International Migration, Integration and Social Cohesion online publications
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Non-coding RNAs in dilated cardiomyopathy
No full textDilated cardiomyopathy (DCM) is characterized by left ventricular dilation and impaired systolic function. Progression of the disease leads to heart failure, a state in which the heart is unable to pump sufficient blood to meet the body's metabolic demands. While DCM is often familial and linked to genetic mutations, causative variants are identified in only 30–40% of cases, primarily in protein-coding genes. Given that only 2% of the human genome encodes protein, it is likely that mutations in non-coding regions explain some of the unresolved cases.This thesis investigates the contribution of two classes of non-coding RNAs to DCM pathogenesis. In the first part we focus on microRNAs (miRNAs), ~22 nucleotide long RNAs molecules that regulate gene expression by inhibiting messenger RNA translation. We screened DCM patients for variants in miRNAs implicated in cardiac contractility and identified two variants that alter the precursor miRNA secondary structure. This resulted in reduced miRNA expression and function, potentially contributing to the DCM phenotype in these individuals.The second part explores circular RNAs (circRNAs), covalently closed RNA loops generated by back-splicing. We identified thousands of circRNAs in the human heart, several of which are dysregulated in DCM. Titin, which encodes the largest human transcript, generates the most circRNAs. We show that these TTN-derived circRNAs regulate expression and splicing of key cardiac genes, and that loss of the most abundant TTN-derived circRNA disrupts sarcomere organization and reduces contractility in vitro. Finally, we report a circRNA derived from a well-known cardiac gene as a novel biomarker for heart failure.</p
At the confluence of the senses:Cortical processing of multisensory stimuli and context
Get PDFWe sample the world through multiple senses – vision, touch, audition and more – each entering the brain through physically separate pathways, yet merging into a unified experience. This thesis aims to investigate how the brain integrates multiple senses and how multisensory context shapes sensory processing. In Chapter 2, we show that mice can linearly combine visual and auditory cues. Chapter 3 examines the mouse posterior parietal cortex as a site for integration visual and tactile evidence and, although no multisensory-specific neuronal activity was found, we identified detection-related signals and demonstrated this region’s causal role in visuotactile decision-making, independent of sensory modality. In Chapter 4, we report that adding an additional relevant sensory modality extended the period during which the primary visual cortex contributed to visual perception, revealing that multisensory context modulates cortical activity and dynamics. Finally, Chapter 5 focuses on neuron-level mechanisms: layer 5 pyramidal tract neurons in the rat somatosensory cortex encode touch through bursting activity, unlike other cell types, highlighting their unique role in tactile encoding. Together, these findings advance our understanding of the neural principles that support multisensory processing, from behavior to circuits to single-cell function
Knowing better is doing better?:A comprehensive evaluation of sports-based intervention to prevent juvenile delinquency
No full textSportgerichte interventies worden steeds vaker naar voren geschoven als een geschikte strengths-based benadering, maar de effecten van deze interventies blijken vaak bescheiden (e.g., Jugl et al., 2023). Mogelijke verklaringen zijn dat (a) interventies in de praktijk niet altijd worden uitgevoerd zoals bedoeld, (b) coaches moeite kunnen hebben om hun pedagogische taken goed te vervullen, en (c) de doelgroep sterk uiteenloopt in achtergrond en behoeften. Om meer inzichten te verkrijgen in deze verklaringen is in het huidige proefschrift een onderzoek uitgevoerd naar één specifieke gedragsinterventie: ‘Alleen Jij Bepaalt wie je bent’ (AJB; Hartog et al., 2017). In dit proefschrift onderzochten we: (1) de implementatiegetrouwheid van AJB, (2) de mate waarin de sportcoaches een therapeutische alliantie met de jongeren wisten op te bouwen en (3) de effecten van AJB op delinquent gedrag en op risico- en beschermende factoren voor jeugddelinquentie, met bijzondere aandacht voor de heterogeniteit binnen de doelgroep. Het onderzoek combineerde verschillende soorten meetmethoden én verzamelde informatie bij meerdere betrokkenen.Onze bevindingen benadrukken de meerwaarde van het combineren van kwantitatieve en kwalitatieve methoden, vooral bij het evalueren van complexe psychosociale interventies binnen een sterk heterogene doelgroep. De uitgebreide evaluatie van AJB vergrootte ons inzicht in hoe de interventie in de praktijk werd geïmplementeerd, welke bevorderende en belemmerende factoren hierbij een rol speelden, en voor welke jongeren AJB beter lijkt te werken dan voor anderen. Daarnaast bood het onderzoek concrete handvatten voor het verbeteren van de effectiviteit van AJB. Zo slaagden coaches er goed in een veilige en ondersteunende omgeving te creëren, maar werden er ook moeilijkheden gezien in het consequent toepassen van gepersonaliseerde, doelgerichte strategieën die essentieel zijn voor gedragsverandering.<br/
The Dutch pancreatic cancer project:Towards improving nationwide outcomes and international standardization
Get PDFDit proefschrift is bestaat uit drie onderdelen, in deel 1 worden innovaties binnen de academische chirurgie uitgelicht. Een systematisch review laat zien dat alternatieve trial designs steeds meer worden gebruikt, en obstakels binnen chirurgisch onderzoek kunnen voorkomen. Tevens laat een Delphi studie zien dat door de evoluerende rol en verantwoordelijkheden van jonge academische chirurgen, ondersteuning, mentorschap en begeleiding bij carrièreplanning noodzakelijk is. Deel 2 richt zich op het verbeteren van landelijke uitkomsten voor patiënten met alvleesklierkanker door te focussen op implementatie, standaardisatie, overleving en kwaliteit van leven. Dit deel omvat onder andere de landelijke PACAP-1 trial, waarin vijf “best practices” in de zorg voor patiënten met alvleesklierkanker zijn geïmplementeerd, middels een stepped-wedge cluster gerandomiseerd design. Implementatie van de “best practices” zorgde niet in een verbetering van 1-jaarsoverleving (24% versus 23%). De slechte overleving, samen met de bevinding dat de meerderheid van de patiënten (61%) geen tumor gerichte behandeling kregen, benadrukt de noodzaak voor meer gepersonaliseerde behandelingsopties. Daarnaast bevestigd de LIDOPAN trial dat pijn een belangrijk probleem is voor patiënten met pancreascarcinoom en chronische pancreatitis, en dat het gebruik van intraveneus lidocaïne dit maar deels kan verhelpen. Deel 3 evalueert de registratie en harmonisatie van internationale resultaten na alvleesklierchirurgie. Onder andere door studies opgezet door de Global Audits on Pancreatic Surgery Group (GAPASURG: chirurgische registraties van Noord Amerika, Duitsland, Nederland en Zweden). Ten slotte, focust deel vier op het optimale tijdstip van starten van systemische therapie bij patiënten met asymptomatisch gemetastaseerde kanker. Binnen de TIMEPAN trial, kunnen patiënten met asymptomatisch gemetastaseerd pancreascarcinoom kiezen tussen direct starten van chemotherapie, of wachten met chemotherapie totdat klachten ontstaan. Tevens zijn een systematisch review en survey zijn verricht om kennis te verkrijgen over de huidige beschikbare literatuur, en de mening van experts, over dit onderwerp. Concluderend, wordt op meerdere manieren gekeken hoe landelijk en internationaal uitkomsten voor patiënten met alvleesklierkanker kunnen worden verbeterd
Traumatic foundations and intersecting paths:Change mechanisms and treatment of childhood trauma, childhood-related posttraumatic stress disorder, and borderline personality disorder
Get PDFWe studied several interconnected concepts: childhood trauma (CT), posttraumatic stress disorder (PTSD), and borderline personality disorder (BPD). When we examined the link between five individual CT subtypes (i.e., sexual, physical, and emotional abuse, and physical and emotional neglect) and PTSD severity, only higher exposure to childhood emotional abuse was related to a higher PTSD severity. Additionally, we studied two PTSD treatments: eye-movement desensitization and reprocessing (EMDR) and imagery rescripting (ImRs). We examined the role of non-fear emotions (i.e., shame, guilt, anger, and disgust) in PTSD changes during treatment and found several differences between changes in these emotions and changes in PTSD symptoms in the short and the long term. We also directly compared the change mechanisms of EMDR and ImRs. The findings indicated that ImRs works via changes in the distress and encapsulated belief ratings related to the trauma memories. In contrast, our findings did not support the hypothesis that EMDR works via changes in memory vividness. Moreover, we studied whether CT and dissociation were moderators of the effectiveness of different formats of schema therapy (ST) for BPD. We found that dissociation was associated with higher treatment retention for a combined individual and group ST format, compared to group ST and treatment-as-usual. Lastly, we examined the effectiveness of psychological treatments for BPD in a multilevel meta-analysis. We analyzed within-treatment effects, and we included a wide range of study designs. The findings indicated that several specialized treatments are related to higher effect sizes compared to the average of all treatments
An untold tale of tolerance:Conditioning dendritic cells to restore immune balance using tolerogenic nanocarriers
Get PDFChronic inflammatory disorders, including various autoimmune diseases and allergies, put a significant burden on our societies. As these conditions stem from a breach in immune tolerance, immune modulation could provide novel avenues for disease prevention or cure. Dendritic cells (DCs) are specialized immune cells that can effectively induce the development of regulatory T cells (Tregs), critical adaptive immune cells for dampening inflammation. Both active metabolites of vitamin D3 (VD3) and retinoic acid (RA) can induce tolerogenic DCs, subsequently fostering a Treg response in vitro. Nanocarriers, such as liposomes or plant-based bioparticles, can be used to combine VD3 or RA with autoantigens or allergens and target these factors simultaneously to DCs in tissue to achieve disease-specific tolerance in vivo. In this thesis, we embarked upon developing a nanocarrier-based vaccine product for future in vivo modulation of DCs. We established negatively charged liposomes as most suitable for administering adjuvants to DCs. We found that various subsets of DCs treated with VD3 or RA, in soluble or liposome-loaded form, induced the development of CD4+ but also CD8+ Tregs in vitro. Furthermore, we established an activating yet hypo-allergenic effect of peanut allergen-loaded bioparticles on DCs. Finally, we present a randomized controlled phase I clinical trial examining the peripheral immune effect of subcutaneous VD3 administration in birch pollen allergic patients. Thus, this thesis encompasses the first steps toward a putative DC-targeted vaccine treating chronic inflammation
Anorectal malformations:A complex disease in need of a multidisciplinary approach
Get PDFIn children born with an anorectal malformation (ARM), the anus is wrongly placed outside the external sphincter complex. Different types of ARM exist, and in patients with ARM different associated anomalies can occur. Additional anomalies are described, among others, as part of the VACTERL-association (Vertebral, Anorectal, Cardiac, Trachea-Esophageal, Renal and Limb anomalies), but also anomalies of the spinal cord or gynecological anomalies are described. In the first part of this thesis, the types of ARM are introduced and it is described what additional anomalies might be associated with any type of ARM. In addition, the value of screening for the different types of anomalies is demonstrated throughout this part. The studies performed in Chapter 1-5 were retrospective cohort studies. In the second part, a complex type of ARM; rectal atresia (RA) is discussed in Chapter 6-8. Finally, Chapter 9-10 form the third part of this thesis describing problems later in life in patients with ARM in primary school or after transitioning to adulthood
Per una storia della pala d'altare dipinta nel Regno di Napoli (1443-1530)
Get PDFLa presente tesi offre una disamina dedicata alla pala d’altare nel Regno di Napoli tra il 1443 e il 1530, volta a integrare una considerevole lacuna nell’ambito degli studi sulla pala d’altare italiana. Affrontando la materia con un taglio tipologico, l’indagine ha come obiettivo quello di tracciare un percorso evolutivo dei diversi tipi di pale elaborati e diffusi nelle province regnicole, rilevandone le specificità formali, gli elementi tecnico-strutturali relativi alla conformazione e all’assemblaggio, la genesi e l’arco cronologico di produzione, senza tralasciare gli aspetti figurativi e stilistici.Il connubio tra influssi diversi dovuti alla centralità mediterranea in cui il Regno di Napoli si colloca sia geograficamente sia storicamente, quali quelli veneto-adriatici, tirrenici, centro-italiani iberici, fiamminghi, ha determinato la fabbricazione di pale d’altare connotate da peculiarità tipologiche spesso anomale rispetto ad altri contesti della penisola italica, nonché da processi evolutivi precipui. Tale ecletticità della pala regnicola si concretizza nell’intramontabilità del polittico che resiste anche all’avvento della pala a campo unificato e per il quale si registra un continuo rinnovamento nelle forme con un’inesauribile combinazione di sistemi di assemblaggio, carpenterie, ornati e moduli architettonici, all’insegna, talora, di fenomeni di ibridazione tra soluzioni tardogotiche e rinascimentali e tra elementi propri di tradizioni culturali diverse.Il lavoro è articolato in due volumi. Il primo raccoglie un primo capitolo introduttivo e metodologico; un secondo capitolo dedicato allo studio dei contratti delle pale d’altare, con il quale è possibile proiettarsi nella fase del concepimento dell’opera antecedente alla sua confezione materiale; un terzo capitolo consacrato all’individuazione e alla disamina delle tipologie con cui la pala regnicola si è espressa nell’arco cronologico considerato; e, infine, un’appendice documentaria. Il secondo volume, a controcanto del primo, consta di un catalogo di schede relative alle pale d’altare considerate nel precedente volume, debitamente repertoriate e commentate da note tecniche e storico-artistiche
Healing the civic body:Forensic investigation and biopolitical strategies in Flemish towns, 1250-1500
Get PDFPeace procedures, called Zoendingen in Dutch sources or Apaisement in French ones, were procedures of reconciliation, used in the County of Flanders from the thirteenth century onwards. At the urban level, they operated as a law court aimed to mediate conflicts between citizens. Many type of altercations could lead to violence, although actors generally fought to protect their honour and status, and that of their kinship group. Peace procedures represented an honorable alternative to violence, which promoted community well-being and social cohesion, by awarding honorable and financial compensations to citizens. The first chapter describes the legal structure of Ghent and Douai, on which this dissertation is focused, to highlight the interests that led urban governments to deploy such legal infrastructures. The next chapter explores the notion of citizenship, to identify how individuals and groups were perceived by urban authorities. Chapter three investigates how the mechanisms of the court could effectively compensate the loss of honor, and how this notion was linked to health at several levels. The following chapter establishes the court’s reliance on the expertise of medical professionals, which in turn increased medical professional’s prestige. It then shows how Flemish governments integrated notions of labor and communal well-being into their perception of the body, using the knowledge produced medical professionals in court to manage the city’s life forces and promote what they defined as the common good. The final chapter demonstrates that Flemish municipal government partook in biopolitical negotiations, seeking to control, police and monopolize the city’s medical market, and by doing so, were led to rethink political power distribution in their cities
Word learning:When associative learning meets social-pragmatic expectations
Get PDFHow we learn words has been a long-standing debate in psycholinguistics. Social-pragmatic approaches argue that word learning is underpinned by learners’ social-cognitive abilities, which allow them to determine the communicative intentions of their interlocutors. Associative learning approaches, on the other hand, suggest that word learning is possible thanks to the human ability to track the frequency of co-occurrences between a word and its referent. An intermediate approach is the communicative/intentional framework, which posits that the relationship between a word and its referent is mediated by the speaker's intention to refer to a particular (set of) object(s). The studies presented in this dissertation take this assumption as their theoretical backdrop and pose two general research questions: 1) to what extent do social-pragmatic cues affect cross-situational word learning?; and 2) when in time do social-pragmatic effects emerge when learning words across situations? We designed five experiments that tested the effects of speaker reliability and speaker informativeness on cross-situational word learning. The results neither support nor contradict the hypothesis that exposure to an unreliable speaker results in learning fewer words and/or relying on associative learning mechanisms. Furthermore, the evidence that participants were sensitive to speaker reliability was inconsistent. However, when the effect of speaker informativeness on word learning was measured over time (by means of an eye-tracker), the results showed that speaker informativeness influenced the initial selection of objects as potential referents. This finding highlights the importance of fine-grained measures when studying how we learn words