Brain pretargeted nuclear imaging for the diagnosis of various neurodegenerative diseases is a quickly developing field. The tetrazine ligation is currently the most explored approach to achieve... Show moreBrain pretargeted nuclear imaging for the diagnosis of various neurodegenerative diseases is a quickly developing field. The tetrazine ligation is currently the most explored approach to achieve this goal due to its remarkable properties. In this work, we evaluated the performance of F-537-Tetrazine, previously developed by Biogen, and N-(3-[18F]fluoro-5-(1,2,4,5-tetrazin-3-yl)benzyl)propan-1-amine, previously developed in our group, thereby allowing for the direct comparison of these two imaging probes. The evaluation included synthesis, radiolabeling and a comparison of the physicochemical properties of the compounds. Furthermore, their performance was evaluated by in vitro and in vivo pretargeting models. This study indicated that N-(3-[18F] fluoro-5-(1,2,4,5-tetrazin-3-yl)benzyl)propan-1-amine might be more suited for brain pretargeted imaging. Show less
BackgroundThe 2022 consensus statement of the European Atherosclerosis Society (EAS) on lipoprotein(a) (Lp(a)) recognizes the role of Lp(a) as a relevant genetically determined risk factor and... Show moreBackgroundThe 2022 consensus statement of the European Atherosclerosis Society (EAS) on lipoprotein(a) (Lp(a)) recognizes the role of Lp(a) as a relevant genetically determined risk factor and recommends its measurement at least once in an individual's lifetime. It also strongly urges that Lp(a) test results are expressed as apolipoprotein (a) (apo(a)) amount of substance in molar units and no longer in confounded Lp(a) mass units (mg/dL or mg/L). Therefore, IVD manufacturers should transition to molar units. A prerequisite for this transition is the availability of an Lp(a) Reference Measurement Procedure (RMP) that allows unequivocal molecular detection and quantification of apo(a) in Lp(a). To that end an ISO 17511:2020 compliant LC-MS based and IFCC-endorsed RMP has been established that targets proteotypic peptides of apolipoprotein(a) (apo(a)) in Lp(a). The RMP is laborious and requires highly skilled operators. To guide IVD-manufacturers of immunoassay-based Lp(a) test kits in the transition from mass to molar units, a Designated Comparison Method (DCM) has been developed and evaluated.MethodsTo assess whether the DCM provides equivalent results compared to the RMP, the procedural designs were compared and the analytical performance of DCM and RMP were first evaluated in a head-to-head comparison. Subsequently, apo(a) was quantified in 153 human clinical serum samples. Both DCM and RMP were calibrated using external native calibrators that produce results traceable to SRM2B. Measurement uncertainty (MU) was checked against predefined allowable MU.ResultsThe major difference in the design of the DCM for apo(a) is the use of only one enzymatic digestion step. The analytical performance of the DCM and RMP for apo(a) is highly similar. In a direct method comparison, equivalent results were obtained with a median regression slope 0.997 of and a median bias of - 0.2 nmol/L (- 0.2%); the intermediate imprecision of the test results was within total allowable error (TEa) (CVa of 10.2% at 90 nmol/L).ConclusionsThe semi-automated, higher throughput, LC-MS-based method for Lp(a) meets the predefined analytical performance specifications and allowable MU and is hence applicable as a higher order Designated Comparison Method, which is ideally suited to guide IVD manufacturers in the transition from Lp(a) mass to molar units. Show less
Senjor, E.; Pirro, M.; Svajger, U.; Prunk, M.; Sabotic, J.; Jewett, A.; ... ; Kos, J. 2024
Cystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell... Show moreCystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell stage, called split-anergy. We show that N-glycosylation determines the localization and cellular function of cystatin F. Cystatin F mostly exhibited high-mannose glycosylation in U-937 cells, both high-mannose and complex glycosylation in NK-92 and primary NKs, and predominantly complex glycosylation in super-charged NKs. Manipulating N-glycosylation with kifunensine increased high-mannose glycosylation of cystatin F and lysosome localisation, which decreased cathepsin C activity and reduced NK cytotoxicity. Mannose-6-phosphate could significantly reduce the internalization of extracellular cystatin F. By comparing NK cells with different cytotoxic potentials, we found that high-mannose cystatin F was strongly associated with lysosomes and cathepsin C in NK-92 cell line. In contrast, in highly cytotoxic super-charged NKs, cystatin F with complex glycosylation was associated with the secretory pathway and less prone to inhibit cathepsin C. Modulating glycosylation to alter cystatin F localisation could increase the cytotoxicity of NK cells, thereby enhancing their therapeutic potential for treating cancer patients. Show less
Baca, M.; Popović, D.; Agadzhanyan, A.K.; Baca, K.; Conard, N.J.; Fewlass, H.; ... ; Nadachowski, A. 2024
The narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of... Show moreThe narrow-headed vole, collared lemming and common vole were the most abundant small mammal species across the Eurasian Late Pleistocene steppe-tundra environment. Previous ancient DNA studies of the collared lemming and common vole have revealed dynamic population histories shaped by climatic fluctuations. To investigate the extent to which species with similar adaptations share common evolutionary histories, we generated a dataset comprised the mitochondrial genomes of 139 ancient and 6 modern narrow-headed voles from several sites across Europe and northwestern Asia covering approximately the last 100 thousand years (kyr). We inferred Bayesian time-aware phylogenies using 11 radiocarbon-dated samples to calibrate the molecular clock. Divergence of the main mtDNA lineages across the three species occurred during marine isotope stages (MIS) 7 and MIS 5, suggesting a common response of species adapted to open habitat during interglacials. We identified several time-structured mtDNA lineages in European narrow-headed vole, suggesting lineage turnover. The timing of some of these turnovers was synchronous across the three species, allowing us to identify the main drivers of the Late Pleistocene dynamics of steppe- and cold-adapted species. Show less
Background: Measures against COVID-19 in nursing homes affected not only clients but also staff. However, staff perspectives on the importance of these measures remain underexplored. Objective: To... Show moreBackground: Measures against COVID-19 in nursing homes affected not only clients but also staff. However, staff perspectives on the importance of these measures remain underexplored. Objective: To investigate measures related to staff during the COVID-19 pandemic, staff perspectives of important measures and the involvement of staff in deciding on these measures. Design: A qualitative study. Setting(s): We analysed minutes of nursing home outbreak teams in the Netherlands and conducted group meetings with Dutch nursing home staff in different positions, prioritizing measures and discussing staff' involvement in deciding on the measures. Participants were recruited purposefully. Participants: The minutes of 41 nursing home organizations were collected during March-November, 2020. Four group meetings were organized in the same period, each with 5 to 7 participants, resulting in 23 participants. Methods: The meeting minutes were analysed using qualitative content analysis, whereas reflexive thematic analysis was used for the group meeting data. The group meetings were conducted online and structured by the Nominal Group Technique to discuss the importance of measures for staff. Results: Measures implemented for staff focused on prevention of COVID-19 transmission, (suspension of) educational activities, testing, additional tasks and staffing capacity, promoting wellbeing, and other means of support. The implemented measures overlapped with the measures considered important by staff. In addition, staff considered measures on decision-making support and communication to be important. Staff prioritized the measures in the group meetings because they affected their well-being, workforce scheduling, decision-making, or infection prevention. Furthermore, the group meetings revealed that decision-making shifted from mainly implementing national measures to more context-adjusted decision-making in the staff's or clients' situations. Conclusions: We showed that although nursing home staff were not always involved in decisionmaking during the first COVID-19 wave, there was overlap between the measures implemented by the organizations and measures considered important by staff. We suggest that organizations 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
Inaugural Lecture by Prof.dr. Florian A. Schneider on the acceptance of his position as professor Modern China at Leiden University on Monday 6 May 2024
Oratie uitgesproken door Prof.dr. Nadine N.W. Akkerman bij de aanvaarding van het ambt van hoogleraar Vroegmoderne Literatuur en Cultuur aan de Universiteit Leiden op vrijdag 3 mei 2024
Inaugural Lecture by Prof.dr. Nadine N.W. Akkerman on the acceptance of her position as professor of Early Modern Literature & Culture at Leiden University on Friday 3 May 2024
Security is something that people tend to care about. But is it also something that they should care about? To explore this question, this dissertation first develops a new conceptual framework of... Show moreSecurity is something that people tend to care about. But is it also something that they should care about? To explore this question, this dissertation first develops a new conceptual framework of security. Next, it analyses how security relates to some key values for liberal democratic societies. The first of these is well-being. It is argued that there are important ways in which security can contribute to somebody’s well-being – but there are also ways in which security may hamper a person’s flourishing. The second value is freedom. It is shown that in public decision-making freedom and security may come at each other’s cost – yet there are also ways in which the two can work to each other’s benefit. The third value is equality. It is demonstrated that in order for a society to meet the demands of equality it must provide its members with a particular set of securities – while at the same time the pursuit of equality puts another set of securities out of reach. Ultimately, this dissertation finds no reason for considering security to be good for its own sake, but it argues that security can be good for the sake of well-being, freedom, and equality. Show less
Human vocal communication and music perception represent advanced cognitive skills, seemingly innate and universal. These faculties encompass a range of perceptual and cognitive abilities. Cross... Show moreHuman vocal communication and music perception represent advanced cognitive skills, seemingly innate and universal. These faculties encompass a range of perceptual and cognitive abilities. Cross-species research sheds light on the origins of musicality by investigating whether these traits are shared by nonhuman species. Songbirds, notably zebra finches, serve as valuable models due to their complex vocalizations and similarities to humans in auditory perception. My thesis explored zebra finches' sensitivity to spectral and temporal sound features. Chapter 2 examines the influence of song duration and spectral characteristics on song discrimination, while Chapter 3 tests song preferences. Chapter 4 investigates sequential and spectral feature recognition. Chapter 5 focuses on melody recognition. Zebra finches demonstrate perceptual flexibility, adapting focus based on stimulus characteristics. These findings underscore the importance of training conditions and stimulus nature in shaping auditory perception. Overall, my thesis enhances understanding of auditory cognition and cognitive flexibility among songbirds. Show less
