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Food Prints on Core Crime Provisions:Conflict-driven starvation triggering individual criminal responsibility
Full text linkMechanisms of USPs, and Sequential Cleavage of Ubiquitin Chains on PCNA by USP1/UAF1
No full textIn every cell in our body, proteins are the tiny molecular machines that carry out all the different functions of the cell, virtually performing every single active process in the human body. A single protein can perform multiple roles within the cell, which needs to be tightly regulated so that we do not develop disease. By attaching ubiquitin to a protein, the cell can change the fate of that protein: switching between pathways or directing it towards degradation. In this thesis, we study the molecular process in which ubiquitin is removed from other proteins in a process called ‘deubiquitination’, with a focus on the mechanisms of deubiquitinating enzymes that belong to the USP family. The results reveal novel insights in the function and regulation of different USPs. Importantly, it shows that individual USPs distinguish themselves in important ways on a molecular level, despite their many similarities. We show that USP1/UAF1 uses a unique ubiquitin-chain cleaving mechanism unlike any other USP. USP48 is revealed to have a C-terminal peptide, party similar to that of other USPs, which distinguishes itself in important way. Finally, we show that the mechanism of catalysis itself, thought to be highly conserved in USPs, actually varies between different USPs and is more complex than we realized. These biochemical and structural studies of this thesis allow us to gain detailed insights into the nuances of proteins, which can guide and aid us in better understanding the cell
The age of biomarkers:Predicting age-related decline with molecular signatures
No full textPeople age differently, and these differences go beyondchronological age. Biological age indicates how quicklyor slowly an individual’s body is aging, with highervalues than peers indicating unhealthy aging and lowervalues healthy aging. Biological age can be assessed andpredicted through biomarkers (measurable indicatorsof biological states or processes), which provide apersonalized measure of aging and, thereby, valuableinsights into its variability across individuals.The main goal of this thesis is to improve the predictionof biological aging. To achieve this, we evaluatedexisting biomarkers for biological age (Part I), developednew biomarkers (Part II), and explored their potentialapplications (Part III).<br/
Mechanism of DNA daughter strand incision during the initiation of mismatch repair
No full textThis thesis will focus on the early steps of MMR, namely on the function of MutS andMutL during the reaction steps from mismatch recognition to DNA strand incision.Further details regarding the initiation of repair and the mode of communication ofMutS and MutL on DNA are detailed in our review [Chapter 2]
Procedural aspects of limitation of liability for maritime claims
No full textLimitation of liability is an essential principle of maritime law, implemented to shield shipowners and other maritime actors from ruinous financial liabilities arising from the risks associated with international shipping. While the current global rules regulating this principle, such as the International Convention on Limitation of Liability for Maritime Claims (LLMC 1976/1996) has significantly harmonized the substantive aspects of the rules, the procedural aspects for enforcing this right remain largely unharmonised and unregulated at the international level. Therefore, this thesis identifies a critical gap in legal research, exploring how national procedures interpret various aspects of these rules with the aim to provide insights into these procedural divergences towards enhancing predictability and clarity.<br/
Decoding Hematopoietic-Stromal Interactions in MPN:The Role of Hedgehog Signaling and Inflammation
No full textThis research highlights the complex, cell type specific roles of hedgehog signaling as well as its links to inflammation in the development of Myeloproliferative Neoplasm (MPN). We show that in hematopoietic cells, the GLI1 transcription factor is activated via non-canonical, inflammation linked pathways, promoting clonal expansion and further inflammatory cytokine secretion driving critical disease phenotype. Additionally, we describe how in non-hematopoietic stromal cells, canonical GLI2 activation drives fibrosis. In both cases, inflammation emerges as a central disease driving mechanism.Targeting GLI1, GLI2, and CXCL4, effectively reduces fibrosis and inflammatory signalling, suggesting a path forward beyond the current first line treatment option of JAK inhibitor monotherapy. Our research also suggests that blocking PDGFRβ-driven inflammation could prevent disease progression and secondary malignancies.Thus, future MPN treatment strategies should take combinatorial strategies into consideration, guided by biomarkers such as GLI1 expression and circulating inflammatory cytokines. Overall, this mechanism-based approach offers new hope for more effective, disease-modifying therapies in MPN patients.<br/
Neural mechanisms of associative motor learning: ''Insights into memory formation and skill acquisition''
Full text linkThis PhD dissertation centers on the exploration of how memory formation occurs in thebrain, with a specific focus on memory formation during associative motor learning. Thekey questions addressed are related to the neurological processes that take place whenacquiring new motor skills, aiming to uncover the underlying neural mechanisms thatallow us to time our movements with precision at a millisecond level. Therefore, I haveemployed a basic classical eyeblink conditioning paradigm, better known as Pavlovianeyeblink conditioning. This paradigm is chosen due to the well-defined nature ofthe neuronal circuits involved in eyeblink conditioning, making it an ideal model forstudying the processes of neuronal plasticity within these circuits during the formationof memories in a healthy and disordered brain. To study these processes, I focused onexploring stimulus generalization and stimulus discrimination as well as the impact ofenvironmental enrichment on eyeblink conditioning. Further, I investigated the role ofthe metabotropic glutamate receptor (GRM7) in mGluR7 knockout and Purkinje cell-specific tamoxifen induced mice to assess the timing of the eyeblink response and thesensorimotor deficits present in neurofibromatosis type 1 and spinocerebellar ataxia1 mouse models. Finally, I also studied how to use mobile phone-based technology tostudy eyeblink conditioning in humans. These studies are conducted in conjunctionwith the eyeblink conditioning paradigm.<br/
Money, capitalism, and development:The south Schumpeterian hypothesis in developing countries
Full text linkDifferent medium, same processes?:Reading comprehension instruction in primary school incorporating audio and video
Full text linkReading comprehension is an important skill for academic success and functioning in society more broadly. However, nowadays, there is an increasing amount information available in spoken form, providing new ways for learning and acquiring information. The dissertation evaluates how children understand informative videos relative to informative texts, and explores the possibilities of audio and video as part of reading comprehension instruction. It describes four experimental studies conducted in the context of Dutch primary education. Part I of the dissertation focuses on providing insight into how children proceed in understanding information presented in text versus video form. Results showed that understanding texts and videos that present the same information is associated with similar comprehension processes (Chapter 2 and 3). This provides empirical evidence for the theory of a general comprehension skill underlying comprehension of different media. The findings speak against the common assumption that videos are processed more passively or superficially than written text. This provided the foundation for Part II of the dissertation, which focused on investigating whether audio and video materials can be used to foster inferencing. Inferences are implicit relations in a text that readers need to fill in. The ability to recognize these ‘gaps’ of information is an important skill for understanding both written and non-written media, like videos. It was, however, found to be difficult to stimulate the generation of inferences (Chapter 4 and 5), both during reading and during listening to audio and videos.<br/
