Two independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function... Show moreTwo independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function variants in NPAT, a gene that encodes a cyclin E/CDK2 effector required for S phase entry and a coactivator of histone transcription, in two families with multiple members affected with colorectal cancer. Enrichment of loss-of-function and predicted deleterious NPAT variants was identified in familial/early-onset colorectal cancer patients compared to non-cancer gnomAD individuals, further supporting the association with the disease. Previous studies in Drosophila models showed that NPAT abrogation results in chromosomal instability, increase of double strand breaks, and induction of tumour formation. In line with these results, colorectal cancers with NPAT somatic variants and no DNA repair defects have significantly higher aneuploidy levels than NPAT-wildtype colorectal cancers. In conclusion, our findings suggest that constitutional inactivating NPAT variants predispose to mismatch repair-proficient nonpolyposis colorectal cancer. Show less
Berg, L.N. van den; Aardoom, J.J.; Kiveron, L.E.; Botterweg, R.D.; Akker-van Marle, M.E. van den; Chavannes, N.H.; Hoitsma, E. 2024
Background: Multiple sclerosis (MS) is a persistent inflammatory condition impacting the brain and spinal cord, affecting globally approximately 2.8 million individuals. Effective self-management... Show moreBackground: Multiple sclerosis (MS) is a persistent inflammatory condition impacting the brain and spinal cord, affecting globally approximately 2.8 million individuals. Effective self-management plays a crucial role in the treatment of chronic diseases, including MS, significantly influencing health outcomes. A personal health record (PHR) is a promising tool to support self-management, potentially empowering patients and enhancing their engagement in treatment and health. Despite these promising aspects, challenges in implementation persist and PHRs are still a relatively new concept undergoing rapid development.Objective: This study aimed to assess the feasibility and usability of the PHR. Secondary objectives included evaluating implementation determinants, and exploring preliminary effects on quality of care for both patients and healthcare professionals (HCPs), self-management, self-efficacy for patients, job satisfaction, efficiency, and demand for HCPs, and preliminary effects on costs and health-related quality of life.Methods: This study had a mixed-methods design. Quantitative data of patients (n = 80) and HCPs (n = 12) were collected via self-reported questionnaires at baseline (T0), after one year (T1), and after two years (T2). One focus group interview was conducted at T2 with patients (n = 7), and another one with HCPs (n = 4), to get a more in-depth understanding of the feasibility and usability of the PHR via the Unified Theory of Acceptance and Use of Technology framework, and to further explore the secondary objectives in-depth.Results: Most patients never logged in during the first year and logged in a couple of times per year during the second year, averaging around 15 min per log-in session. The HCPs mainly logged in a couple of times per year over the two years with an average use of six minutes per session. Patient usability and satisfaction scores were below average and moderate, respectively: with SUS-scores of 59.9 (SD = 14.2, n = 33) at T1 and 59.0 (SD = 16.3, n = 37) at T2, and CSQ-8 scores of 21.4 (SD = 5.0, n = 34) at T1, and 22.1 (SD = 5.0, n = 39) at T2. HCPs had similar usability and satisfaction scores. Multiple facilitators and barriers were identified by both patients and HCPs, such as (in)sufficient knowledge of how to use the PHR, lack of staff capacity and ICT obstacles. No significant differences were found in the preliminary effects. Qualitative data showed, among others, that both patients and HCPs saw the benefit of the PHR in terms of performance expectancy, by gaining more insight into health and health data, but challenges remained regarding effort expectancy, such as log-in issues and experiencing difficulties with information retrieval.Conclusion: The feasibility and usability were considered moderate by patients and HCPs; however, potential regarding the performance of the PHR was observed. Implementation challenges, such as the complexity of usage, lowered the adoption of the PHR. The evolving nature of PHRs requires ongoing evaluation and adaptation to optimize their potential benefits. Utilizing a participatory design approach and a dedicated implementation team could help in achieving this optimization, ultimately enhancing their adoption. Show less
The global trade of plastic waste has raised environmental concerns, especially regarding pollution in waste-importing countries. However, the overall environmental contribution remains unclear due... Show moreThe global trade of plastic waste has raised environmental concerns, especially regarding pollution in waste-importing countries. However, the overall environmental contribution remains unclear due to uncertain treatment shares between handling plastic waste abroad and domestically. Here, we conduct a life cycle assessment of global plastic waste trade in 2022 across 18 countries and six plastic waste types, alongside three “nontrade” counterfactual scenarios. By considering the required cycling rate, which balances importers’ costs and recycling revenues, we find that the trade resulted in lower environmental impacts than treating domestically with the average treatment mix. The trade scenario alone reduced climate change impact by 2.85 million tonnes of CO2 equivalent and mitigated damages to ecosystem quality, human health, and resource availability by 12 species-years, 6200 disability-adjusted life years (DALYs), and 1.4 billion United States dollars (USD in 2013), respectively. These results underscore the significance of recognizing plastic waste trade as a pivotal factor in regulating global secondary plastic production when formulating a global plastics treaty. Show less
Throughout the history of computer science, a major challenge has been how to assert that software is free of bugs and works as intended. Software bugs can lead to serious negative impacts on any... Show moreThroughout the history of computer science, a major challenge has been how to assert that software is free of bugs and works as intended. Software bugs can lead to serious negative impacts on any software system. Throughout the main body of the thesis, we implemented a series of studies on exploring ways to apply formal methods systematically for the verification of complex object-oriented libraries such as the Java Collection Framework. We start with specifying and verifying methods in the java.util.LinkedList class, but we encounter challenges with methods that take an interface type as a parameter. To address this, we proposed to use histories as method calls and returns to completely determine the concrete state of any implementation and thus can be seen as a way to reason about the interface. The executable history-based (EHB) approach embeds histories and attributes directly as Java objects. This approach could be seamlessly integrated in the KeY theorem prover itself. However, the EHB approach still has its limitations, particularly when it comes to reasoning about the heap and properties of user-defined attributes.To mitigate this, we introduce the logical history-based (LHB) approach, which models histories as an external abstract data type with functions. Building on the LHB approach, we have developed a history-based refinement theory for reasoning about hierarchy in object-oriented programs. Show less
A group of bacterial proteases, the Pro-Pro endopeptidases (PPEPs), pos-sess the unique ability to hydrolyze proline-proline bonds in proteins. Sincea protease’s function is largely determined by... Show moreA group of bacterial proteases, the Pro-Pro endopeptidases (PPEPs), pos-sess the unique ability to hydrolyze proline-proline bonds in proteins. Sincea protease’s function is largely determined by its substrate specificity,methods that can extensively characterize substrate specificity are valuabletools for protease research. Previously, we achieved an in-depth characteri-zation of PPEP prime-side specificity. However, PPEP specificity is alsodetermined by the non-prime-side residues in the substrate. To gain a morecomplete insight into the determinants of PPEP specificity, we character-ized the non-prime- and prime-side specificity of various PPEPs using acombination of synthetic combinatorial peptide libraries and mass spec-trometry. With this approach, we deepened our understanding of the P3-P30 specificities of PPEP-1 and PPEP-2, while identifying the endogenoussubstrate of PPEP-2 as the most optimal substrate in our library data. Fur-thermore, by employing the library approach, we investigated the alteredspecificity of mutants of PPEP-1 and PPEP-2. Additionally, we character-ized a novel PPEP from Anoxybacillus tepidamans, which we termed PPEP-4. Based on structural comparisons, we hypothesized that PPEP-4 displaysa PPEP-1-like prime-side specificity, which was substantiated by the experi-mental data. Intriguingly, another putative PPEP from Clostridioides diffi-cile, CD1597, did not display Pro-Pro endoproteolytic activity.Collectively, we characterized PPEP specificity in detail using our robustpeptide library method and, together with additional structural informa-tion, provide more insight into the intricate mechanisms that govern prote-ase specificity. Show less
Malaria continues to wreak havoc in tropical regions, due largely to the lack of an effective vaccine. Vaccine candidates based on whole parasites have shown promising results in malaria-naïve... Show moreMalaria continues to wreak havoc in tropical regions, due largely to the lack of an effective vaccine. Vaccine candidates based on whole parasites have shown promising results in malaria-naïve individuals, but their potency in malaria-exposed individuals is considerably lower. This dissertation described the development of a chemical strategy for boosting such parasites’ potency in pursuit of more efficacious malaria vaccines for use in endemic areas.Chapter 2 outlined the adaptation of a method for chemically modifying microbial cell surfaces.Chapter 3 showed the chemistry underlying this modification system to be stably compatible with in vivo usage.Chapter 4 demonstrated that when the chemical modification system was used to introduce immune-potentiating agents onto bacteria, better immune responses ensued.Chapter 5 tied it all together by using the chemical modification system to potentiate malaria parasites, and showed that doing so markedly improved immune responses in an in vivo immunization model.Chapter 6 summarized these findings in the context of malaria vaccine development and posited next steps forward. Show less
In this dissertation we investigate the emotional and psychiatric effects of glucocorticoids (e.g. cortisol, dexamethasone and prednisone). Glucocorticoids are widely used and their possible... Show moreIn this dissertation we investigate the emotional and psychiatric effects of glucocorticoids (e.g. cortisol, dexamethasone and prednisone). Glucocorticoids are widely used and their possible psychiatric side effects are well known. It is still unclear who is susceptible to side effects and what mechanism is behind this. In this thesis we try to better understand the underlying causes. For example, we use a relatively new static method in this research field, which can analyze changes over time better than the usual methods. In a study, we show that in depressed study participants, changes in certain affect items preceded changes in cortisol levels, while in control participants this was the other way around. Furthermore, we explore a hypothesis that may explain the mechanism of the psychiatric side effects of glucocorticoids. This mechanism is also used for a strategy to prevent the psychiatric side effects. The strategy is based on the fact that synthetic glucocorticoids are very similar to the body's own hormone cortisol, but their binding to the two cortisol receptor proteins and their effects may be different. By achieving a balanced activation of the two cortisol proteins when using glucocorticoids, the psychiatric side effects could possibly be prevented. In summary, this thesis provides further insight into the emotional and psychiatric side effects of glucocorticoids, but the search for a better understanding of the neuropsychiatric side effects remains a pressing concern, which will hopefully benefit patient care in the future. Show less
The lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main SC lipid classes are ceramides (CER), cholesterol and... Show moreThe lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier function. The three main SC lipid classes are ceramides (CER), cholesterol and free fatty acids. In inflammatory skin diseases, such as atopic dermatitis and psoriasis, the SC lipid composition is altered compared to the healthy SC composition. The studies presented in this thesis focused on the effect of the CER subclass composition on the lipid organization, molecular arrangement and barrier function of the skin. First, the CER compositional changes were examined in the SC of seborrheic dermatitis patients, an inflammatory skin disease. A particular emphasis was paid to the ratio of two important CER subclasses, sphingosine CER (CER NS) and phytosphingosine CER (CER NP), and its correlation to the skin barrier. In the subsequent chapters lipid model systems with a simple CER subclass composition were used to study the influence of the CER NS: CER NP molar ratio on the barrier function and lipid organization. Show less
The dissertation investigates the role of lexical tone in spoken word recognition and production. In particular, it focuses on three groups of speakers: native speakers of Standard Chinese, bi... Show moreThe dissertation investigates the role of lexical tone in spoken word recognition and production. In particular, it focuses on three groups of speakers: native speakers of Standard Chinese, bi-dialectal speakers of Standard Chinese and Xi’an Mandarin, and bilingual speakers of Standard Chinese and English. Through a series of experiments employing the eye-tracking visual world paradigm and the picture-word interference paradigm, four key issues were explored: the role of lexical tone in Mandarin spoken word recognition; tonal interference in bi-dialectal spoken word recognition; the activation of lexical tone in bilingual spoken word production; and the influence of lexical tone on the bilingual mental lexicon. The findings of this dissertation not only showed how Mandarin listeners utilize tonal information during tone word recognition but also revealed dynamic tonal interaction between language systems. Overall, this dissertation contributes to a deeper understanding of lexical access by highlighting the significant role of lexical tone in both monolingual and bilingual contexts, shedding light on the intricate processes involved in spoken word recognition and production across languages. Show less
Manumission is the release from slavery, and therefore, a transition from the most extreme form of subjugation into another position and status in society. Some historians have defined manumission... Show moreManumission is the release from slavery, and therefore, a transition from the most extreme form of subjugation into another position and status in society. Some historians have defined manumission as a formal act, often understood as a gift that severed the bond between slave and master. More recently researchers have emphasized that it was a lengthy process that involved pre-existing dependencies and resulted in new hierarchies. This article takes a fresh look at the process and tries to gain a fuller understanding of manumission by examining it from the position of the manumitted and their social relations. Taking into consideration a wide range of documentary sources from colonial, notarial and Dutch governmental archives, we reconstruct the dependencies that were created in the process of manumission. The dependencies that evolved during manumission processes were related to family and other kinship ties, but also had an urban, communal, religious, economic and institutional logic. Manumission was not only an act at a specific moment, but also a process, and it was not a bilateral, but a multilateral one. With the instrument of manumission and within the limits set by economic reality and the colonial government, the manumittees tried to make meaningful life choices that transformed slave society profoundly. We find that they created complex dependencies across boundaries of status and racial categorization. Show less
High-grade osteosarcoma, a primary malignant bone tumour, is experiencing a global increase in reported incidence with varied prevalence. Despite advances in management, which include surgery and... Show moreHigh-grade osteosarcoma, a primary malignant bone tumour, is experiencing a global increase in reported incidence with varied prevalence. Despite advances in management, which include surgery and neoadjuvant chemotherapy often an unsatisfactory outcome is found due to poor or heterogeneous response to chemotherapy. Our study delved into chemotherapy responses in osteosarcoma patients and associated molecular expressions, focusing on CD95 receptor (CD95R), interferon (IFN)-γ, catalase, heat-shock protein (Hsp)70, and vascular endothelial growth factor (VEGF). Employing immunohistochemistry and Huvos grading of post-chemo specimens, we analysed formalin-fxed parafn-embedded (FFPE) osteosarcoma tissue of resected post-chemotherapy specimens from Dr. Soetomo General Academic Hospital in Surabaya, Indonesia (DSGAH), spanning from 2016 to 2020. Results revealed varied responses (poor 40.38%, moderate 48.08%, good 11.54%) and distinct patterns in CD95R, IFN-γ, catalase, Hsp70, and VEGF expression. Signifcant diferences among response groups were observed in CD95R and IFN-γ expression in tumour-infltrating lymphocytes. The trend of diminishing CD95R expression from poor to good responses, accompanied by an increase in IFN-γ, implied a reduction in the count of viable osteosarcoma cells with the progression of Huvos grading. Catalase expression in osteosarcoma cells was consistently elevated in the poor response group, while Hsp70 expression was highest. VEGF expression in macrophages was signifcantly higher in the good response group. In conclusion, this study enhances our understanding of immune-chemotherapy interactions in osteosarcoma and identifes potential biomarkers for targeted interventions. Show less
This thesis has studied several modalities how to increase the organ utilisation rate. The results in this thesis indicate that the acceptance of kidneys with acute kidney injury stage 1 or 2 will... Show moreThis thesis has studied several modalities how to increase the organ utilisation rate. The results in this thesis indicate that the acceptance of kidneys with acute kidney injury stage 1 or 2 will significantly contribute to the donor pool as AKI kidneys have comparable outcomes and should therefore not be discarded. Clinically relevant biomarkers such as cell-free unmethylated-INS DNA, FMN, GSN, IGFBP3 and IGF2R were identified or explored in the first part of this thesis and may, if analysed and/or validated thoroughly, contribute to a better assessment of organ viability supporting the justified decision whether to accept or decline the donor organ.The second part of this thesis describes different aspects of the organ preservation technique of abdominal normothermic regional perfusion (aNRP). This relatively new machine perfusion technique has been shown to be feasible and safe, however, consensus regarding assessment parameters during perfusion, protocols and outcome measurements is still lacking. Despite of an inspiring surgical enthusiasm and keeninterest to accept this modality as a new standard, a randomised clinical trial is still required and entirely ethically justifiable in order to scientifically demonstrate superiority of this method for each individual abdominal organ comparing it to other successful (ex-situ) preservation and perfusion strategies. If aNRP can be shown to obtain better post transplantation outcomes whilst increasing organ utilisation, it may be the least complex and most cost-effective strategy in organ preservation. On the other hand, aNRP will only be used in DCD donors. As such, uncertainty regarding the quality of higher risk organs from DBD donors will still be evaluated ex-situ during cold and/or warm machine perfusion with the potential to repair or even regenerate injured organs and making them ‘transplantable’ again. Show less
Demand for palliative care is expected to rise due to an ageing population, an increase in chronic diseases, and multimorbidity. Currently, many countries, including the Netherlands, are dealing... Show moreDemand for palliative care is expected to rise due to an ageing population, an increase in chronic diseases, and multimorbidity. Currently, many countries, including the Netherlands, are dealing with a high demand and shortages of professionals in the healthcare sector. Because of the different nature of providing palliative care compared to curative care and the expected increase in demand for palliative care, the focus of this thesis is to gain insight into the emotional impact of providing palliative care on healthcare professionals.This thesis highlights the emotional stressors healthcare professionals encounter in providing palliative care. Building personal relationships with patients bring both rewarding and emotionally experiences, especially when patients are dying. Among palliative care professionals higher burnout rates were found in general settings than in specialised palliative care settings, possibly due to insufficient training and attention to the emotional impact of providing palliative care in the former.Education and group meetings are seen as crucial for raising awareness and reducing stress. This thesis emphasizes the need for team and organisational support to adequately address the wellbeing of healthcare professionals in this growing field. It requires shared responsibility and action from organisations, teams and healthcare professionals to care about the care for healthcare professionals providing palliative care. Show less
During the Cold War, the Dutch Army Medical Service (MGD) promoted the health and operational readiness of the Royal Netherlands Army. Medical war preparations were an integral part of this. The... Show moreDuring the Cold War, the Dutch Army Medical Service (MGD) promoted the health and operational readiness of the Royal Netherlands Army. Medical war preparations were an integral part of this. The evacuation, treatment and nursing of sick and wounded soldiers in wartime required the formulation of procedures and doctrines as well as an extensive organization, complete with supplies and equipment, trained personnel and mobilization plans. However, these activities were shrouded in uncertainty as the prospect of biological, chemical or even nuclear warfare called into question all casualty estimations based on previous conflicts.The central question in this dissertation is how the MGD dealt with the nuclear threat perception and how military-medical war preparations were influenced by it. Against the backdrop of the ominous prospects of future warfare, military physicians tried to legitimize their war preparations and make sense of them. This mechanism is made clear using the concept of sociotechnical imaginaries: constructed optimistic images of the future that are based on the collective belief in scientific and technological progress. This study shows that the MGD maintained an optimistic outlook from the beginning through the end of the Cold War, but the reasoning that supported this viewpoint evolved over time. Show less
Emotions significantly influence our perceptions and interactions with the environment, yet the impact of our emotional states on judging and responding to others remains underexplored. In this... Show moreEmotions significantly influence our perceptions and interactions with the environment, yet the impact of our emotional states on judging and responding to others remains underexplored. In this thesis, I examined how (romantic) attraction influences our attention (Part I), how we judge others’ intentions (Part II), and whether mimicking another facilitates bond formation (Part III). In two empirical chapters, I demonstrate that people have a strong attentional bias towards visual attractiveness and a tendency to indicate interest in establishing a romantic connection to attractive others. In the subsequent empirical chapter, I show that men are more likely to judge women they find attractive as more sexually aroused. Crucially, in a real-life dating study, I show that men who are attracted to another are more likely to assume mutual interest. Further, I introduce a framework suggesting that people align their actions and emotional states with others to foster romantic relationships. The final empirical chapter suggests that mimicking the attraction cues of others enhances bond formation. Overall, this dissertation sheds light on how attractiveness and attraction affect our attention, our social cognition, and the synchronization of actions and emotions, offering insights into the mechanisms underlying romantic connections. Show less
In this thesis, I focused on studying the above- and belowground interactions of J. vulgaris from a plant-soil feedback (hereafter, PSF) perspective. I investigated the temporal variation of... Show moreIn this thesis, I focused on studying the above- and belowground interactions of J. vulgaris from a plant-soil feedback (hereafter, PSF) perspective. I investigated the temporal variation of negative PSF and examined the effects of root-associated bacteria on plant performance and aboveground herbivores. Additionally, I tested the role of PSF in relation to plant population structure and the significance of soil legacy effects in natural conditions. The findings reveal that temporal dynamics in PSF are driven by changes in plant sensitivity and in the soil microbiome. Although bacteria isolated from J. vulgaris roots can negatively affect plant performance, they can also affect aboveground herbivores and other plant species. Consequently, these bacteria may not be suitable for biological control of J. vulgaris. Moreover, I discovered that soil nematodes can mediate plant-plant interactions, but often favoring J. vulgaris. In my field work, I detected soil legacy effects, but seedling recruitment spatial patterns of J. vulgaris were not soil-mediated. The insights gained from studying PSF and above- and belowground interactions have the potential to reshape traditional approaches employed in controlling invasive plants. This thesis emphasizes the importance of transitioning PSF experiments from indoor to outdoor settings considering various influencing factors simultaneously. Show less
