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Oncogene aandrijvers van serine- en glycinesynthese in kanker en therapeutische toepassingen
No full textCancer cells rewire their energy metabolism during tumorigenesis. My host lab recently showed that the majority of T-cell acute lymphoblastic leukemia (T-ALL) samples overexpress serine/glycine synthesis enzymes and that these leukemic cells depend on this pathway for cancer progression. Whereas non-malignant cells typically take up serine and glycine from their environment and will not synthesize it themselves, some cancer cells activate this endogenous serine/glycine synthesis pathway to feed their high requirements of generating ATP, purines, lipids, reductive equivalents to control redox homeostasis and α- ketoglutarate to regulate DNA demethylation. From this perspective, it is essential to discover genetic drivers of the serine/glycine pathway allowing us to stratify patients for adjuvant therapeutic targeting of the serine/glycine pathway. The ribosomal RPL10 R98S mutation induces serine/glycine synthesis addiction in T-ALL, but other mechanisms remain unknown. We aimed at delineating additional genetic defects underlying serine/glycine synthesis addiction in leukemia and solid cancers.
RNA-Seq analysis revealed that T-ALL, lung adenocarcinoma (LUAD) and neuroendocrine prostate cancer patients with overexpression of transcription factor NKX2-1 show significantly increased expression of serine/glycine synthesis enzymes. We confirmed binding of NKX2-1 to the promoter and enhancer regions of serine synthesis enzyme genes in lung cancer and T-ALL and showed that NKX2-1 overexpression increases mRNA and protein expression levels of serine/glycine synthesis enzymes up to 3-fold in cancer cell lines. Furthermore, NKX2-1 overexpression enabled cancer cells to proliferate upon limited serine/glycine availability and this was abrogated by knocking down PSPH. Metabolic profiling revealed that NKX2-1 driven serine/glycine synthesis was used to generate ATP, glutathione and nucleotides. Accordingly, NKX2-1 lung tumor-bearing mice showed elevated glutathione serum levels. Moreover, we could show that NKX2-1 expressing cells have an altered lipidome and methylome. Lastly, similar to known serine/glycine dependent cancer models, NKX2-1 cancer cells are sensitive to the repurposed serine/glycine synthesis targeting drug sertraline and topoisomerase inhibitor etoposide. Conformingly, while NKX2-1 positive LUAD is associated with early disease progression, etoposide treated patients with high NKX2-1 expression present improved outcomes. We identify NKX2-1 as a novel oncogenic transcription factor driving overexpression of serine/glycine synthesis enzymes in cancer. Our data support that NKX2-1 positive cancers depend on serine/glycine synthesis for their proliferation and survival. Hence, this pathway represents a novel therapeutic vulnerability in NKX2-1 positive cancers.
Following these findings and given the observation that the serine/glycine synthesis pathway can act as a drug resistance mechanism in multiple cancer subtypes, we tested the potential of the antidepressant sertraline in combination therapy in vitro in T-ALL cell lines. We found that sertraline acts synergistically with proteasome and histone deacetylase inhibitors in vitro in cancer cell lines, but additional in vivo experiments in animal models are required to validate these findings.status: Publishe
Op weg naar heterogeen Multi-core Systems-on-Chip voor Edge Machine Learning
No full textIn this research, the focus is on the the design of energy-efficient and flexible hardware architectures and hardware-software co-optimization strategies to enable early design space exploration of hardware architectures for (extreme)-edge-computing. The research first looks into the design of the highly specialized single hardware accelerator optimized for the application of object detection in drones. As the application and model to be accelerated are fixed, the hardware is optimized for mapping only convolutional and dense layers of a DL model in an object detection pipeline. Emerging DL applications deployed on the (extreme) edge devices, however, require multi-modal support, which demands, on the one hand, the need for much more flexible hardware accelerators and, on the other hand, complete standalone systems with the always-on and duty-cycled operation. Heterogeneity in hardware acceleration can enhance a system's flexibility and energy efficiency by utilizing various energy-efficient hardware accelerators supporting multiple DL workloads on a single platform. With this motivation, the research presents a versatile all-digital heterogeneous multi-core system-on-chip with a highly flexible ML accelerator, a RISC-V core, non-volatile memory, and a power management unit. A highly energy-efficient heterogeneous multi-core system-on-chip is presented next by combining a digital and analog in-memory computing core controlled by a single RISC-V core. Increasing the core count further can benefit the performance of a system. However, data communication in multi-core platforms can quickly become a bottleneck if the design is not optimized. Classical network-on-chips (NoCs) have been extensively used in multi-core CPUs to address the data communication bottleneck. However, these NoCs use serial packet-based protocols suffering from significant protocol translation overheads toward the endpoints. In this research's final part, an open-source, fully AXI-compliant NoC fabric is proposed to address better the specific needs of multi-core DL computing platforms requiring significant burst-based communication. The NoC enables scaling DNN platforms to multi-accelerator systems, thus, allowing the journey toward high-performance heterogeneous multi-core systems.status: Publishe
Het begrijpen van bimanuele motorische controle bij kinderen met unilaterale cerebrale parese vanuit een gedrags- en neurologisch perspectief
No full textIn daily life, we perform a lot of activities without consciously thinking about it, like buttoning a shirt or using cutlery. During childhood, these activities are still challenging, but due to practice and experience typically developing children (TDC) learn how to use both hands in a controlled manner. These activities all require bimanual motor control, a complex interplay of neurological processes and motor output mechanisms, which results in the ability to perform fast and accurate movements (bimanual dexterity) as well as synchronizing the spatial and temporal components of both hands in order to achieve the same goal (bimanual coordination). Nevertheless, this process can be hampered in case of a brain lesion occurring in developmental stages of the brain which is the case in children with unilateral cerebral palsy (uCP).
Children with uCP exhibit sensorimotor impairments on one side of the body, primarily in the upper limb which significantly affects their daily activities. Up till now, research mainly focuses on the functional hand use which investigates the efficacy of the non-dominant hand, or more-impaired hand, during bimanual tasks. Although these clinical assessments provide valuable information, they do not assess the precise control between both hands during a bimanual task. In contrast, objective, innovative methods like 3D motion analysis and robotics, have been brought forward as possible assessment methods to quantify bimanual motor control. However, research using this state-of-the-art technology in children with uCP is still very limited. Consequently, also the understanding of the underlying neural mechanisms of bimanual motor control is still very much unexplored. Bimanual motor control depends on two white matter pathways: the corpus callosum (CC), connecting the brain hemispheres, and the corticospinal tract (CST), linking the cortex to the spinal cord. However, the structural properties of these neural pathways can be diminished in children with uCP, potentially impacting their bimanual motor control. Therefore, the main scope of this doctoral manuscript is to enhance our understanding of bimanual motor control in children with uCP and identify its neural correlates, with the use of state-of-the-art technology. These new insights, can ultimately contribute to optimizing the treatment of bimanual motor control in children with uCP, aiming to enhance their independence during daily life activities.status: Publishe
Gelijkheid voorbij rechten. Naar een theorie van rechtvaardigheid voor tijdelijke arbeidsmigratie
No full textThis research tackles rights differentiation as a way to attenuate the pressure put by large scale labor migration on the welfare state and the prospects of native workers. It examines and evaluates mid-way possibilities between closed borders and renouncing the welfare state, by drawing on and balancing new normative demands of our contemporary reality: a) novel interests of temporary migrants and b) a fair distribution of burdens among host populations and those left behind in source countries; and c) the viability of the welfare state, which requires rethinking welfare rights as a complex bundle that needs to be disaggregated based on the nature and underlying normative rationale of each entitlement. The research aims at developing plausible normative criteria that delineate morally relevant differences between different kinds of immigrants and provide guidance for developing corresponding rights packages that adequately protect their relevant interests.status: Publishe
Mood enhancement technologie: juridische en ethische uitdagingen
No full textThis interdisciplinary doctoral research starts with an analysis of different proposals for defining human enhancement technologies in order to provide a stipulative definition. Two main challenges associated with the proposed definition are also discussed - a reference to the term normality and the distinction between therapy and enhancement. After analysing the feasibility of using the proposed definition for lawmaking and policymaking purposes, the research continues onto an analysis of the often-occurring arguments in the ethics debate concerning human enhancement technologies. Some of them have strong religious and ideological underpinnings, and some occasionally come with problems of rhetorical types. Nevertheless, these arguments are normatively analysed in order to identify where eventual societal discontent with human enhancement technologies might be. Moreover, the same research approach is taken for other arguments and principles of ethics often referred to in the enhancement debate, such as autonomy, human dignity, justice, identity, privacy, safety and prevention of harm. All of these arguments are examined through the lens of the wide reflective equilibrium method. Based on this, normative insights about how these arguments can be used to support the interpretation of the current regulatory framework for human mood enhancement technologies are provided. This doctoral thesis then focuses on the examination of a current regulatory framework for human mood enhancement technologies. In particular, a comprehensive analysis of the applicable norms from the selected United Nations (UN), Council of Europe (CoE) and European Union (EU) human rights instruments is provided. Such legal analysis allows understanding of the relationship between various human rights principles, rules and concepts triggered by this type of technology in order to sort out legal uncertainties and gaps stemming from the same legal instruments. Their connections, overlaps, and potentially mutually supportive roles with the arguments presented within the ethics chapter are outlined and discussed throughout the text of this doctoral thesis. The concluding chapter establishes a set of normative recommendations on how UN, CoE, and EU policymakers and lawmakers should tackle the legal uncertainties and ethical issues of human mood enhancement technologies.status: Publishe
De impact van interspecific interacties op de evolutie van antimicrobiële resistentie in bacteriële gemeenschappen
No full textIt is widely accepted that the discovery of antimicrobial compounds represents one of the most important findings of the previous century, however, the overuse of antimicrobials has contributed to accelerated resistance development, leading to the evolution of multi-resistant "superbugs".
Bacteria are social organisms that commonly live in dense communities surrounded by a multitude of other species. The social interactions (i.e., the average fitness effect of one cell on another) between these species not only shape the bacterial communities but also influence their susceptibility to antimicrobials. While several studies have shown that mixed-species communities are more tolerant toward antimicrobials than their monospecies counterparts, only limited empirical data are currently available on how interspecies interactions influence resistance development. Therefore, the primary aim of this PhD thesis is to further explore and deepen the knowledge of how interspecies social interactions between microorganisms in microbial communities influence the emergence and spread of antimicrobial resistance (AMR).
In the first part, we propose a theoretic framework outlining the potential impact of interspecies social behavior on different aspects of resistance development. We identify factors by which interspecies interactions might influence resistance evolution and conclude that considering the social life of bacteria is imperative to the rational design of more effective antibiotic treatment strategies with a minimal hazard for resistance development.
We proceed by presenting the initial case study of how the social interactions in a duo-species biofilm composed of the brewery isolates Pseudomonas rhodesiae and Raoultella terrigena influence the adaptation to the broad-spectrum antimicrobial sulfathiazole. We show that resistance evolution of brewery isolates can differ greatly between mono- and mixed-species conditions. Due to the limitations of the use of poorly characterized natural brewery isolates, we subsequently focus our research on significantly better-described organisms for which many more molecular biology tools and techniques are available.
We select Salmonella Typhimurium, as it is an important food-borne pathogen and excellent model organism, and in the next step, evaluate its physiological response to a competitive environment, focusing particularly on the implications for the emergence of antimicrobial resistance. We show that the potential of Salmonella to develop antimicrobial resistance de novo, can vary greatly in the presence of different intestinal bacterial species. Specifically, we observe a strong increase in the mutation rate of Salmonella when cultivated in the presence of Enterobacter cloacae subsp. cloacae, a common inhabitant of the human gastrointestinal system. We are yet unable to fully characterize the underlying mechanism, though the higher oxidative stress due to the presence of E. cloacae subsp. cloacae and activation of certain stress response mechanisms in S. Typhimurium seem to be implicated. In addition, we identify a compound and a plant extract that are able to attenuate the increased mutation rate of Salmonella in the presence of E. cloacae subsp. cloacae.
In the final part of the research work, we demonstrate the use of mathematical modelling and specialized software to follow the evolution and spread of resistance in a microbial community in silico. Specifically, we evaluate several different simulations of population dynamics in microbial communities by varying a diverse range of parameters that correspond to various environmental conditions, and show that the developed software provides us with a way to study and follow the emergence and spread of antimicrobial resistance in a more feasible and reproducible way.
Overall, the observations made throughout this research illustrate that the interactions between bacteria can profoundly impact the development of AMR, however, further studies will be needed to fully unravel and experimentally validate the proposed mechanisms implicated in our case studies and probe into the yet unexplored ones outlined in the theoretical treatise.status: Publishe
Kunstmatig zicht voor blinden: ontwikkeling van een intracorticale visuele prothese met hoge resolutie
No full textBlindness affects over 43 million people worldwide, severely impacting their daily life. Current solutions remain limited, with medical treatments often unavailable. While retinal implants have restored partial vision in some cases, their effectiveness is restricted to individuals with residual retinal function. For those with complete vision loss due to optic nerve or retinal degeneration, direct electrical stimulation of the visual cortex offers an alternative. However, existing cortical implants suffer from a low resolution due to limited brain coverage, a small number of stimulation sites and inadequate electrode technology.
To address these limitations, we developed high-density, flexible intracortical electrode arrays using ultra-thin, biocompatible polyimide with biodegradable coatings to enable safe insertion into both superficial and deeper regions of the primary visual cortex. These arrays, featuring low-impedance iridium oxide microelectrodes, allowed for stable, long-term and safe stimulation and recording over a large area. The system demonstrated excellent performance during chronic implantation in non-human primates, with high levels of neural activity recorded even after a year. The integration with custom-designed electronics for electrical stimulation and wireless transcutaneous power transfer marked two important steps towards a fully implantable visual prosthesis.
Finally, to further improve resolution, advanced stimulation strategies such as intracortical bipolar current steering were employed. This technique selectively activated distinct neural populations based on current direction, reducing overlap and increasing the number of independently addressable sites by up to ninefold. These innovations represent a major advancement toward scalable, high-resolution visual prostheses capable of restoring meaningful vision.status: Publishe
Naar een queer penologie? Onderzoek naar de ervaringen, noden en het mensenrechtenkader van lesbische, homoseksuele, biseksuele, transgender en intersekse personen in Belgische gevangenissen
No full textOver recent decades, heightened societal and scholarly awareness of sexual and gender diversity has led to the emergence of queer criminology as a distinct research field. This body of work has significantly expanded our understanding of the experiences of LGBTQ+ individuals within criminal justice systems, with a particular focus on their heightened vulnerability, discrimination, and violence in prison contexts. However, this scholarship remains geographically concentrated, primarily reflecting empirical studies from the United States, the United Kingdom, and Australia. As a result, its applicability to other national settings, including Belgium, remains underexplored. Within the Belgian context specifically, academic attention to the lived experiences of incarcerated LGBTQ+ people has been notably sparse.
This gap in empirical knowledge is particularly stark in light of evolving international human rights instruments, such as the Yogyakarta Principles and the Council of Europe's CPT standards, which articulate protections for LGBTQ+ persons deprived of liberty. While largely non-binding, these instruments are gaining traction in jurisprudence, notably within the European Court of Human Rights.
The framing of incarcerated LGBTQ+ individuals as a 'vulnerable group' is prominent in both legal standards and academic discourse. While this framing draws attention to their exposure to harm and discrimination, it also risks reinforcing essentialist or paternalistic narratives that undermine individual agency. This study critically engages with the vulnerability discourse, interrogating the structural roots of marginalisation and how institutional responses shape or perpetuate differential treatment.
Addressing these gaps, the study investigated the lived experiences of incarcerated LGBTQ+ individuals in Belgium, examined the operationalisation of international human rights standards, and explored the relevance of a queer penological framework. A mixed- and multi-methods approach was employed, encompassing 18 Belgian prisons. The research included an exploratory survey with prison staff (N=257), a mini-survey of investigating judges (N=38), in-depth interviews with both staff (N=33) and incarcerated LGBTQ+ individuals (N=32), and correspondence with currently incarcerated LGBTQ+ people (N=5).
Findings highlight a growing institutional recognition of LGBTQ+ diversity within Belgian prisons, evidenced by training initiatives and policy tools such as Beyond Binary Bars, a self-help guide for incarcerated transgender persons developed by civil society actors in collaboration with prison authorities. Nonetheless, training remains limited in scope—primarily addressing transgender identities—and often engages only staff already sensitised to LGBTQ+ issues, inadvertently entrenching polarised views. A notable development is the 2023 issuance of guidelines for the treatment of transgender detainees by the Belgian FPS Justice and prison administration. These guidelines—aligned with the CPT standards—advocate placement based on gender self-determination, balanced with institutional safety concerns. However, the guidelines are non-binding, and their practical implementation remains inconsistent. Staff awareness of the guidelines is limited, and earlier practices, reliant on legal sex designation and medical evaluations, persist in influencing placement decisions.
Empirical data from staff and incarcerated individuals reveal enduring marginalisation, including discrimination, subtle verbal violence, and exclusion. While severe physical or sexual violence was less frequently reported, several serious incidents were documented. Despite these challenges, instances of acceptance, solidarity, and allyship (both from staff and fellow incarcerated individuals) were documented, revealing a more complex and nuanced landscape.
Institutional responses to same-sex relationships varied widely, ranging from punitive and restrictive to permissive and accommodating, with more openness noted in women's prison units. These inconsistencies reflect broader tensions between policy aspirations and on-the-ground realities.
In sum, the research presents a nuanced portrait of the Belgian prison system's engagement with incarcerated LGBTQ+ people. While normative progress is evident through policy developments and emerging forms of support, significant gaps remain between policy and practice. These include uneven implementation, resistance among staff, and persistent stigmatisation of LGBTQ+ identities. This study contributes to bridging these gaps by offering empirical insight into incarcerated LGBTQ+ individuals' lived experiences, while advancing critical reflection on vulnerability and reflecting on the potential of a queer penological approach.status: Publishe
Den groten herbarius Printed by Maria Ancxt (1547): A Unique Copy in the Collection of the Hospital Sisters of Herentals
No full textstatus: Publishe
Trombo-inflammatie in Staphylococcus aureus sepsis: het ontrafelen van het web van neutrofiel peptidylarginine deiminase 4 en extracellulaire 'traps'
No full textSepsis is defined as life-threatening organ damage caused by a dysregulated host immune response to infection and is a frequent cause of morbidity and mortality worldwide. Sustained organ dysfunction and immune dysregulation put sepsis survivors at risk for complications resulting in long-term impaired quality of life. Staphylococcus aureus is the number one bacterial cause of death with mortality rates up to 35% in the case of methicillin-resistant S. aureus (MRSA).
Neutrophils are our first line of defense against invading pathogens. One mechanism to combat infection is the formation of neutrophil extracellular traps (NETs), extracellular chromatin fibers complexed with neutrophil proteins, that are released from activated neutrophils. NETs can trap and neutralize bacteria, but excessive NET release can contribute to organ damage by propagating thrombosis and inflammation ("thromboinflammation"). NETs directly activate platelets and coagulation factors, and also bind von Willebrand factor (VWF), thus providing a scaffold for thrombus growth. Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme involved in NET formation that also modifies plasma proteins involved in thrombus formation. Citrullination of a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS13) results in its inactivation, meaning it no longer cleaves VWF multimers and thus results in accumulation of ultra-large VWF multimers. PAD4 can be expressed by neutrophils and other immune cells. NETs interact with immune cells from the innate and the adaptive immune systems, but it is unknown whether NETs contribute to immune dysregulation in sepsis. In addition, S. aureus bacteremia is frequently associated with the development of acute kidney injury (AKI) but it remains unknown whether NETs are involved in this pathophysiology.
In this thesis we aimed to investigate the impact of NETs and neutrophil PAD4 in Staphylococcus aureus sepsis by combining insights from in vitro and in vivo experimental techniques, along with analyses of clinical samples. We have elucidated the impact of NETs and PAD4 on the VWF/ADAMTS13 axis and set out to determine to which extent neutrophils contribute to elevated levels of PAD4 in MRSA sepsis. Furthermore, we examined interactions between NETs and immune cells in MRSA sepsis and we delved into the impact of NETs on MRSA-induced AKI.
In a longitudinal analysis of samples from hospitalized patients with S. aureus bacteremia, we found that levels of NETs, PAD4, and VWF were elevated, whereas ADAMTS13 activity was initially decreased. Elevated levels of PAD4 correlated with decreased ADAMTS13 activity in these patients and we confirmed PAD4-induced inactivation of ADAMTS13 in human plasma in vitro. Our findings support an indirect link between PAD4 and VWF during S. aureus sepsis. Aiming to delineate the specific roles of NETs, neutrophil PAD4, and VWF in MRSA sepsis, we optimized a mouse model of MRSA through intravenous administration of bacteria. We examined the impact of genetic deficiency for neutrophil PAD4 or VWF in this model, in comparison to wild-type animals. We found that an increase in neutrophil counts and propensity to form NETs protected wild-type mice during sepsis. Our data support that NETs are an important host defense strategy early after sepsis onset and protect against disease severity during MRSA sepsis in mice treated with granulocyte colony-stimulating factor (G-CSF) prior to sepsis induction. Our data support the use of G-CSF as a new tool to study neutrophil biology in murine sepsis models, which could also be further explored as a potential treatment strategy. Experiments with neutrophil-specific PAD4-deficient mice also revealed that elevated levels of PAD4 during sepsis do not predominantly originate from neutrophils. VWF did not impact sepsis outcome nor altered NET release, thus highlighting the need to redefine the VWF/NET axis in MRSA sepsis.
We found that NETs might impact immune cell recruitment in the kidney following MRSA injection, where immune cells contributed to abscess formation. MRSA infection in the kidney resulted in the development of renal fibrosis. NETs may protect against MRSA-induced AKI by containing bacteria in the renal papilla if present in large amounts upon stimulation with G-CSF. In the spleen, NETs had no major impact on the immune cell repertoire. We observed the occurrence of splenic extramedullary hematopoiesis in murine MRSA sepsis, but the impact of NETs and neutrophil PAD4 on these immature myeloid cell populations remains to be defined.
Taken together, our findings show that NETs are protective in the early phases of MRSA sepsis, only in mice that received G-CSF prior to bacteremia induction, potentially acting through better containment of bacteria in peripheral organs. This has important implications for treatment schemes given the clinical interest of decreasing NET burden in sepsis and it also underlines the need to develop biomarkers to define disease stages along with treatable targets across the sepsis timeline. Combining insights from high-throughput multi-omics approaches and machine learning-based data integration could help to define patient-specific sepsis stages, paving the way for personalized medicine in sepsis.
In summary, this thesis brings new insights into MRSA sepsis pathophysiology and defines new directions for future work. Recognizing disease- and patient- specific features paves the way towards individualized patient therapy which is key to ameliorate sepsis prognosis.status: Publishe