Leiden University Scholary Publications
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Colloidal mechanical metamaterials
Get PDFThis thesis describes how to scale down concepts of macroscopic mechanical metamaterials to the thermal scale using a system of flexibly-linked colloids. Using this system, square lattices were made and an analysis method was developed to quantitatively extract the normal modes. The resulting mode spectra exhibited the expected number of soft modes, nonlinear effects onto stiffer modes, and harmonic stiff modes. The experimental findings were complemented by Brownian particle simulations, a linear response model, and Monte-Carlo based stochastic conformation sampling. Next, colloids assembled in rigid anisotropic units made it possible to create the archetypical auxetic metamaterials, the rotating diamond lattice and rotating triangle, or Kagome, lattice. Adding magnetic interactions in the system provided control over the conformation and the possibility for actuation. Ring-like structures of four particles are stable in their diamond conformation in presence of magnetic interactions, and this symmetry can be broken by using particles of different sizes. Finally, a method was developed to use anisotropic building blocks such as cubic particles in flexible colloidal structures.Biological and Soft Matter Physic
trans-Cyclooctene-caged-IL-1β immunocytokine-constructs ligated to unmodified nanobodies allow click-2-release-based control of cytokine activity
Get PDFImmunocytokines have emerged as a promising modality in cancer therapy, capitalizing on the precision of antibodies to deliver cytokines selectively to tumours. Yet, the toxicity of the cytokine portion of these antibody-cytokine constructs remains a major dose-limiting issue. We present a new approach to control cytokine function without affecting binding of the targeting moiety. By modifying the cytokine with trans-cyclooctene carbamates at the lysine positions, we can reduce the binding to the receptor of various highly pro-inflammatory cytokines. Then, using a click-2-release (C2R)-approach, we can reactivate the cytokine activity by reacting it with a variety of tetrazines, through a Diels-Alder-pyridazine-elimination cascade. Finally, we show that the caged cytokines can be conjugated via a sortase motif to an unmodified targeting nanobody resulting in a targetable caged immunocytokine construct.Seventh Framework Programme (FP7)CoG-865175; 101188789-TIGERChemical Biology & Immunolog
The systemic right ventricle and the Fontan circulation: addressing late complications
Get PDFThanks to advances in care, more patients with congenital heart disease (CHD) are reaching adulthood (ACHD). However, many face serious long-term complications such as heart failure. This thesis focuses on two complex CHD groups: patients with a systemic right ventricle (sRV) and those with a Fontan circulation. Treating these complications remains challenging, as these groups are often excluded from large clinical trials. For sRV patients, I studied the heart failure drug sacubitril/valsartan, one of the four pillars of standard heart failure treatment. Our findings suggest it is safe and may improve heart function, exercise capacity, and quality of life. I also examined SGLT2 inhibitors—another treatment pillar—which show promise for sRV-related heart failure. An eHealth-supported care pathway was developed for remote monitoring and support. I also investigated the role of valve surgery and chronic pacing. In Fontan patients, I explored long-term complications such as veno-venous collaterals and arrhythmias. Closing these collaterals can improve oxygen levels, while atrial arrhythmias are linked to impaired autonomic function. As the ACHD population grows, effective therapies are crucial. This research provides important insights and a foundation for future studies to improve long-term outcomes and quality of life.LUMC / Geneeskund
Position paper ten behoeve van de Eerste Kamercommissie EZ/KGG (3 juni 2025)
Get PDFThe politics and administration of institutional chang
Impact of black phosphorus nanosheet exposure on growth, reproduction, antioxidant mechanisms, and transcriptomic responses in Daphnia magna
No full textBlack phosphorus nanosheets (BPNS), a novel two-dimensional nanomaterial, have garnered significant attention in biomedical and technological applications due to their exceptional physicochemical properties. However, their widespread use raises concerns about potential environmental risks. In this study, we elucidate the toxicological mechanisms of BPNS on Daphnia magna (D. magna), a model aquatic organism. The results reveal that BPNS is efficiently absorbed and accumulates in the intestinal tract of D. magna. Exposure to low concentrations of BPNS significantly alters developmental and reproductive performance, as evidenced by a 2-day acceleration in the time to first brood and an increase in body length from 3.1 to 3.3 mm. Furthermore, BPNS exposure induces oxidative stress in D. magna, characterized by elevated reactive oxygen species (ROS) levels, enhanced activities of superoxide dismutase (SOD) and catalase (CAT), and increased malondialdehyde (MDA) concentrations. RNA sequencing analysis indicates that dysregulation of iron homeostasis plays a pivotal role in mediating oxidative stress in D. magna. Concurrently, detoxification mechanisms are activated, as evidenced by upregulation of genes associated with chitin and carbohydrate metabolism, as well as cuticle structure components. Additionally, BPNS exposure modulates key signaling pathways, including the lysosomal pathway, starch and sucrose metabolism, and steroid biosynthesis, which collectively enhance the stress tolerance of D. magna. These findings provide critical insights into the ecological implications of BPNS release into aquatic ecosystems, highlighting the need for comprehensive risk assessments of emerging nanomaterials.Environmental Biolog
Interferon signatures fuel B cell hyperactivity and plasmablast expansion in systemic lupus erythematosus
Get PDFSystemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an array of autoantibodies, in particular anti-nuclear antibodies (ANA). The disease is also hallmarked by an expansion of plasmablasts (PB) and hypergammaglobulinemia. The mechanisms underlying this hyperactivity and its relation to autoantibody production is not clear. We aimed to characterize B cell hyperactivity in SLE to identify its underlying mechanisms. Using deep phenotyping with spectral flow cytometry and scRNAseq, we demonstrate that a high frequency of PB relative to memory B cells marks a subgroup of SLE patients, particularly those with higher disease activity and positive for Sm/RNP autoantibodies. We identified the origin of this phenotype in a prominent IFN signature in PB and increased activation in the switched CD27+ memory B cell compartment. PB from this group of SLE patients displayed high levels of CD45RB and somatic hypermutation frequencies similar to memory B cells. Repertoire analysis revealed a highly polyclonal expansion of PB and skewing towards IgG1. B cell hyperactivity correlated with hypergammaglobulinemia, especially increased IgG serum levels. In summary, we show for the first time a direct relationship between IFN and PB expansion in a subgroup of SLE patients. Increased activation and differentiation of class-switched B cells driven by IFN may directly underlie PB expansion and hypergammaglobulinemia. These results provide insight into the pathways leading to B cell hyperactivity and autoantibody production which may guide the tailoring of B cell-and IFN-targeted therapies.Pathophysiology and treatment of rheumatic disease
Separating quantum and classical computing: rigorous proof and practical application
Get PDFThis thesis probes under what conditions quantum computing presents an advantage over classical computing. Its first result is a proof of a stronger set of conditions that separate quantum and classical computing. Other key results focus on quantum machine learning (developing shadow models), circuit cutting (developing machine learning methods to make best use of it, and proving rigorous limitations), and bounded advice classes.Computer Systems, Imagery and Medi
Patients' and health care professionals' perspectives on remote patient monitoring in chronic obstructive pulmonary disease exacerbation management: initiating cocreation
Get PDFBackground: Chronic obstructive pulmonary disease (COPD) exacerbations cause physiological and psychological distress, affecting overall health and quality of life. Early diagnosis of exacerbations is crucial for preserving lung function, preventing hospitalizations, and reducing health care costs. While remote patient monitoring (RPM) offers the potential for early exacerbation detection, challenges remain in recognizing symptoms in a timely manner. A noninvasive breath analysis device is under development to monitor patients with COPD and detect exacerbations before symptoms arise by measuring breath biomarkers through volatile organic compounds. This study encompassed the initial cocreation phase to align the use of the breath analysis device and corresponding care process with current COPD exacerbation management and user needs. Objective: We aimed to explore perspectives on COPD care processes, exacerbation management, and RPM in the Netherlands through 3 objectives: (1) identify stakeholders in COPD exacerbation care, (2) understand existing COPD care, and (3) explore stakeholder experiences and expectations regarding RPM in COPD care. Methods: Following the Center for eHealth Research and Disease Management Roadmap, 4 research activities were conducted between March 2024 and September 2024 for the initial cocreation phase: (1) desk research, (2) interviews, (3) project group meeting, and 4) coanalysis focus group. Desk research involved reviewing literature and COPD (exacerbation) care guidelines. Semistructured interviews (N=34) were conducted with 18 patients, 14 health care professionals (HCPs), 1 caregiver, and 1 hospital policy adviser. Topics included COPD diagnosis, exacerbation management, stakeholder roles in COPD care, and RPM experiences or expectations. The project group meeting between interviews and the focus group verified interim findings and guided the focus group content. In total, 6 patients participated in a coanalysis focus group to review interview quotes on exacerbations and RPM. The framework method was used to analyze the interviews and the focus group through abductive coding. Results: Seven key stakeholders were identified in COPD care, patients, pulmonologists, general practitioners, nurse practitioners, nurse specialists, physiotherapists, and informal caregivers. We observed a lack of uniformity in COPD care, exacerbation management, and information provision across HCPs. Patients reported struggling to recognize exacerbations. Although patients with experience in RPM reported positive experiences, they questioned the added value in early detection of exacerbations. Those without RPM experience were receptive to its use for symptom tracking but were concerned about reduced in-person care and overreliance on data. HCPs reported seeing value in RPM for between-visit monitoring and efficiently allocating resources but stressed the need for clear guidelines and noted barriers, such as language proficiency and technology usability. Conclusions: This study highlights the opportunities to improve COPD care and optimize exacerbation management with RPM. among HCPs and with patients, provide clear exacerbation management guidelines, and ensure inclusivity.Public Health and primary carePrevention, Population and Disease management (PrePoD
Counts, cities and commerce: a comparative study of the institutional foundations of international trade in late medieval Flanders, Holland and Zeeland
Get PDFOver the past few decades, the historiography of international trade in late medieval Europe has been greatly influenced by the New Institutional Economics. Central in this perspective is the claim that economic outcomes were primarily determined by so-called institutions, or the rules of the economic game. The present article contributes to this debate by exploring the explanatory factors that impacted upon the choice of the main commercial markets in the Low Countries between 1384 and 1433. More specifically, it assesses the role of institutional frameworks in the decisions made by three important trading groups, the Hanse, the Genoese and the Portuguese, to base most of their trade either in the county of Flanders or in the competing counties of Holland and Zeeland. The article first compares the commercial privileges in which governments set out many of the rules that shaped the activities of foreign traders in these two areas and then considers the mechanisms that allowed merchants to resolve commercial conflicts. The overall conclusion is that institutions alone cannot explain the choice of markets by foreign merchants in the Low Countries during this period.Europe 1000-1800: Collective Identities and Transnational Network
Genetic analysis of selection bias in a natural experiment: investigating in utero famine effects on elevated body mass index in the Dutch hunger winter families study
Get PDFNatural-experiment designs that compare survivors of in utero famine exposure to unaffected controls suggest that in utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, n = 950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation, and 49% were their unexposed same-sex siblings or "time controls" born before or after the famine in the same hospitals. We computed body mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r = 0.42, P .092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.Molecular Epidemiolog