Research questionAre age at last childbirth and number of children, as facets of female reproductive health, related to individual lifespan or familial longevity?DesignThis observational study... Show moreResearch questionAre age at last childbirth and number of children, as facets of female reproductive health, related to individual lifespan or familial longevity?DesignThis observational study included 10,255 female participants from a multigenerational historical cohort, the LINKing System for historical family reconstruction (LINKS), and 1258 female participants from 651 long-lived families in the Leiden Longevity Study (LLS). Age at last childbirth and number of children, as outcomes of reproductive success, were compared with individual and familial longevity using the LINKS dataset. In addition, the genetic predisposition in the form of a polygenic risk score (PRS) for age at menopause was studied in relation to familial longevity using the LLS dataset.ResultsFor each year increase in the age of the birth of the last child, a woman's lifespan increased by 0.06 years (22 days; P = 0.002). The yearly risk for having a last child was 9% lower in women who survived to the oldest 10% of their birth cohort (hazard ratio 0.91, 95% CI 0.86–0.95). Women who came from long-living families did not have a higher mean age of last childbirth. There was no significant association between familial longevity and genetic predisposition to age at menopause.ConclusionsFemale reproductive health associates with a longer lifespan. Familial longevity does not associate to extended reproductive health. Other factors in somatic maintenance that support a longer lifespan are likely to have an impact on reproductive health. Show less
Willemsen, R.F.; Versluis, A.; Aardoom, J.J.; Petrus, A.H.J.; Silven, A.V.; Chavannes, N.H.; Dijke, A. van 2024
Introduction: Depressive and anxiety disorders are common mental disorders ranking among the leading causes of global disease burden. Not all clients currently benefit from therapy and clients are... Show moreIntroduction: Depressive and anxiety disorders are common mental disorders ranking among the leading causes of global disease burden. Not all clients currently benefit from therapy and clients are looking for modern ways of therapy. Online psychotherapy is a promising option for better meeting clients’ needs. Recently, a new psychotherapy concept has emerged that combines videoconferencing sessions with support through a mobile application. The latter allows for ecological momentary assessments and interventions, facilitates communication between patients and therapists in between sessions through chat, and allows for incorporating feedbackinformed treatment principles. Material and methods: The study was a retrospective observational matched cohort study, comparing online psychotherapy with Therapy As Usual (TAU) for clients with depressive or anxiety disorders. Data were obtained via questionnaires, which are part of standard clinical care. Primary outcomes included general mental functioning, and symptoms of depression and anxiety. Secondary outcomes were efficiency, client satisfaction, and therapy costs. Primary endpoints were analyzed using linear mixed models analysis, with an interaction term between time and group. Secondary outcomes were analyzed using linear regression. Results: Larger improvements were observed in the online compared to the TAU group for general mental functioning and depressive disorder (i.e., General mental functioning: B = -8.50, 95 CI: − 15.01 − − 1.97, p = 0.011; Depressive disorder: B = − 3.66, 95 % CI: − 5.79 – -1.54p < 0.01). No significant differences in change over time between the two groups were observed for anxiety disorder (B = -3.64, 95 % CI: (− 13.10 – 5.82) p = 0.447). The total number of sessions was significantly higher in the online psychotherapy group than in TAU (B = 3.71, p < 0.01), although clients were matched on treatment time in weeks. Treatment session duration in minutes was comparable across the groups. Discussion: Online psychotherapy with app support showed to be a promising alternative to TAU for depressive and anxiety disorders. More research is needed to evaluate the effectiveness, cost-effectiveness and client satisfaction of online psychotherapy compared to TAU, such as randomized controlled trials or studies multiple baseline series designs, and in-depth qualitative research. Show less
BACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nIntranasal administration of respiratory vaccines offers many advantages such as eliciting both systemic and mucosal immunity at the point of viral entry.... Show moreBACKGROUND\nMETHODS\nRESULTS\nCONCLUSIONS\nIntranasal administration of respiratory vaccines offers many advantages such as eliciting both systemic and mucosal immunity at the point of viral entry. Immunogenicity of intranasal vaccination can be improved through the use of adjuvants. Bacteria-like particles derived fromLactococcus lactishave the potential to serve as a vaccine adjuvant.This clinical study investigated the safety, reactogenicity and immunogenicity of intranasal seasonal influenza vaccine adjuvanted with gram-positive matrix particles (FluGEM®).\nThis was a first-in-human, randomized, double-blind, controlled, dose-escalation study performed at the Centre for Human Drug Research (CHDR), the Netherlands. Participants aged 18-49 were randomized in a 3:1 ratio to receive FluGem® in ascending doses (two-dose regimens) together with a standard trivalent inactivated influenza vaccine or unadjuvanted TIV only. Primary outcomes were safety and tolerability. Secondary outcomes were serum hemagglutination inhibition (HI) antibody titers and mucosal IgA. The most immunogenic dose was used in an additionalelderly cohort (>65 years).\nNinty participants were included. Intranasal FluGem®was safe and well tolerated. The majority of adverse events were mild (97.4 %) with (un)solicited adverse events comparable across all dose levels and control groups. All groups showed geometric mean increases ≥ 2.5-fold. Seroconversion (≥40 % participants) was achieved at both day 21 (single-dose) and 42 (two-dose) for the 1.25 mg dose and on day 42 (two-dose only) for the 2.5 mg dose. Highest geometric mean IgA increases were observed in the 1.25 mg group on day 21. Immunogenicity was less pronounced in elderly.\nIntranasal vaccination of FluGEM®was safe and tolerable in healthy adult volunteers aged 18-49 years and 65 and older. Highest immunogenicity was observed for 1.25 mg and 2.5 mg doses (compared to 5 mg) suggesting a potential non-linear dose-response relationship.More research is needed to further investigate the capabilities of bacteria-like peptides as adjuvants. Show less
This thesis explored the molecular pharmacological mechanisms of targeting CB2R via investigation of novel drug discovery concepts such as target binding kinetics, allosteric modulation and biased... Show moreThis thesis explored the molecular pharmacological mechanisms of targeting CB2R via investigation of novel drug discovery concepts such as target binding kinetics, allosteric modulation and biased signaling. Central to the investigation of CB2R pharmacology was developing new assays and providing an overall kinetic view, aimed at bringing fresh insights that could be further integrated into the field of GPCR research. To this end, the development and application of state-of-the-art and novel cellular and biochemical assays contributed to a better understanding of agonist-mediated CB2R activation and signaling, which can advance drug discovery efforts for treatments of diseases that involve CB2R.It’s about time that novel concepts for GPCRs are incorporated into early drug discovery programs, where a kinetic view is applied to provide a better translational perspective. Show less
The studies in this thesis jointly led to an evidence-based, expert-based and experience-based conceptualization of the challenging rehabilitation environment in five clusters. This... Show moreThe studies in this thesis jointly led to an evidence-based, expert-based and experience-based conceptualization of the challenging rehabilitation environment in five clusters. This conceptualization has been incorporated into the CREATE-tool, a team-self assessment tool that can be used to implement and evaluate the challenging rehabilitation environment in geriatric rehabilitation departments.This CREATE-tool is able to identify areas for improvement for the challenging rehabilitation environment at ward level and professionals are satisfied with the use of the tool. Show less
Nanoparticles can be used as delivery systems for both small molecules and macromolecules such as proteins, peptides or oligonucleotides. This thesis focuses on the use of liposomes, nanometric... Show moreNanoparticles can be used as delivery systems for both small molecules and macromolecules such as proteins, peptides or oligonucleotides. This thesis focuses on the use of liposomes, nanometric vesicles formed by a lipid bilayer enclosing an aqueous core. Liposomes are highly versatile delivery systems. Fine tuning their physicochemical properties such as size, shape, rigidity or surface charge allows the control of the liposome's biological effect. Among the different applications for liposomes, antigen delivery is especially interesting. Liposomes can protect antigens from degradation, and they can direct the antigen delivery to specialised cells such as antigen-presenting cells (APCs), key for the induction of immune responses. APCs will present antigens to T cells to generate an immune response. The way in which these cells present the antigen will determine the type of immune response generated, either a pro-inflammatory response necessary to fight viral and bacterial infections or a tolerogenic response useful to temper down inflammation, for example in the context of cardiovascular diseases like atherosclerosis. Therefore, these formulations can be used as vaccines against inflammatory diseases and as prophylactic vaccines against infectious diseases. In this thesis, we examine key aspects of liposome formulations including the elucidation of target antigens to be used in a tolerogenic vaccine against atherosclerosis, the manufacture of these formulations using microfluidics, the use of vitaminD3 as a tolerogenic adjuvant and the role of liposome rigidity in the tolerogenic effect of these nanoparticles. Furthermore, we explore the use of liposomes to induce protective anti-viral immunity against influenza. Show less
Although classical DC (cDC), which are derived from myeloid progenitors,are specialized in antigen processing and (cross)presentation. However, theyalone are sometimes not enough to prime efficient... Show moreAlthough classical DC (cDC), which are derived from myeloid progenitors,are specialized in antigen processing and (cross)presentation. However, theyalone are sometimes not enough to prime efficient CD8+ T-cell responses. Theconcept of DC licensing by CD4+ T-cell “help” for anti-tumor CTL responses wasdiscovered in 1990s. Since then, ample mouse studies have been conducted aimingto discover the mechanism of the “help” signals. In this thesis, I delved intothe molecular mechanisms of CD4+ T-cell “help” as a critical signal that cansuccessfully activate human cDC1 and describe the clinical significance of cDC1licensing in human cancers. I also explored the role of type I interferon(IFN-I) signaling as part of cDC1 licensing machinery, and identified tumor-infiltratingKi67+CXCL13+CD4+ T-cells as IFN-I producers in the context of help delivery tocDC1 in the tumor. With the intention to employ the knowledge of DC biology incancer treatments, I also explored the potential of DC targeting immunotherapies.Lastly, as an integral component of my exploration into DC biology, Iinvestigated how myeloid progenitors respond to both external and internalstress. Show less
The aim of the research described in this thesis was to use structure-based design to optimise multiple properties of aryl sulfoxide monoacylglycerol lipase inhibitors as anti-inflammatory analgesics.
This dissertation is an attempt at interrogating the relationship between world empire and universal ideology in Late Antiquity. It argues that universalism is a recurring, and almost inevitable,... Show moreThis dissertation is an attempt at interrogating the relationship between world empire and universal ideology in Late Antiquity. It argues that universalism is a recurring, and almost inevitable, condition of any aspiration for global domination, a pattern that emerged in early Christianity and still animates political ideologies of today such as liberal democracy and socialism. It also argues that the nature of such global ambitions requires the universal ideology they espouse to be supersessionist, which invariably results in an ideological, and occasionally physical, clash with other systems of thought. Furthermore, it posits that such beliefs most commonly manifest themselves in eschatological and apocalyptic thinking, for the obvious reason that in commenting about the end of the world and the fate of humanity, it is impossible to avoid talking about the other. As its case-studies, it deals with nascent Islam, its emergence as a non-supersessionist movement and its transition to supersessionism as an imperial religion, as well as apocalyptic Judaism and Christianity. Show less
The aim of this thesis is to develop automatic methods for quantifying the severity of SSc disease from CT images through direct and indirect routes. The indirect route involves lung, lobe, and... Show moreThe aim of this thesis is to develop automatic methods for quantifying the severity of SSc disease from CT images through direct and indirect routes. The indirect route involves lung, lobe, and vessel segmentation (Chapter 2) and PFT estimation from segmented vessels (Chapter 5). The direct route focuses on directly estimating PFT (Chapter 4) and scoring ILD from CT (Chapter 3). Chapter 2 introduces a deep-learning network for lobe segmentation using a multi-task semi-supervised model and an alternating training strategy, evaluated on an external CT dataset. A Python package for calculating segmentation metrics is developed (see Chapter 8 Supplementary material). Chapter 3 presents a deep learning framework for automating SSc-ILD scoring, using a cascade of two neural networks to select craniocaudal positions and estimate pattern ratios, with synthetic data augmentation and a heat map method for output explanation. Chapter 4 proposes a deep-learning framework for automatic PFT estimation from CT scans, exploring the influence of segmented lungs and vessels, and introducing regression attention maps (RAM) to highlight contributing regions. Chapter 5 extends Chapter 4's work by enhancing PFT estimation performance with point cloud (PNN-Vessel) and graph neural networks (GNN-Vessel) based on vessel centerlines, and combining different networks for optimal results. Show less
Wat offline niet mag ook online niet. De Nederlandse en Uniewetgever drukken steeds vaker uit dat het normenkader op onlineplatforms gelijk is aan de offlinewereld. Hoewel de Nederlandse wetgever... Show moreWat offline niet mag ook online niet. De Nederlandse en Uniewetgever drukken steeds vaker uit dat het normenkader op onlineplatforms gelijk is aan de offlinewereld. Hoewel de Nederlandse wetgever in het geval van doxing heeft gekozen voor een strafbaarstelling wordt desinformatie binnen de EU enkel online gereguleerd. Ook de digitaledienstenverordening volgt een exceptionalistische benadering waarbij, bijvoorbeeld, tussen onlineplatforms en zeer grote onlineplatforms wordt gedifferentieerd. Deze bijdrage bespreekt deze exceptionalistische benadering en laat zien dat het in het belang van de vrijheid van meningsuiting (zowel online als offline) kan zijn om te differentiëren tussen online en offline normstellingen. Show less
The overarching goal of this thesis is to set the foundations, but also make the first essential steps towards establishing a comprehensive, mesoscopic, hydrodynamic theory of epithelial tissues.... Show moreThe overarching goal of this thesis is to set the foundations, but also make the first essential steps towards establishing a comprehensive, mesoscopic, hydrodynamic theory of epithelial tissues. The stage is set by an exhaustive study of topological defects in passive p-atic liquid crystals, singularities in the orientation field, that allow us to bridge our continuum theory with the discrete epithelial cellular network. After questioning the very existence of active liquid crystals, we confirm they form a new, distinct universality class of orientationally ordered systems, of which tissues are a typical case. We then proceed to identify the precise nature of their orientational order. Although complex and long debated, we show that tissues exhibit only 6-fold (hexatic) and 2-fold (nematic) orientational order, at small and large scales respectively. Before concluding, we establish a predictive, quantitative duality between topological defect dynamics and cell intercalation. Cell intercalation is the origin of collective cell migration, an essential mechanism of epithelial tissues, necessary for functions such as morphogenesis, wound healing, and even cancer progression. Our results are supported by a combination of experiments, analytics, and numerical simulations. The analytic and computational toolkit we utilize comprises concepts, mathematics, and models from hydrodynamics, theory of elasticity, statistical physics, and topology. Finally, we close with some thoughts on the emergence in living systems, revolving around our central theme of epithelial tissues. Show less
Gender separatist utopian literature portrays communities that are populated with only women while men live elsewhere or at times as slaves. This separatism brings about issues of sociopolitical... Show moreGender separatist utopian literature portrays communities that are populated with only women while men live elsewhere or at times as slaves. This separatism brings about issues of sociopolitical and emotional conflict between women and men. This subgenre carries great potential for the interrogation of the supposed biologically inherent differences between women and men, and also among women in the same gender groups. I concentrated on the narrative cycle of hope, destruction, and rebirth present in many literary examples from this subgenre. The cycle starts out with the complete destruction of the current state of affairs in their respective worlds in order to achieve a state of tabula rasa. In this research project, I examined a wide variety of gender separatist feminist utopian texts, spanning from the work of Christine de Pizan from the 1400s -absent in most of the overviews of this genre dominated by men- up until the work of Leigh Richards in 2004 (a pseudonym for Laurie R. King). Keeping the scope of my corpus as wide as I could helped me gain a literary overview of the subgenre, with a clear focus on the last decades of the 20th century. My dissertation engages with questions regarding whether the connection between this narrative cycle and utopian disillusionment can lead to a perceived failure of the utopian ideal, whether feminist utopianism can be located in feminist dystopian narratives of destruction, how this cycle can interact with the common traditions of utopian literature, feminist utopian literature, and feminist theory, and how women's subjectivity in these works of literature relates to the problem of history, how the 'female subject' sees her role in relation to her sociopolitical context, and how the mechanism of hope, destruction and optimism interact in this subgenre. Show less
Antibiotic-resistant bacteria pose a major health threat. Addressing this challenge requires among others the development of new antibacterial compounds. The research described in this thesis... Show moreAntibiotic-resistant bacteria pose a major health threat. Addressing this challenge requires among others the development of new antibacterial compounds. The research described in this thesis focuses on discovering novel antibiotics from soil bacteria, specifically Streptomyces and Paenibacillus.Despite the vast potential encoded within bacterial genomes, only a fraction of the natural products have been explored experimentally. A critical obstacle in antibiotic discovery is the repeated rediscovery of known compounds, a process called replication. This underscores the urgent need for innovative strategies in antibiotic discovery to uncover new chemical entities effectively. To overcome this challenge we developed an efficient analytical platform called nanoRAPIDS, designed for the discovery and dereplication of low-abundance bioactive compounds through at-line nanofractionation, molecular networking, and bioactivity assays. nanoRAPIDS platform was successfully applied to analyze the bioactive crude extracts of Bacillus and Streptomyces and highlighting the individual mass features that contribute to the activity in the crude extract. Advanced spectroscopic techniques such as LC-MS-based metabolomics, molecular networking, and nanofractionation enabled the detection and characterization of antibiotics in complex bacterial extracts. Synthetic chemistry and bioinformatics allowed the discovery, optimization, and refinement of the antibacterial properties of compounds of interest. Key discoveries included tridecaptin Oct-His9 effective against colistin-resistant Pseudomonas aeruginosa, and paenitracin bioactive against vancomycin-resistant Enterococcus faecium. Other novel compounds identified included paenilipoheptins, quinazolinones, actinomycin L, and tridecaptin lipopeptides. The research described in this thesis uses a wide range of computational, biological, and analytical chemical approaches to activate cryptic biosynthetic pathways and find new chemistry, thus contributing to the need for new chemical space as the basis for our future antibiotics. The findings highlight that there still is a lot of potential in soil bacteria as sources of novel antibiotics, to aid us in the continuing combat against multi-resistant bacterial infections. Show less
This thesis first provides a grammar sketch of Teke-Kukuya which is a Bantu language spoken in the Republic of Congo, covering the topics on its segmental phonology and prosodic system, noun... Show moreThis thesis first provides a grammar sketch of Teke-Kukuya which is a Bantu language spoken in the Republic of Congo, covering the topics on its segmental phonology and prosodic system, noun classes and noun phrases, verbal morphology and TAM conjugations, as well as some syntactic issues based on newly collected data. The second part of the thesis investigates the interaction between syntax and information structure in this language. The author discusses word order variation and expressions of information structure with particular interests in a dedicated immediate-before-verb (IBV) focus position in this language. Since the IBV focus construction shares many grammatical properties with clefts, both segmentally and tonally, the author makes the hypothesis that diachronically the IBV focus strategy originates from a basic cleft, and it has been grammaticalised towards a monoclausal focus construction. The thesis also gives a synchronic analysis on the structural representation of the IBV focus construction, discussing the subject agreement asymmetry in subject/non-subject relatives and the associated class 1 subject marking alternation in the IBV focus construction. Show less
