International Migration, Integration and Social Cohesion online publications
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Development of a bacterial chassis for amine synthesis
Get PDFThe biocatalytic synthesis of chiral amines from carbonyl compounds and ammonia represents a major advancement in sustainable synthetic chemistry. Using whole cells for bioamination offers advantages such as low preparation cost and direct applicability; however, amine toxicity often limits these reactions when living cells are used. This thesis focuses on the generation, characterization, and biocatalytic application of amine-tolerant bacteria for sustainable, high-yielding amine synthesis. We employed adaptive laboratory evolution to generate amine-tolerant Escherichia coli strains that enabled the enantioselective reductive amination of prochiral ketones, achieving yields of up to 80% at high substrate loadings (up to 23 g L-1), without cofactor supplementation. Additionally, the adapted strains facilitated the bioamination of alcohols with modest to good efficiency—typically outperforming non-adapted cells—and enabled the bioproduction of short-chain alkyl amines via enzymatic decarboxylation of amino acid precursors. The genomes of the amine-tolerant strains revealed a multifactorial adaptive response—primarily involving membrane modifications, stress coping, and regulatory mechanisms—that conferred cross-resistance to structurally diverse amines, likely through cell reinforcement or amine exclusion. Collectively, this thesis deepens our understanding of microbial adaptation to chemical stress and advances the development of robust whole-cell biocatalysts for amine production.</p
Risk factors and implications of anaesthesia induced hypotension
Get PDFThis thesis studied haemodynamic perturbation in the perioperative and intensive care settings. The aims of the chapters were to: · Evaluate the implications of the use of different thresholds of hypotension in perioperative haemodynamic research. (Chapter 2) · Provide an overview of the echocardiographic changes in cardiac function due to general anaesthesia and intermittent positive pressure ventilation. (Chapter 3) · Determine the modifiable risk factors in anaesthesia induction for post-induction hypotension. (Chapter 4) · Explore whether time of day of anaesthesia induction affects the incidence of haemodynamic instability. (Chapter 5) · Compile the literature on biological sex as a risk factor of post-induction and intra-operative hypotension. (Chapter 6) · Investigate the performance of a hypotension-prediction algorithm in spontaneously breathing patients without ventilatory support in the post-operative and intensive care settings. (Chapter 7) · Chapter 9 discusses the implications of the aforementioned research and the avenues for future research that remain.</p
From shake to shape:<i>In vitro </i>studies on how shear stress regulates erythropoiesis
Get PDFAlthough red blood cell (RBC) transfusion is one of the most common clinical practice, its dependency on donor blood presents challenges related to supply, storage, and infection risk. Alternatives to blood transfusions are being explored, among which, in-vitro RBC production is one of the most promising. Nevertheless, scaling manufacturing to transfusion-relevant quantities requires dynamic bioreactors that expose cells to mechanical forces like shear-stress. This thesis investigates how shear-stress influences erythroid differentiation to advance both the biological understanding of erythropoiesis and the optimization of large-scale RBC production. Erythroblasts cultured under moderate levels of shear-stress showed accelerated maturation, achieving enucleated CD49d⁻/CD235a⁺ reticulocytes four days earlier than under static conditions. Transcriptomic analyses revealed the downregulation of DNA replication genes and overexpression of cholesterol biosynthesis and uptake pathways, leading to transient membrane lipid remodeling that possibly enhances mechanical resilience. Functional studies identified mechanosensitive channel PIEZO1 and its downstream effector, the Gárdos channel, as active during differentiation, suggesting a feedback mechanism linking membrane lipid composition, ion flux, and cell volume regulation. Moreover, in-vitro RBC differentiation can provide models to study pathological erythropoiesis, as it has been shown in this thesis by the characterization of a novel β-spectrin mutation (SPTBc.6219G>A) associated with hereditary elliptocytosis. In summary, this work elucidates the mechanotransductive responses of erythroid precursors to shear-stress, demonstrating their impact on lipid metabolism, ion channel activity, and differentiation kinetics. These findings provide foundations for optimizing bioprocess parameters in RBC biomanufacturing and for implementing dynamic culture systems as models to investigate both normal and diseased erythropoiesis
From the battlefield to the courtroom (and back):The interplay between international humanitarian law and international criminal law
Get PDFInternational humanitarian law (IHL) was created to work preventatively, on the battlefield; for its part, international criminal law (ICL) has been drafted for use in retrospect, in a courtroom-setting. This thesis considers the interplay between these two branches of public international law. While the clarification and development of IHL by international criminal courts and tribunals was very welcome, the manner in which it has been applied during international trials was not always correct and may also be critiqued. In addition, the application of IHL in retrospect, as part of the prosecution and adjudication of alleged war crimes or other international crimes, such as crimes against humanity, is challenging. The scope of application of IHL, for example, has been assessed through a criminal law ‘lens’, leading to a significant broadening of its scope. The resultant expansive application of IHL by international criminal courts and tribunals may have a negative impact on the protection of persons under IHL or other bodies of law. Similarly, rulings on questions related to the conduct of hostilities may impact the legal framework governing military operations in times of armed conflict, and thus affect members of the military or on indeed other persons working with IHL during conflicts. The present book critically analyses the case law of war crimes trials before the International Criminal Tribunals for the former Yugoslavia and Rwanda, the Special Court for Sierra Leone, and the International Criminal Court (ICC) and finds that more attention must be paid to ensure that IHL is correctly applied. For the ICC, statutory changes are required to avoid war crime provisions being applied incorrectly, intentionally or not, and the law distorted to prevent impunity; otherwise, such distortions may result in a version of IHL that can no longer be applied preventatively on the battlefield. Of equal note is that those reading international criminal and humanitarian law judgments must be mindful of the scope and limitations of such rulings
Angel-headed hipsters:Psychedelic militancy in nineteen-eighties North America
Get PDFThe psychedelic dimension of religious experience occupies a marginal position in the scholarship of American culture. For the last seven decades, scholars have viewed the psychedelicist church movement as, variously, an excuse for taking illegal drugs, an inauthentic mode of religious fellowship, and a purely oppositional “counter-culture.” More recent scholarship challenges these interpretations by emphasizing the legitimacy of the experiences occasioned by psychedelics.Psychedelicism in the 1980s took shape as the “zine scene,” a vast information network composed of approximately ten thousand self-publishers. The convergence of underground networks that coalesced into this expansive literary microcosm can be traced back to the SubGenius Church. This fellowship of psychedelicist hipsters organized its members into an epistolary network. This intra-church postal exchange was the seed out of which the zine scene bloomed. However, the SubGenius Church would not retain its position at the fore of the zine scene indefinitely. A mass defection ensued after the SubGenius leadership brokered deals with major media corporations. The subsequent commercialization of the Church provoked long-time SubGeniuses to relocate to Factsheet Five, a newly created fanzine directory. It was here that the zine scene developed into a major cultural phenomenon.Through an examination of the hipster militants of the zine scene, this dissertation re-centers psychedelicist fellowships in 1980s hip culture. It is only by recognizing the interplay between the hipsters of the psychedelicist church movement, and hip capitalism, that the role of esotericism in American culture can be understood
TRIP13 and germline gene expression in cancer:Mechanisms of acquired radioresistance
Get PDFCancer is a major global health challenge, characterized by increasing incidence rates and significant therapeutic obstacles. Despite the diversity among cancer types, they share common characteristics, referred to as the hallmarks of cancer, which serve as critical drivers of tumor progression. These hallmarks have been effectively exploited as therapeutic targets, given their essential role in supporting cancer cell proliferation and survival. Recent research has identified a subset of germline-cancer (GC) genes—normally restricted to germline cells but aberrantly expressed in tumors—that regulate key processes such as meiosis, gene regulation, and DNA repair, with their activation linked to poor prognosis. In this thesis, we demonstrate that high GC gene expression in lung cancer cell lines is associated with enhanced DNA double-strand break (DSB) repair, increased proliferation, and radioresistance. Among these genes, TRIP13 was identified as a key driver of this phenotype. Functional studies showed that TRIP13 inhibition or knockout reduces clonogenic survival, sensitizes cells to ionizing radiation, and downregulates DNA repair proteins. Repeated radiation exposure induced TRIP13 expression, conferring acquired radioresistance and correlating with poor prognosis in lung cancer patients. Moreover, we show that melatonin (MT), acting via the MTNR1B receptor, downregulates TRIP13 and its downstream DNA repair proteins. TRIP13 inhibition also diminished EGFR expression and phosphorylation, indicating additional oncogenic functions beyond DNA repair. Collectively, these findings uncover a novel mechanism of therapeutic resistance driven by aberrant germline gene activation and highlight TRIP13 as a promising therapeutic target to enhance the efficacy and specificity of lung cancer treatment.</p
Exploring the outflows and evolution of accreting neutron stars:A multi-wavelength approach
No full textNeutron stars and black holes (i.e. compact objects) are the evolutionary end states of massive stars, when these collapse and undergo a spectacular supernova explosion. These massive stars often form in binary systems, where mass transfer (accretion) can occur. When one of the stars in a binary system evolves into a compact object, its immense gravity causes accreted material to release vast amounts of energy, primarily emitted as X-rays. These systems are hence called “X-ray binaries”. X-ray binaries can also produce powerful outflows such as collimated jets, as well as winds launched from the accretion disc. This thesis is devoted to multi-wavelength observational studies of neutron stars in X-ray binaries, in particular to characterize their outflows and to understand certain aspects of their evolution. I combine X-ray and radio measurements to trace the coupling between the accretion inflow (via X-rays) and jet outflow (via radio), and investigate the role of additional X-ray emission from the neutron star surface in deriving the inflow-outflow behaviour. Furthermore, I use X-ray to near-infrared data to study accretion disc winds. I show that neutron star X-ray binaries can launch disc winds in much smaller systems than previously expected, and discuss the implications for the evolution of these systems. Finally, I present a study on the formation channel of a peculiar neutron star X-ray binary, and the impactful discovery of an unexpected velocity kick in its formation. I show that an uncommon supernova mechanism might impart velocity kicks, which was not previously realised
Molecular mechanisms and biomarkers of aging and lifespan extension
No full textThe aim of this thesis was to identify novel regulators of longevity, test pharmacological interventions, and explore the role of lipid metabolism in aging using both genetic and systems-level approaches. In Chapter 2, we identified the opioid antagonist naltrexone as a potential geroprotective compound by mimicking the FOXO3A pathway in silico. In C. elegans, low-dose naltrexone extended healthspan and lifespan via SKN-1/NRF2-mediated regulation of innate immunity and stress resistance. Chapter 3 utilized 85 recombinant inbred lines (RIAILs) of C. elegans to integrate transcriptomic, proteomic, and lipidomic data with lifespan and other life-history traits. We observed substantial variability in longevity, positively associated with developmental time, and mapped both established and novel regulators, including rict-1, gfm-1, and mltn-1. In Chapter 4, we investigated mitochondrial stress response (MSR) activation by doxycycline across the same RIAIL panel. Lifespan extension was highly strain-specific, and QTL mapping identified fipp-1/FIP1L1 as a new regulator of the UPRmt, validated in worms and human cells. Chapter 5 extended this work to human plasma lipidomics, revealing triglyceride accumulation with age, modulated by physical activity. Chapter 6 further identified lipid acyl-chain lengthening as a conserved hallmark of aging in worms, flies, mice, and humans, and linked it to cardiovascular disease progression. Knockdown of lipid elongation enzymes in C. elegans extended lifespan and reversed lipid remodeling. Finally, Chapters 7 and 8 integrate these findings, highlighting new therapeutic targets, molecular biomarkers, and lipid remodeling mechanisms in aging and lifespan regulation
Linking microbial community and gross nitrogen transformations in forest soils:Methods and experiments
No full textGross nitrogen (N) transformations in forest soils underpin ecosystem productivity and regulate the risk of N loss. Soil biota, particularly microbes, drive these key processes, while climatic and soil-related factors regulate microbial communities and thereby shape the rates and interrelationships of gross N transformations. In recent decades, major advances in understanding the soil N cycle have been achieved through stable isotope techniques that quantify individual processes and genomic tools that characterise microbial communities.This thesis advances a process-based understanding of soil N transformations in temperate forests—ecosystems that provide essential services yet are highly vulnerable to global change. Specifically, it investigates the regulatory factors of internal soil N transformations and explores how microbial communities mediate these processes. These objectives are addressed through an integrative approach that combines literature reviews on microbial N transformations and analytical methods with experimental studies in Dutch and Luxembourg forests. The findings contribute to integrating microbial dynamics into ecosystem-scale models of forest N cycling, thereby improving predictions of soil N dynamics under future environmental change
Golden slumber?:The elusive role of sleep in emotional memory
Get PDFEmotional memories shape how we perceive ourselves and the world. While they often serve adaptive functions, they have also been linked to the onset and persistence of affective disorders. Sleep is frequently disturbed in these conditions and has been proposed to play a key role in emotional memory processing. Empirical evidence, however, remains inconclusive, and theoretical accounts diverge: whereas some suggest sleep preserves or amplifies memories’ emotional tone, others propose a downregulating effect of sleep. This dissertation investigated whether, and under what conditions, sleep modulates the emotional impact of memories. Across a series of studies, we combined naturalistic paradigms with behavioural and psychophysiological measures. Using socially distressing tasks, we induced autobiographical experiences and later reminded participants of them after intervals including either sleep or wakefulness. Emotional responses triggered by the previously induced memories were assessed through subjective ratings and physiological measures (e.g., facial blushing). Contrary to our predictions, sleep could not be reliably linked to changes in the emotional tone of memories. The observed alterations in emotional responses were often unrelated to memory and sleep. Instead, findings suggest that factors such as future relevance and sleep quality may moderate emotional memory processes. Together, these results highlight the complexity of the relationship between sleep and emotional memories and challenge the idea of sleep as a simple mechanism for reducing or amplifying memories’ emotional tone. While healthy sleep may support general emotion regulation, it does not consistently reshape emotional memories. This work underscores the need for more nuanced models to capture how emotional experiences are processed over time