Accurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have... Show moreAccurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have supported the PK prediction of the CNS target sites and the translation of PK data between species and between populations, given their mechanistic, physiology-based structure. In this thesis, we have developed a CNS PBPK model which could predict adequately the brainECF, brainICF, and CSF unbound PK profiles and provide important insights into the brain unbound pharmacokinetics of patients with CNS diseases. Early prediction of the brain target site pharmacokinetics of the right patient population can prioritize drugs with the favored brain PK profiles, which might optimize and accelerate the CNS drug development process. Show less
This thesis aims at identifying the conducive conditions of coercive diplomacy in the context of nuclear proliferation. Drawing on the US experience with Iran, Libya, and South Africa, we examined... Show moreThis thesis aims at identifying the conducive conditions of coercive diplomacy in the context of nuclear proliferation. Drawing on the US experience with Iran, Libya, and South Africa, we examined the driving factors behind US coercive diplomacy’s divergent and paradoxical results or outcomes in these countries. We chose our case studies based on two factors: the different stages or levels of their nuclear programs when confronted by the US and the nature of the demands formulated by the coercer in relation to the bilateral relations of the parties involved. We hypothesized that two conditions could compel a target subjected to coercive diplomacy to abandon its nuclear (weapons) program: if the coercer’s strategy exploits the target’s vulnerabilities and if the coercer demonstrates the motivation to have a sustained campaign to compel its target to abandon its nuclear weapons program. The interactions between the US and each of the targets mentioned above provide insights into improving coercive diplomacy, both theoretically and practically. The interplay between domestic politics and international pressures theoretically inspires our approach. We emphasized the critical role of domestic actors in alleviating or increasing systemic pressure related to the targets’ nuclear programs. We used neoclassical realism and process tracing to describe these dynamics and unravel the causal relationships between the coercer’s demands and the targets’ responses. Using the structured-focused comparative methodology, we reinforced our findings’ relevance and triangulated our primary and secondary sources. Our findings support the hypothesis of the driving effect of domestic variables in relation to external pressures. Hence, we identified similar and diverse mechanisms in our three cases, which helped us verify the validity of our initial hypotheses and confirmed the relevance of our research strategy regarding the complexity of coercion dynamics in the non-proliferation domain. Show less
This book examines the issuance of mining licenses in Indonesia from an environmental perspective. It shows how mining licensing has directly contributed to environmental degradation and how... Show moreThis book examines the issuance of mining licenses in Indonesia from an environmental perspective. It shows how mining licensing has directly contributed to environmental degradation and how consecutive governments have failed to take effective action addressing this problem. The main cause is the low quality of the relevant laws and policies, which is mostly a result of the priority law- and policymakers accord to mining development and a lack of interest in and knowledge about solving environmental problems. This situation has been exacerbated by a lack of public participation and bureaucratic “siloism”: government agencies often develop their own policies and regulations without efforts at co-ordination with other relevant government agencies. Only in a few cases have there been better results, when government agencies developing a policy had a strong interest in its implementation, when their officials disposed of adequate expertise, and when there was a favourable national political situation. Unfortunately, these conditions have rarely been present in Indonesia. Show less
The application of nanomaterials in industrial processes and consumer products provides many societal benefits, but can also lead to the release of nanomaterials into the environment. The work in... Show moreThe application of nanomaterials in industrial processes and consumer products provides many societal benefits, but can also lead to the release of nanomaterials into the environment. The work in this dissertation aims to provide insights into the potential environmental impacts that may follow from this, with specific reference to populations and communities of freshwater invertebrates. Based on experimental studies conducted under conditions reflecting those in natural ecosystems, this dissertation shows that commonly applied methodological approaches can lead to an underestimation of the long-term impacts of nanomaterials on freshwater organisms, particularly at the level of populations and communities. In doing so, this dissertation provides perspective on the role of relevance and realism in ecotoxicological assessments, and shows that impact assessments at higher ecological levels can provide sensitive and reliable insights that can serve as a basis for regulation, and guide the development of safer and more sustainable chemicals, substances and materials. Show less
This research investigates tensions associated with positive organizational change (POC) that prioritizes strengths-based dialogue over talk about organizational problems or deficits (Fitzgerald et... Show moreThis research investigates tensions associated with positive organizational change (POC) that prioritizes strengths-based dialogue over talk about organizational problems or deficits (Fitzgerald et al., 2010) by bridging the concept of organizational shadow (Bowles, 1991; Fitzgerald et al., 2010; Jung, 1968) with dialectical tension theory (Baxter & Simon, 1993). A recent flurry of studies suggests toxic positivity results in the marginalizing of individuals for expressing their emotions that may not always be positive (Collins, 2022; Cross, 2022; Tufvesson, 2020). A key question this research addresses is what do with the "elephants in the room" that represent what people think is undiscussable in a POC context? Interviews with 41 organizational development practitioners, with more than 600 cumulative years of experience leading POC initiatives using the Appreciative Inquiry (AI) methodology, identified the contexts in which tensions are likely to arise, the theoretical implications of tensions, and practical strategies to navigate tensions in a POC context. This study’s findings advance scholarship on positive organizing by naming the voice, leadership, and temporal shadows. These shadows emerge as three dialectical tensions: free expression and limited expression of what is discussible in the change process, hierarchical and collaborative leadership, and short-term orientation versus long-term orientation. The results of this study demonstrate experienced POC practitioners navigate tensions underlying the voice, leadership, and temporal shadows by using nuanced strategies, such as creating space to hear divergent perspectives, coaching leaders to demonstrate agility in support of collaborative initiatives, and reframing tension such that one pole does not negate the other. Show less
AI-powered emotion recognition, typing with thoughts or eavesdropping virtual assistants: three non-fictional examples illustrate how AI may impact society. AI-related products and services... Show moreAI-powered emotion recognition, typing with thoughts or eavesdropping virtual assistants: three non-fictional examples illustrate how AI may impact society. AI-related products and services increasingly find their way into daily life. Are the EU's fundamental rights to privacy and data protection equipped to protect individuals effectively? In addressing this question, the dissertation concludes that no new legal framework is needed. Instead, adjustments are required. First, the extent of adjustments depends on the AI discipline. There is nothing like 'the AI'. AI covers various concepts, including the disciplines machine learning, natural language processing, computer vision, affective computing and automated reasoning. Second, the extent of adjustments depends on the type of legal problem: legal provisions are violated (type 1), cannot be enforced (type 2) or are not fit for purpose (type 3). Type 2 and 3 problems require either adjustments of current provisions or new judicial interpretations. Two instruments might be helpful for more effective legislation: rebuttable presumptions and reversal of proof. In some cases, the solution is technical, not legal. Research in AI should solve reasoning deficiencies in AI systems and their lack of common sense. Show less
This thesis adopts a data-driven, multimodal approach to explore the complexity of psychiatric disorders, emphasizing the integration of diverse datasets to achieve a deeper understanding of these... Show moreThis thesis adopts a data-driven, multimodal approach to explore the complexity of psychiatric disorders, emphasizing the integration of diverse datasets to achieve a deeper understanding of these conditions. It illustrates this methodology across several chapters, each focusing on different aspects and biomarkers relevant to stress-related psychiatric disorders. Chapter 2 reevaluates the effects of intranasal oxytocin through a multimodal lens. Chapter 3 connects cortisol's in-vivo effects with brain responses and molecular architectures. Chapter 4 introduces a multimodal machine learning model to predict remission in depressive disorder, aiming for both accuracy and explanatory power. Chapter 5 examines the concept of resilience as a discrepancy between expected and observed mental health post-stress, assessing its predictive value for mental health outcomes. Finally, Chapter 6 explores a novel genetic risk score for stress-related disorders, testing its utility and applicability in various contexts. Through a comprehensive and data-centric approach, the thesis aims to uncover new insights into the etiology and treatment of psychiatric disorders, highlighting the importance of considering their multimodal nature. Show less
In the Netherlands, the title of Minister of State is granted to a select set of senior politicians and administrators, generally towards the end of their career. They are appointed by the monarch,... Show moreIn the Netherlands, the title of Minister of State is granted to a select set of senior politicians and administrators, generally towards the end of their career. They are appointed by the monarch, acting on a proposal by the cabinet. In this capacity, they are then asked to perform certain activities or to carry out specific tasks. Both the content of the Minister of State role itself and the appointment process are quite vague. Nevertheless, this exclusive ministerial title has considerable social status. The aim of this research study is to provide insight into the title of Minister of State. The problem description is as follows: What development has taken place in the role of Minister of State; what has the legal and political significance of the Minister of State been; and what can be said about the present-day role of Minister of State, in the Netherlands and in various other countries? Chapter 2 investigates the development of the Minister of State from a historical perspective. In Chapter 3 the various appointments as Minister of State are studied for each monarch. Chapter 4 examines the present-day role of Minister of State. In Chapter 5 a comparative legal study is made of whether other countries also have a Minister of State and what parallels and differences can be seen in relation to this title in the Netherlands.Chapter 6 brings together the findings of the research study and presents the conclusions that were drawn. Show less
In this thesis I highlight the applications of Oxford Nanopore Technologies (ONT) sequencing. This technique is a relatively new approach in the sequencing field, where nanopores are embedded in a... Show moreIn this thesis I highlight the applications of Oxford Nanopore Technologies (ONT) sequencing. This technique is a relatively new approach in the sequencing field, where nanopores are embedded in a membrane, DNA molecules are pulled through nanopores and an electrical current serving as the sequencing signal. This technique yields reads-lengths of >10Kbp and has no theoretical upper limit towards read-length. The positive impact on data quality due to improved chemistry is underlined, improved chemistry leads to less sequencing errors and a more homogeneous coverage over complex genomic architectures. Benefits for increased read-lengths are assessed for resolving fragmented genome assemblies that were previously based solely on short-read sequencing data. Furthermore, the assembly of a large genome using ONT data is described, indicating ONT is a suitable candidate for resolving extremely large genomes using sophisticated assembly approaches. And finally, the potential for on-site sequencing is evaluated. Exploiting simplicity, mobility and accuracy provided by this new technique. The central hypothesis of this thesis is that Oxford Nanopore Technologies long-read sequencing can be valuable for established genomics applications, such as whole genome sequencing and metagenomic characterization of microbial communities. Show less
In the light of the fragility of current liberal democracies, this dissertation aims to contribute to rethinking political order by reconstructing Hegel’s account in the Philosophy of Right. His... Show moreIn the light of the fragility of current liberal democracies, this dissertation aims to contribute to rethinking political order by reconstructing Hegel’s account in the Philosophy of Right. His theory of political order has relevance as it explores how modern freedom, i.e. liberal rights and a market, can coexist with republican self-government. The reconstruction shows how a liberal order, i.e. based on the principle of individual autonomy and an instrumental account of government, must entail a loss of freedom and social and political pathologies: citizens for instance cannot acquire stable identities in the social whole and alienate themselves from the political realm. Moreover, it works out Hegel’s alternative account of political order in which freedom depends on the interplay of the opposed dynamics of the state and society: the state institutions pursuing the good of the community as a whole, while the members of civil society pursue their own good. Finally, the dissertation shows how Hegel offers a coherent and subtle account of republican citizenship and self-government, in which self-government does not depend primarily on the influence citizens exercise on political outcomes but on their ability to identify with the good of the community as a whole. Show less
This dissertation explores the United Nations' comprehensive approach to managing the Israel-Arab Conflict from 1967 to 1982, presenting a shift from examining peace operations as isolated efforts... Show moreThis dissertation explores the United Nations' comprehensive approach to managing the Israel-Arab Conflict from 1967 to 1982, presenting a shift from examining peace operations as isolated efforts to viewing them as interconnected elements of a broader peace architecture. It introduces a critical analysis of the roles played by the Office of Special Political Affairs and the Office of Chief Coordinator of Peacekeeping in the Middle East, arguing that these entities were pivotal in forming a cohesive strategy despite the static mandates of individual peace missions. The research spans six chapters, starting with a historical overview of the UN’s peacekeeping framework since 1948, setting the groundwork for understanding the conflict and the evolution of peacekeeping entities. It then delves into Inter-Operation Collaboration (IOC) and the Secretariat’s political maneuvering, highlighting the impact of significant events like the Camp David Accords and the 1982 Israeli invasion of Lebanon. These events marked a shift in focus from state-centric to Israeli-Palestinian issues, challenging the UN’s influence. The conclusion assesses the UN’s role in shaping the diplomatic and security landscape of the region, underlining the organization's contributions and limitations in fostering peace and stability amidst a complex geopolitical scenario. This research offers valuable insights into the dynamics of UN peacekeeping operations in regional conflicts. Show less
Drug candidates with a covalent binding mode have gained interest since the approval of multiple covalent anticancer drugs, but were long avoided due to concerns regarding promiscuous reactivity... Show moreDrug candidates with a covalent binding mode have gained interest since the approval of multiple covalent anticancer drugs, but were long avoided due to concerns regarding promiscuous reactivity with off-target proteins. In this dissertation, the scope and versatility of the newly discovered in situ thiol–alkyne reaction is evaluated: the nonactivated alkynes exhibit an unprecedented target reactivity with excellent thiol selectivity, thus potentially outperforming currently used cysteine-reactive warheads. Chapter 1 starts with the history of (ir)reversible covalent inhibition, the reactivity of (non)activated alkynes, and the serendipitous discovery of the thiol–alkyne reaction. Established technologies for direct detection of covalent protein–drug adducts are reviewed in Chapter 2, and in Chapter 3 a detailed guide for the evaluation of (ir)reversible covalent inhibitors to obtain relevant kinetic parameters is provided, accompanied by kinetic simulations and step-wise protocols for enzymatic activity assays. In Chapter 4, the nitrile warhead in reversible CatK inhibitor odanacatib (ODN) is replaced with alkyne warheads to investigate whether it an irreversible covalent adduct is formed with cysteine protease cathepsin K (CatK) despite having a small recognition element. In Chapter 5, we evaluate if nonactivated alkynes can target noncatalytic cysteine residues by replacing the irreversible covalent acrylamide warhead in EGFR/HER2 inhibitor neratinib by an alkyne warhead. In Chapter 6, the impact of substituents on the alkyne warhead is explored using a panel of ubiquitin-based ABPs bearing substituents on the propargylamide warhead. Finally, the most important findings are summarized in Chapter 7, and placed in the context of covalent drug discovery. Show less
Schistosomiasis is a parasitic infection caused by worms of the genus Schistosoma. It is a neglected tropical disease, affecting mainly populations living in poverty without adequate sanitation.... Show moreSchistosomiasis is a parasitic infection caused by worms of the genus Schistosoma. It is a neglected tropical disease, affecting mainly populations living in poverty without adequate sanitation. Treatment relies on one drug mainly, praziquantel, and its efficacy is dependent on the diagnostic tool used.Due to the parasite’s intravascular localisation, it is difficult to directly quantify them in infected humans. Thus, methods of detection like worm-derived circulating cathodic antigen (CCA) in urine or circulating anodic antigen (CAA) in urine and serum, have gained more attention. This thesis aims to explore and shed light on how to interpret schistosome-related circulating antigens CCA and CAA. We have addressed the interpretation of schistosome related assays in endemic and non-endemic regions, supported by data obtained from an animal study. Different diagnostic value can be attributed to different assays within different contexts. The results highlight the importance of a better understanding of antigen excretion patterns by different species to support optimalisation of antigen-based diagnostics of schistosomiasis. Show less
Voltammetry plays a crucial role in modern scientific research by offering valuable insights into the electrochemical properties of materials, with wide-ranging applications in fields such as... Show moreVoltammetry plays a crucial role in modern scientific research by offering valuable insights into the electrochemical properties of materials, with wide-ranging applications in fields such as materials science, energy storage, corrosion studies, and sensor development.Gold, known for its exceptional inertness, provides a unique platform for studying intricate electrochemical processes due to its stability and slow electrochemical behavior. However, certain questions regarding gold voltammetry have remained unresolved throughout history. To address these gaps, our research employed a combination of electrochemical cyclic voltammetry and advanced in situ techniques like surface-enhanced Raman spectroscopy (SERS), Rotating ring-disk electrode (RRDE), and Electrochemical quartz crystal microbalance (EQCM).Through our investigations, we not only redefined the mechanism of gold oxide formation but also uncovered the reasons behind the structural reconstruction of gold oxide. Additionally, we elucidated the electrochemical interfacial structure on gold from a novel perspective focusing on charge distribution.The significance of these findings lies in their fundamental nature, with the potential to inspire researcher to reconsider interpretations of voltammetry behaviors across various materials and research fields. We anticipate that our work will stimulate further exploration and innovation in the realm of electrochemistry, paving the way for new discoveries and advancements. Show less
Despite the history of studies on methanol formation from CO2, the dominant elementary reaction steps that constitute the chemical mechanism for this catalyzed process are not determined. Two main... Show moreDespite the history of studies on methanol formation from CO2, the dominant elementary reaction steps that constitute the chemical mechanism for this catalyzed process are not determined. Two main issues may cause doubt about the current level of understanding: 1) the very large difference in the coverage-dependent sticking probabilities for CO2 and CO and unavoidable CO contamination 2) the complex oxidation of the copper surface and unavoidable build-up of a (partial) oxide layer.In this thesis, we studied the sticking probability of O2 on Cu(111) and compared results to previous experimental and theoretical results. The dissociative chemisorption of O2 on Cu(111) is a direct, activated process with a minimum barrier of approximately 100 meV.In an attempt to develop a method that may undeniably quantify the reactivity of CO2 onto clean and H-containing Cu surfaces, we investigated co-adsorbed CO and O on Cu(111) and Cu(211) with RAIRS. Cu(211) oxidizes much more readily than Cu(111). For incomplete oxidation, the system CO adsorbs to small isolated metallic Cu edges and patches. Fully oxidized Cu(211) binds CO but in a rather different form than clean metallic Cu. The vibrational frequency of adsorbed CO is changed as the co-adsorbed O coverage varies on Cu(211). Show less
This thesis investigates the contribution of quantum computers to machine learning, a field called Quantum Machine Learning. Quantum Machine Learning promises innovative perspectives and methods... Show moreThis thesis investigates the contribution of quantum computers to machine learning, a field called Quantum Machine Learning. Quantum Machine Learning promises innovative perspectives and methods for solving complex problems in machine learning, leveraging the unique capabilities of quantum computers. These computers differ fundamentally from classical computers by exploiting certain quantum mechanical phenomena. The thesis explores various proposals within quantum machine learning, such as the application of quantum algorithms in topological data analysis. With respect to topological data analysis, results demonstrate that quantum algorithms solve problems considered inefficient in classical settings. The thesis also explores structural risk minimization in quantum machine learning models, identifying crucial design choices for new quantum machine learning models. Additionally, it introduces quantum models in reinforcement learning, which deliver comparable performance to traditional models and are superior in certain scenarios. The final part identifies learning tasks in computational learning theory where quantum learning algorithms have exponential advantages. In summary, this thesis contributes to understanding how quantum computers can address complex machine learning problems, from topological data analysis to reinforcement learning and computational learning tasks. Show less
The dissertation explores the relationship between online and offline anti-corruption activism in Banten, Indonesia. It examines the historical background of anti-corruption activism in Indonesia,... Show moreThe dissertation explores the relationship between online and offline anti-corruption activism in Banten, Indonesia. It examines the historical background of anti-corruption activism in Indonesia, the comparison of online discourse of corruption framed by national civil society organizations (CSOs) and local activists, the impact of online activism on citizenship characteristics, and its potential transformation into strong or weak offline mobilization. The study uses social media ethnography to examine the materiality of being online and its relation to corruption and anti-corruption campaigns. The research reveals that corruption is primarily constructed as a legal discourse in national anti-corruption campaigns, while in Banten, morality and religious discourse are used to frame corruption. Online anti-corruption activism in Banten involves digital acts of reporting and sharing corruption news and flaming to resist corrupt leaders. This approach has led to the development of 'digital affective citizenship', where citizens express anger, hate, passion, and disgust towards corrupt leaders. The dissertation also discusses the characteristic of citizens in Banten that reflects "powerless angry citizens," who desire to influence political outcomes through corruption but feel powerless due to the mismatch between their desire and the limitations of participatory channels and organizations. Show less
Chinese materia medica (CMM), comprising a diverse array of natural substances from plants, animals, and minerals, has been integral to Traditional Chinese Medicine (TCM) throughout history. This... Show moreChinese materia medica (CMM), comprising a diverse array of natural substances from plants, animals, and minerals, has been integral to Traditional Chinese Medicine (TCM) throughout history. This study investigates the dynamic evolution of CMM, noting shifts in species for improved therapeutic effects and the abandonment of those with adverse outcomes. By examining historical CMM specimens, particularly those in Dutch collections, tangible evidence of this evolution emerges.The Westhoff collection, spanning 140 years, reveals significant changes alongside enduring practices. A handwritten catalogue accompanying the collection aligns with modern CMM practices, indicating a remarkable continuity. Comparative analyses of historical collections and contemporary CMM in EU markets over three centuries emphasize the stability of core medicinal plant taxa. Additionally, the study validates the delayed luminescence (DL) technique for discerning CMM storage times, showing promising results.Despite challenges in preservation, historical CMM specimens offer unique insights into medicine's history, underscoring their importance for further research and understanding. Show less
Radiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined... Show moreRadiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined in clinical studies, although their success has been limited. We used mouse tumor models to understand how radiotherapy induces T cell priming and subsequent anti-tumor immunity. In a model resembling lymphocyte-depleted cancer, we identified obstacles to systemic radiotherapy-induced T cell responses and proposed interventions to overcome them. Additionally, we explored strategies to counter local T cell suppression in the tumor microenvironment. In poorly immunogenic tumors, radiotherapy can provoke a T cell response, but this is counteracted by the generation of immunosuppressive Tregs. Combining radiotherapy with checkpoint immunotherapy, despite its success in humans, unexpectedly amplified the Treg response, further hindering cytotoxic T-cell activity. Our findings suggest this immunotherapy may not benefit these cancers. We discovered that molecules like CD80 and CD86, capable of stimulating T cells via the CD28 receptor, have distinct roles in promoting cytotoxic and Treg cells. Blocking CD86 enhanced cytotoxic T cell responses post-radiotherapy, leading to tumor rejection. Our study elucidates how tumor characteristics shape T-cell responses, how radiotherapy can evoke both favorable and unfavorable responses, and how targeted antibody immunotherapy can influence this interplay. Show less
