The reconstruction of the Proto-Berber light verbs (i.e. CCC, *ălməd ‘to learn’, VCC, *agəm ‘to draw water’, CC *ăǵən ‘to lie down’ and C̄C: *ăffəɣ ‘to go out’), has received considerable attention... Show moreThe reconstruction of the Proto-Berber light verbs (i.e. CCC, *ălməd ‘to learn’, VCC, *agəm ‘to draw water’, CC *ăǵən ‘to lie down’ and C̄C: *ăffəɣ ‘to go out’), has received considerable attention in Berber historical linguistics. But, verbs that have u in the second syllable such as Ghadamsi əmdu ‘to finish’ and əṭkur ‘to fill’ require further study. These verbs share several formal similarities with the regular light verb of the type *ălməd ‘to learn’, but they have not yet been integrated into a model of the Proto-Berber verbal system. This paper will propose a reconstruction of the Proto-Berber light verb, incorporating these verbs as a subclass of the light verb, whose difference in vocalisation is triggered by the presence of a plain vowel in the second syllable of the stem. Show less
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
Holstein, Y. van; Mooijaart, S.P.; Oevelen, M. van; Deudekom, F.J. van; Vojinovic, D.; Bizzarri, D.; ... ; Trompet, S. 2024
Prognostic information is needed to balance benefits and risks of cancer treatment in older patients. Metabolomics-based scores were previously developed to predict 5- and 10-year mortality ... Show morePrognostic information is needed to balance benefits and risks of cancer treatment in older patients. Metabolomics-based scores were previously developed to predict 5- and 10-year mortality (MetaboHealth) and biological age (MetaboAge). This study aims to investigate the association of MetaboHealth and MetaboAge with 1-year mortality in older patients with solid tumors, and to study their predictive value for mortality in addition to established clinical predictors. This prospective cohort study included patients aged ≥ 70 years with a solid malignant tumor, who underwent blood sampling and a geriatric assessment before treatment initiation. The outcome was all-cause 1-year mortality. Of the 192 patients, the median age was 77 years. With each SD increase of MetaboHealth, patients had a 2.32 times increased risk of mortality (HR 2.32, 95% CI 1.59–3.39). With each year increase in MetaboAge, there was a 4% increased risk of mortality (HR 1.04, 1.01–1.07). MetaboHealth and MetaboAge showed an AUC of 0.66 (0.56–0.75) and 0.60 (0.51–0.68) for mortality prediction accuracy, respectively. The AUC of a predictive model containing age, primary tumor site, distant metastasis, comorbidity, and malnutrition was 0.76 (0.68–0.83). Addition of MetaboHealth increased AUC to 0.80 (0.74–0.87) (p = 0.09) and AUC did not change with MetaboAge (0.76 (0.69–0.83) (p = 0.89)). Higher MetaboHealth and MetaboAge scores were associated with 1-year mortality. The addition of MetaboHealth to established clinical predictors only marginally improved mortality prediction in this cohort with various types of tumors. MetaboHealth may potentially improve identification of older patients vulnerable for adverse events, but numbers were too small for definitive conclusions. The TENT study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22–10-2019. 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
Deursen, L. van; Vaart, R. van der; Chavannes, N.H.; Aardoom, J.J. 2024
Introduction Cancer survivors face physical, lifestyle, psychological, and psychosocial challenges. Despite the availability of aftercare services, survivors still have unmet needs. Digital... Show moreIntroduction Cancer survivors face physical, lifestyle, psychological, and psychosocial challenges. Despite the availability of aftercare services, survivors still have unmet needs. Digital aftercare programs may ofer support, but their use is limited. This study aimed to examine what is needed to improve uptake and adoption of these programs. Additionally, it explored sociodemographic and clinical variables that may infuence these needs. Methods A mixed-methods approach was used, involving qualitative interviews and a questionnaire. The research was guided by the COM-B model of behaviour, which considers capability, opportunity, and motivation crucial for behaviour. Qualitative analysis was performed using the framework method. Statistical analyses involved descriptive statistics and regression analysis. Results Fourteen cancer survivors were interviewed, and 213 participants completed the questionnaire. Findings indicated that most respondents had a positive or neutral attitude towards digital aftercare programs, believing these could address their cancer-related challenges. Still, only a small percentage had experience with them, and most were unaware of their existence. Many expressed a desire to be informed about them. Some were uncertain about their efectiveness. Others were concerned about a lack of reimbursement. No signifcant infuence of the sociodemographic and clinical variables was found. Conclusion Cancer survivors are generally positive about digital aftercare programs but are often unaware of their availability. Raising awareness, clarifying their value, and providing support and reimbursement could enhance uptake and adoption. Implications for Cancer Survivors The current insights can help improve participation in digital aftercare programs, ultimately fostering health, well-being, and quality of life of cancer survivors. Show less
By discussing the bodily aspects of undersea immersion, this paper investigates the lived experiences of the photographer’s body in space. To do this, it draws on the work of phenomenological... Show moreBy discussing the bodily aspects of undersea immersion, this paper investigates the lived experiences of the photographer’s body in space. To do this, it draws on the work of phenomenological philosophers who have theorized the body, such as Edmund Husserl, Edward S. Casey, Maurice Merleau-Ponty, and Gaston Bachelard, showing how the body is simultaneously active and passive in its environs. To make this point tangible, it examines a recent photographic work by contemporary Dutch artist Roosmarijn Pallandt, who attempts to capture her bodily sensations by submerging herself underwater while taking photographs. The paper argues that her photographic practice augments the bilaterality of the phenomenal body: being both a physical body (Körper) that needs to hold together kinesthetically and a lived body (Leib) that can go further proprioceptively. Consequently, by employing phenomenology vis-à-vis Pallandt’s photographic practice, the author defines immersivity as being concurrently still and moving, static and dynamic, passive and active, that is: as being inactive in space. Following this line of argument, he puts forward that the bodily immersivity is an instance of sheer inactivity. 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
The mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid... Show moreThe mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid factor (RF) for modern treatment outcomes remains unknown. We aimed to investigate the prognostic value of IgA-ACPA and IgA-RF for treatment outcomes in an early arthritis population. IgA-ACPA/RF isotypes were measured in baseline sera from 480 inflammatory arthritis (IA) patients, who were included in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH). The tREACH trial was a multicentre, stratified, single-blinded trial with a treat-to-target approach. The prognostic value of IgA-ACPA/RF was determined by evaluating differences in (1) quick-attained (< 6 months after diagnosis) and persistent remission rates, (2) DMARD-free remission and (3) biological use between IA patients with and without IgA-ACPA/RF over 3 years of follow-up. IgA-ACPA was present in 23% of patients and overlapped with IgG-ACPA positivity in 94%. Similarly, IgA-RF overlapped with IgM-RF in 90% of patients. IgA-ACPA positivity was associated with lower DFR rates and more biological use, but this effect was largely mediated by the presence of IgG-ACPA, since this effect disappeared after stratification for IgG-ACPA (HR 0.6, 95%CI 0.2-1.6 for DFR). No differences were observed in ‘quick-attained and persistent remission’ rates and for IgA-RF. Their seems to be no additional value of IgA-ACPA and IgA-RF for modern, long-term clinical outcomes. The effects of IgA-ACPA seen in our study are largely mediated by the presence of IgG-ACPA. Based on these results, there is no rationale for measuring these isotypes in daily practice. 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
Zhang, F.; Yao, H.; Langzam, E.; Meng, Q.L.; Meng, X.; Geest, R.J. van der; ... ; Yang, L. 2024
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
