study showed improved detectability of tube walls using SBB (108/108, 100% versus conventional 81/108, 75%, p<0.001). CNRs were 75.9±62.6 (mean±standard deviation) for wall/lumen and 22.0±17.1 for wall/water using SBB and 26.4±15.3 and 101.6±62.5 using conventional. Clinical study demonstrated (i) improved certainty and conspicuity of the vessels using SBB versus conventional (certainty, median score 3 versus 0; conspicuity, median score 3 versus 1 (p<0.001)), (ii) improved sensitivity/specifcity/accuracy of plaque (≥1.0 mm) detectability (0.944/0.981/0.962 versus 0.239/0.743/0.495) (p<0.001), (iii) higher wall/lumen CNR of SBB of (78.3±50.4/79.3±96.7) versus hrMRI (18.9±8.4/24.1±14.1) (p<0.001), and (iv) excellent reproducibility of remodeling index, plaque burden, and eccentricity using SBB versus hrMRI (intraclass correlation coefcient 0.85–0.94). Conclusions SBB can enhance the detectability of intracranial plaques with an accuracy similar to that of hrMRI. Relevance statement This new spectral black-blood technique for the detection and characterization of intracranial vessel atherosclerotic disease could be a time-saving and cost-efective diagnostic step for clinical stroke patients. It may also facilitate prevention strategies for atherosclerosis. Show less
People are sensitive to norms, but under what conditions promoting anti-prejudice norms reduce prejudice remains unclear. Three studies among Dutch participants (total N = 700) examined the effects... Show morePeople are sensitive to norms, but under what conditions promoting anti-prejudice norms reduce prejudice remains unclear. Three studies among Dutch participants (total N = 700) examined the effects of (in)equality norms on prejudice towards migrants. To gain greater clarity, we also examined how potential boundary conditions—namely economic and social ideologies—moderate this relationship. A norm of equality was measured (Study 1) or manipulated (Studies 2a and 2b). In Study 1, a perceived norm of equality predicted lower prejudice towards migrants, operationalised as cold feelings, social distance, and perceived outgroup threat, through the increased personal endorsement of equality, particularly among (economic) rightists. In two experiments (Studies 2a and 2b), as well as in a joint analysis of both studies, we found that inducing an equality norm (vs. not) mitigated prejudice towards migrants, but only among (social) rightists. These findings highlight the positive role of social norms promoting equality in combating prejudice and the importance of considering boundary conditions for this role, such as ideology. We discuss the implications for theory and practice regarding prejudice (reduction). Please refer to the Supplementary Material section to find this article's Community and Social Impact Statement. Show less
As part of the Indo-European language family, the Indo-Iranian branch traces its origins back to the Indo-European homeland on the Pontic-Caspian steppe 5000 years ago. But how did it spread from... Show moreAs part of the Indo-European language family, the Indo-Iranian branch traces its origins back to the Indo-European homeland on the Pontic-Caspian steppe 5000 years ago. But how did it spread from there to Asia? The aim of this thesis is to uncover the early prehistory of Indo-Iranian by investigating its relationship to the Balto-Slavic languages of Eastern Europe, which have been hypothesized to form a subgroup with Indo-Iranian: Indo-Slavic. By comparing the linguistic data with evidence from archaeology and genetics, this thesis traces the migration path of prehistoric Indo-Iranian speakers from the Pontic-Caspian steppe, via the rivers and forests of Eastern Europe, across the Ural Mountains, and southwards to the steppes of Central Asia. Show less
Coronaviruses comprise seven human viruses, some of them the common cold viruses, only causing mild symptoms in healthy individuals, while SARS-CoV, MERS-CoV, and SARS-CoV-2 can potentially cause... Show moreCoronaviruses comprise seven human viruses, some of them the common cold viruses, only causing mild symptoms in healthy individuals, while SARS-CoV, MERS-CoV, and SARS-CoV-2 can potentially cause severe disease and deadly pneumonia. The outbreak of SARS-CoV-2 in 2019 and its rapid worldwide spread has made apparent the need for a fast response to newly emerging viruses and to have effective therapies available. Although vaccines against SARS-CoV-2 were developed at an unprecedented speed, early patients would have benefitted from antiviral drugs. The respiratory tract is the first entry point for coronaviruses, where epithelial cells are infected and also represent the first barrier of defense. Primary human airway epithelial cells that are cultured and differentiated at the air-liquid interface (HAE-ALI) represent an advanced cell culture model recapitulating the human lung epithelium better than mono-cell cultures. In this thesis, four research projects conducted during the PhD track, are described and discussed, which focussed mainly on SARS-CoV-2. Chapter 1 gives an introduction to the overall research topic of coronavirus biology and antiviral drug discovery, and the use of HAE-ALI to study both. Chapter 2 describes the characterization of SARS-oV-2 infection in HAE-ALI. Changes in the cellular composition, caused by culture time or drug treatment, impacted virus replication, and this correlated with the presence of the main susceptible cells, ciliated cells and goblet cells, as well as expression of virus cell-entry factors. Furthermore, the importance of having a diverse epithelium in the cultures was identified, where likely goblet cells play a supportive role in infection. The findings contribute to the understanding of the variable susceptibility to SARS-CoV-2 infection between individuals and across anatomical locations in the respiratory tract, and possibly in chronic lung diseases affecting the epithelium. Chapter 3 then aimed to conduct a comparative study between SARS-CoV, MERS-CoV, and SARS-CoV-2, and two common cold coronaviruses. We employed the HAE-ALI cell culture model to decipher differences in the epithelial transcriptional response upon coronavirus infection. RNA sequencing data showed limited expression of interferon genes in infections with SARS-CoV, MERS-CoV, and SARS-CoV-2, as opposed to the common cold coronaviruses, which corroborated previous studies showing suppression of interferon responses by the these three coronaviruses. Furthermore, SARSCoV-2 infection uniquely lacked the expression of a set of immediate early genes, which are expressed in response to stressors like infection. By utilizing the findings about one of these genes, NR4A1, an inhibitor was identified that blocks SARS-CoV-2 and MERS-CoV replication. Chapters 4 and 5 describe two antiviral drugs that efficiently block the replication of SARS-CoV-2 and other coronaviruses. The first, R-Propranolol, is part of a drug that is approved for the treatment of hemangioma (benign vascular tumor), besides various medical conditions like cardiovascular diseases. R-Propranolol was shown to reduce a proangiogenic factor, which was recently reported to be associated with an increased rate of severe lung pathology in COVID-19. Therefore, this drug could be an interesting candidate to investigate further as host-directed therapy to reduce vascular damage in COVID-19, caused by endothelial dysfunction and pathological angiogenesis. Additionally, a potent antiviral effect of R-Propranolol against SARS-CoV-2 and other coronaviruses was observed, which makes the drug an interesting antiviral with two potential angles of activity. Chapter 5 describes a class of host-directed antivirals, glucosidase inhibitors, which inhibit endoplasmic reticulum (ER) resident alpha-glucosidases, important for protein folding in the ER and quality control. Many viruses, including coronaviruses, use the host’s ER protein quality control machinery for their glycoproteins. For SARS-CoV-2, especially the spike protein, which is crucial for virus attachment and entry into the host cell, is heavily glycosylated and dependent on processing in the ER and Golgi. Several compounds were tested, belonging to two classes, iminosugars and cyclitols. While iminosugars have been studied for decades as potential antiviral drugs, we identified 1,6-epi-cyclophellitol cyclosulfate, a candidate of a new class of glucosidase inhibitors, as superior due to its high specificity for ER alpha-glucosidase II and potent antiviral efficacy. Inhibition of ER alphaglucosidases led to a reduction in spike protein generation and subsequently to a reduced production of infectious virus particles. In addition to SARS-CoV-2, 1,6-epi-cyclophellitol cyclosulfate also blocks the production of SARS-CoV and MERS-CoV progeny, rendering this class of compounds promising broad-spectrum antivirals. In the final chapter, the main findings of the research projects are discussed in the context of recently published studies. Furthermore, the current landscape of SARS-CoV-2 host-directed antiviral therapy and the benefits of using the most relevant cell culture models in antiviral drug discovery are discussed. Show less
This thesis focuses on child labour in producing bountiful supply of cocoa in the cocoa-producing area of Gomoa Ofaso in the Winneba District from 1874 when there was labour shortage up to 1940... Show moreThis thesis focuses on child labour in producing bountiful supply of cocoa in the cocoa-producing area of Gomoa Ofaso in the Winneba District from 1874 when there was labour shortage up to 1940 when colonial Ghana was the principal producer of cocoa globally. This thesis has been divided into six chapters. This thesis, by the use of qualitative research methodology, demonstrated that market forces after the abolition of domestic slavery in 1874 together with the introduction and export of cocoa intensified the use of child labour in this District due to the shortage of labour. The research of child labour in cocoa production in the colonial period is important because it has often been categorised as an example of the worst forms of child labour, yet it has not been adequately studied. This thesis contributes to the discourse on child labour in the colonial period and how the colonial labour problem was dealt with in cocoa production. Show less
Superconductivity refers to a phase of matter in which charge carriers can be moved without dissipating energy. In this special phase, unlike a perfect metal conductor, any external magnetic field... Show moreSuperconductivity refers to a phase of matter in which charge carriers can be moved without dissipating energy. In this special phase, unlike a perfect metal conductor, any external magnetic field lines are expelled from the material. The phenomenon has been a focus of attention both in fundamental science research as well as technological application ever since it was first discovered in Leiden in the year of 1911. Recent fast progress in nano-engineering, fabrication and characterisation enable two-dimensional devices to be realised relatively easily in the lab via top-down or/and bottom-up methods. Van der Waals materials and thin films can be fabricated now with good control and reproducibility. This has not only paved the way for studying clean superconductivity in two dimensions.The advances in nanotechnology combined with the increasing understanding and exploration in solid state physics also allow more control over the superconducting properties of matter. This thesis contributes to the study of conventional phonon-mediated superconductors by exploring the possibility of manipulating (quasi-) two-dimensional (2D) superconductors' properties through the careful design of the devices. The investigations reported in this thesis include clean 2D superconductivity via a top-down fabrication method of exfoliating van der Waals superconductor crystals; understanding critical current magnetic oscillation in van der Waals heterostructure Josephson Junctions; increasing critical current density of thin film superconductor through controlled oxidation. And ambitiously, the increasing of critical temperature of a superconductor by manipulating the material with a superperiodic potential. Show less
Antimicrobial photodynamic therapy (aPDT) is an evolving treatment strategy against human pathogenic microbes such as the Candida species, including the emerging pathogen C. auris. Using a modified... Show moreAntimicrobial photodynamic therapy (aPDT) is an evolving treatment strategy against human pathogenic microbes such as the Candida species, including the emerging pathogen C. auris. Using a modified EUCAST protocol, the light-enhanced antifungal activity of the natural compound parietin was explored. The photoactivity was evaluated against three separate strains of five yeasts, and its molecular mode of action was analysed via several techniques, i.e., cellular uptake, reactive electrophilic species (RES), and singlet oxygen yield. Under experimental conditions (λ = 428 nm, H = 30 J/cm2, PI = 30 min), microbial growth was inhibited by more than 90% at parietin concentrations as low as c = 0.156 mg/L (0.55 µM) for C. tropicalis and Cryptococcus neoformans, c = 0.313 mg/L (1.10 µM) for C. auris, c = 0.625 mg/L (2.20 µM) for C. glabrata, and c = 1.250 mg/L (4.40 µM) for C. albicans. Mode-of-action analysis demonstrated fungicidal activity. Parietin targets the cell membrane and induces cell death via ROS-mediated lipid peroxidation after light irradiation. In summary, parietin exhibits light-enhanced fungicidal activity against all Candida species tested (including C. auris) and Cryptococcus neoformans, covering three of the four critical threats on the WHO's most recent fungal priority list. Show less
Controlling the end-groups of biocompatible polymers is crucial for enabling polymer-based therapeutics and nanomedicine. Typically, end-group diversification is a challenging and time-consuming... Show moreControlling the end-groups of biocompatible polymers is crucial for enabling polymer-based therapeutics and nanomedicine. Typically, end-group diversification is a challenging and time-consuming endeavor, especially for polymers prepared via ionic polymerization mechanisms with limited functional group tolerance. In this study, we present a facile end-group diversification approach for poly(2-oxazoline)s (POx), enabling quick and reliable production of heterotelechelic polymers to facilitate POxylation. The approach relies on the careful tuning of reaction parameters to establish differential reactivity of a pentafluorobenzyl initiator fragment and the living oxazolinium chain-end, allowing the selective introduction of N-, S-, O-nucleophiles via the termination of the polymerization, and a consecutive nucleophilic para-fluoro substitution. The value of this approach for the accelerated development of nanomedicine is demonstrated through the synthesis of well-defined lipid-polymer conjugates and POx-polypeptide block-copolymers, which are well-suited for drug and gene delivery. Furthermore, we investigated the application of a lipid-POx conjugate for the formulation and delivery of mRNA-loaded lipid nanoparticles for immunization against the SARS-COV-2 virus, underscoring the value of POx as a biocompatible polymer platform. Show less
Moet in Nederland desinformatie strafbaar worden gesteld? In dit artikel wordt gekeken wat de laatste ontwikkelingen zijn van desinformatieregulering op het niveau van de Europese Unie. Daarnaast... Show moreMoet in Nederland desinformatie strafbaar worden gesteld? In dit artikel wordt gekeken wat de laatste ontwikkelingen zijn van desinformatieregulering op het niveau van de Europese Unie. Daarnaast wordt gekeken naar Franse wetgeving omtrent desinformatie en wordt belicht hoe de rol van de rechter daarin uiteindelijk zeer beperkt is omwille van de vrijheid van meningsuiting. Ten slotte wordt gewaarschuwd tegen een expliciete strafbaarstelling van desinformatie, bekeken vanuit de soft-lawaanpak van de EU en de hardere juridische aanpak van Frankrijk. Show less
Oudsten, J.E. den; Boer, T.W.M. de; Negrón, R. 2024
Due to improvements in treatment for primary rectal cancer, the incidence of LRRC has decreased. However, 6–12% of patients will still develop a local recurrence. Treatment of patients with LRRC... Show moreDue to improvements in treatment for primary rectal cancer, the incidence of LRRC has decreased. However, 6–12% of patients will still develop a local recurrence. Treatment of patients with LRRC can be challenging, because of complex and heterogeneous disease presentation and scarce − often low-grade − data steering clinical decisions. Previous consensus guidelines have provided some direction regarding diagnosis and treatment, but no comprehensive guidelines encompassing all aspects of the clinical management of patients with LRRC are available to date. The treatment of LRRC requires a multidisciplinary approach and overarching expertise in all domains. This broad expertise is often limited to specific expert centres, with dedicated multidisciplinary teams treating LRRC. A comprehensive, narrative literature review was performed and used to develop the Dutch National Guideline for management of LRRC, in an attempt to guide decision making for clinicians, regarding the complete clinical pathway from diagnosis to surgery. Show less
Introduction Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases,... Show moreIntroduction Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1.Materials and methods This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies.Results 169 irAEs were experienced by 86/143 patients (137 grades 1–2, 32 grades 3–4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597).Conclusion The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction. Show less
