This thesis is focused on the targeting of two antigens often expressed on the surface of cancer cells: MICA and HLA-E. Both antigens are members of the MHC-I family of proteins. They both act as... Show moreThis thesis is focused on the targeting of two antigens often expressed on the surface of cancer cells: MICA and HLA-E. Both antigens are members of the MHC-I family of proteins. They both act as ligands for the NK receptors on NK cells and CD8+ T cells. We target MICA using nanobodies, or VHHs, the small variable regions of camelid-derived heavy-chain only antibodies. The nanobodies are used as nanobody-drug conjugate, fused to the Mertansine-derivative DM1, or as the targeting domain of chimeric antigen receptors to create CAR NK cells. These nanobody-based immunotherapies selectively target and kill MICA-positive cancer cells. We target HLA-E with an antibody directed against a 13-amino acid epitope unique to the cytoplasmic tail of HLA-E. The antibody is specific to HLA-E and can be used for detection of HLA-E positive cells in flow cytometry and immunofluorescence and detection of HLA-E positive tumors in immunohistochemistry. Together with the epitope, the antibody can be used as a novel epitope tag for detection and purification of unrelated proteins. Show less
Big Science, commonly defined as conventional science made big in three dimensions, namely organizations, machines, and politics, brings a plethora of different stakeholders together, often for a... Show moreBig Science, commonly defined as conventional science made big in three dimensions, namely organizations, machines, and politics, brings a plethora of different stakeholders together, often for a long period of time. This includes policymakers, scientists, (scientific) managers as well as local “host” communities. Each group has considerable, though often different, stakes in Big Science. These diverging interests require stakeholders to negotiate and to compromise between and among one another. Using qualitative methods, this dissertation contributes to a deeper understanding of such processes in and around Big Science in two distinct ways. First, it sheds light on how different stakeholders pursue and negotiate their interests within and in relation to Big Science. In doing so, the thesis pays particular attention to non-Western and indigenous actors, two stakeholder groups that the existing literature on Big Science has so far largely neglected. Second, it theorizes how conflicts emerge and develop between and among stakeholders, thus advancing theory-building in the largely undertheorized literature on Big Science. Overall, the dissertation demonstrates that, in contrast to conventional science, Big Science carries significant symbolism for the involved stakeholders, which often impedes effective stakeholder and conflict management. Show less
This thesis explores the role of what has traditionally been considered as neural “noise”, specifically BOLD signal variability and aperiodic neural activity, in human cognitive functions,... Show moreThis thesis explores the role of what has traditionally been considered as neural “noise”, specifically BOLD signal variability and aperiodic neural activity, in human cognitive functions, particularly in metacontrol. The metacontrol model assumes that individuals vary in their cognitive styles between "persistence" and "flexibility." Persistence emphasizes focused goal pursuit, while flexibility allows for easy task switching and consideration of diverse possibilities. Through three empirical studies, this thesis investigates the relationship between two specific forms of neural "noise" – BOLD signal variability and aperiodic neural activity – and metacontrol biases (i.e., persistence vs. flexibility). Chapter 2 emphasizes the importance of resting-state BOLD signal variability in understanding individualized cognitive control styles. Chapter 3 highlights the importance of the aperiodic component of the EEG power spectrum in reflecting demand-specific metacontrol states. Notably, Chapter 4 illuminates the functional significance of aperiodic activity in creative thinking. Overall, the research presented in this thesis highlights the importance of resting-state BOLD signal variability and aperiodic activity in the EEG power spectrum for understanding the neural underpinnings of cognitive functions. Show less
In this thesis, rational points on K3 surfaces are studied. In the first part of Chapter 1 the Brauer group and the the Brauer-Manin obstruction are introduced. The second part of Chapter 1 is... Show moreIn this thesis, rational points on K3 surfaces are studied. In the first part of Chapter 1 the Brauer group and the the Brauer-Manin obstruction are introduced. The second part of Chapter 1 is devoted to the introduction of the refined Swan conductor and the link between the latter and the Brauer-Manin set. The aim of Chapter 2 is to give the first example of a K3 surface over a number field (in fact, over the rational numbers) for which a prime of good reduction is involved in the Brauer-Manin obstruction; this gives a negative answer to a question originally asked by Swinnerton-Dyer. In Chapter 3 the role of primes of good reduction in the Brauer-Manin obstruction is discussed, with a focus on K3 surfaces. Finally, in the last chapter, after introducing some techniques that can be used to compute the refined Swan conductor, several examples of Brauer-Manin obstruction on K3 surfaces are provided, with a focus on Kummer K3 surfaces. Show less
In this dissertation I argue that the proto-daoist text the Zhuangzi and the ethical relation of Levinas are fruitful resources to reconsider the self-other relation in comparative philosophy.... Show moreIn this dissertation I argue that the proto-daoist text the Zhuangzi and the ethical relation of Levinas are fruitful resources to reconsider the self-other relation in comparative philosophy. Comparative philosophy is a hermeneutical practice in which the philosopher's assumptions, beliefs and emotional commitments influence and determine the comparative process. I argue that in order to overcome injustice and theoretical colonization of the cultural other, we need to adopt an ethical attiude in which we reside in the pivot and are willing to take the quesiton of social justice into account Show less
To cope with environmental changes, humans need to adjust their cognitive control states to meet different challenges. Two important cognitive control states are cognitive persistence and cognitive... Show moreTo cope with environmental changes, humans need to adjust their cognitive control states to meet different challenges. Two important cognitive control states are cognitive persistence and cognitive flexibility. Persistence is a state of maintaining stable attention, while flexibility is a state where attention can switch freely. These two states are antagonistic to each other; one cannot switch attention flexibly while being focused, and one cannot focus on a single stimulus while switching attention flexibly. Our understanding of the neural mechanisms underlying these cognitive control states is still limited. Therefore, in this dissertation, we used two brain science research techniques, EEG and fMRI, to study brain activities associated with these two states. To induce these states, the dissertation employed two creative thinking tasks, namely convergent thinking and divergent thinking, and two meditation techniques, focused attention meditation and open monitoring meditation. The results discuss EEG and fMRI indicators related to these states, providing preliminary evidence for research in this field. Show less
The main aim of the present thesis is to investigate the authoritative role of the ancestors in matters of social cohesion, succession, inheritance, property ownership and gender norms. In... Show moreThe main aim of the present thesis is to investigate the authoritative role of the ancestors in matters of social cohesion, succession, inheritance, property ownership and gender norms. In particular the purpose is to ascertain whether religious sources concerning the cult of the ancestors can provide concrete evidence on how justice was actually administrated in Ancient Egypt. The title – Only the dead can tell us – derived indeed from the idea that this core of religious beliefs, which also included necromantic practices, can be invaluable for better understanding Ancient Egyptian society and justice. Show less
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
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
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
BackgroundClostridioides difficile is a leading cause of infectious diarrhea in both humans and livestock. In particular, C. difficile strains belonging to sequence type (ST) 11 are common... Show moreBackgroundClostridioides difficile is a leading cause of infectious diarrhea in both humans and livestock. In particular, C. difficile strains belonging to sequence type (ST) 11 are common enteropathogens. The aim of this study was to determine the presence and genetic relatedness of C. difficile types in dairy cattle and calves.MethodDutch dairy farms were visited between February and December 2021. Feces was collected from adult dairy cattle and calves of two age categories (<4 weeks and 4 weeks-4 months). Fecal samples were also requested from dairy farmers, family members and employees. Fecal samples were cultured in an enrichment medium for 10–15 days and subcultured on solid media for capillary PCR ribotyping and whole genome sequencing.ResultsC. difficile was detected on 31 out of 157 (19.8%) dairy farms. The highest prevalence was found in calves <4 weeks (17.5%). None of the 99 human samples collected were positive. Thirty-seven cultured isolates belonged to 11 different PCR ribotypes (RT) of which RT695 (56.8%) and RT078/126 (16.2%) were most abundant. In the database of the Netherlands National Expertise Centre for C. difficile infections (CDI, >10.000 patient isolates), RT695 was found in only two patients with hospital-onset CDI, diagnosed in 2020 and 2021. Sequence analysis of 21C. difficile RT695 from cattle revealed that all isolates belonged to clade 5, ST11 and contained genes encoding toxin A, toxin B and binary toxin. RT695 strains carried antimicrobial resistance genes typically found in clade 5C. difficile. Groups of genetically related RT695 isolates were found between dairy farms, whereas identical strains were only present in individual farms.ConclusionsC. difficile was found in ∼20% of dairy farms with a predominance of the relatively unknown RT695. Isolates of RT695 belonged to the same clade and sequence type as RT078/126, which is recognized as an important zoonotic type. Show less
Grewal, N.; Idhrees, M.; Velayudhan, B.; Klautz, R.J.M.; Grewal, S. 2024
Abstract: Background: Thoracic aortopathy includes conditions like aortic aneurysms and dissections, posing significant management challenges. In India, care delivery is complicated by geographic... Show moreAbstract: Background: Thoracic aortopathy includes conditions like aortic aneurysms and dissections, posing significant management challenges. In India, care delivery is complicated by geographic vastness, financial constraints, and healthcare resource disparities. Telemedicine and digital health technologies offer promising solutions. Methods: A comprehensive review of literature and clinical experiences was conducted to explore the implementation of remote care strategies for thoracic aortopathy in India. The review included studies from 2000 to 2023 and insights from cardiothoracic specialists. Results: Remote care benefits include improved access to specialized expertise, enhanced patient engagement, and optimized resource utilization. Telemedicine enables consultations without travel, and remote monitoring facilitates early intervention. However, challenges like technology integration, digital literacy, patient engagement, privacy concerns, and regulatory compliance need addressing. Discussion: Telemedicine offers significant advantages but requires overcoming challenges to ensure effective, secure care. Careful planning for technology integration, patient education, robust privacy measures, and supportive regulatory policies are essential. Addressing these issues can bridge the healthcare access gap and improve outcomes in India’s diverse landscape. Show less
