541 research outputs found

    On the robustness of Bayesian phylogenetic gene tree estimation

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    Differences in well-being:the biological and environmental causes, related phenotypes, and real-time assessment

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    Well-being is a complex, and multifaceted construct that includes feeling good and functioning well. There is a growing global recognition of well-being as an important research topic and public policy goal. Well-being is related to less behavioral and emotional problems, and is associated with many positive aspects of daily life, including longevity, higher educational achievement, happier marriage, and more productivity at work. People differ in their levels of well-being, i.e., some people are in general happier or more satisfied with their lives than others. These individual differences in well-being can arise from many different factors, including biological (genetic) influences and environmental influences. To enhance the development of future mental health prevention and intervention strategies to increase well-being, more knowledge about these determinants and factors underlying well-being is needed. In this dissertation, I aimed to increase the understanding of the etiology in a series of studies using different methods, including systematic reviews, meta-analyses, twin designs, and molecular genetic designs. In part I, we brought together all published studies on the neural and physiological factors underlying well-being. This overview allowed us to critically investigate the claims made about the biology involved in well-being. The number of studies on the neural and physiological factors underlying well-being is increasing and the results point towards potential correlates of well-being. However, samples are often still small, and studies focus mostly on a single biomarker. Therefore, more well-powered, data-driven, and integrative studies across biological categories are needed to better understand the neural and physiological pathways that play a role in well-being. In part II, we investigated the overlap between well-being and a range of other phenotypes to learn more about the etiology of well-being. We report a large overlap with phenotypes including optimism, resilience, and depressive symptoms. Furthermore, when removing the genetic overlap between well-being and depressive symptoms, we showed that well-being has unique genetic associations with a range of phenotypes, independently from depressive symptoms. These results can be helpful in designing more effective interventions to increase well-being, taking into account the overlap and possible causality with other phenotypes. In part III, we used the extreme environmental change during the COVID-19 pandemic to investigate individual differences in the effects of such environmental changes on well-being. On average, we found a negative effect of the pandemic on different aspects of well-being, especially further into the pandemic. Whereas most previous studies only looked at this average negative effect of the pandemic on well-being, we focused on the individual differences as well. We reported large individual differences in the effects of the pandemic on well-being in both chapters. This indicates that one-size-fits-all preventions or interventions to maintain or increase well-being during the pandemic or lockdowns will not be successful for the whole population. Further research is needed for the identification of protective factors and resilience mechanisms to prevent further inequality during extreme environmental situations. In part IV, we looked at the real-time assessment of well-being, investigating the feasibility and results of previous studies. The real-time assessment of well-being, related variables, and the environment can lead to new insights about well-being, i.e., results that we cannot capture with traditional survey research. The real-time assessment of well-being is therefore a promising area for future research to unravel the dynamic nature of well-being fluctuations and the interaction with the environment in daily life. Integrating all results in this dissertation confirmed that well-being is a complex human trait that is influenced by many interrelated and interacting factors. Future directions to understand individual differences in well-being will be a data-driven approach to investigate the complex interplay of neural, physiological, genetic, and environmental factors in well-being

    Frontiers of Humanity and Beyond: Towards new critical understandings of borders. Working Papers

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    UIDB/04666/2020 UIDP/04666/2020publishersversionpublishe

    Proteogenomic characterization of 5-Azacytidine effects on acute myeloid leukemia immunopeptidome

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    La 5-azacytidine (AZA) est un mĂ©dicament approuvĂ© pour le traitement des leucĂ©mies myĂ©loĂŻdes aiguĂ«s des patients qui ne sont pas Ă©ligibles Ă  une greffe de cellules souches hĂ©matopoĂŻĂ©tiques. Bien que l’AZA est augmentĂ© significativement le pronostic des patients, le mĂ©canisme d’action prĂ©cis de l’AZA demeure nĂ©buleux. En plus de son activitĂ© d’hypomĂ©thylation, il a Ă©tĂ© montrĂ© que l’AZA a aussi des effets immunologiques. Des Ă©tudes prĂ©cĂ©dentes suggĂšrent que ces rĂ©ponses immunitaires sont causĂ©es par des modifications du rĂ©pertoire de peptides prĂ©sentĂ©s par le CMH-I (MAPs), dont l’expression de MAPs dĂ©rivĂ©s de rĂ©troĂ©lĂ©ments endogĂšnes (EREs) et des cancer-testis antigens (CTAs). Ces gĂšnes sont gĂ©nĂ©ralement rĂ©primĂ©s par la mĂ©thylation de l’ADN. Dans cette thĂšse, nous avons testĂ© cette hypothĂšse Ă  l’aide de sĂ©quençage Ă  haut dĂ©bit et de spectromĂ©trie de masse appliquĂ©s Ă  quatre lignĂ©es cellulaires d’AML diffĂ©rentes. Notre approche protĂ©ogĂ©nomique d’avant-garde a rĂ©vĂ©lĂ© que l’AZA induit la prĂ©sentation de MAPs dĂ©rivĂ©s de CTAs, mais pas d’EREs, malgrĂ© le fait que ces deux groupes de sĂ©quences soient surexprimĂ©s au niveau transcriptomique. Ces rĂ©sultats indiquent que les rĂ©ponses des lymphocytes T observĂ©es chez les patients suite au traitement Ă  l’AZA dĂ©pendent probablement des MAPs dĂ©rivĂ©s des CTAs, et non pas des EREs. Les EREs stimulĂ©s par l’AZA ont tout de mĂȘme un impact sur la rĂ©ponse immunitaire en formant des ARN double-brins menant Ă  une activation de l’immunitĂ© innĂ©e. L’incorporation de l’AZA et l’inhibition subsĂ©quente de la DNMT2 mĂšne cependant Ă  des agrĂ©gats protĂ©iques et Ă  l’autophagie, qui dĂ©grade les transcrits EREs et limite leur surexpression. Nous avons dĂ©montrĂ© que les effets immunologiques de l’AZA peuvent ĂȘtre amplifiĂ©s par un traitement combinĂ© de l’AZA et d’inhibiteurs de l’autophagie. De plus, le travail contenu dans cette thĂšse a montrĂ© que bien qu’elles soient un modĂšle expĂ©rimental pratique, les lignĂ©es cellulaires ont des limitations et doivent ĂȘtre utilisĂ©s avec prudence. Des diffĂ©rences majeures ont Ă©tĂ© observĂ©es entre des lignĂ©es cellulaires supposĂ©ment identiques provenant de fournisseurs Ă©tablis. Nos analyses ont permis de dĂ©montrer quelle lignĂ©e cellulaire Ă©tait la plus similaire Ă  la lignĂ©e parentale. Ainsi, ce travail fourni des recommandations pour amĂ©liorer les lignes directrices d’utilisation des lignĂ©es cellulaires en recherche.5-azacytidine (AZA) is approved for the treatment of acute myeloid leukemia (AML) patients ineligible for hematopoietic cell transplantation. Although AZA treatment has substantially improved patient outcomes, there remains a lack of clear understanding of the mechanisms driving these responses. In addition to its hypomethylating activity, AZA has been shown to have immunological effects. Previous reports suggest that these immune responses occur due to alterations in the repertoire of MHC-I-associated peptides (MAPs), including the expression of MAPs deriving from endogenous retroelements (EREs) and cancer-testis antigens (CTAs). These genes are typically silenced by methylation. With this thesis, we aimed to test this hypothesis using high-coverage RNA sequencing and mass spectrometry in four different AML cell lines. Our state-of-the-art proteogenomic approach uncovered that AZA treatment induced MAPs deriving from CTAs, but not EREs, despite both being upregulated at the RNA level. This indicates that T-cell responses post-AZA treatment are more likely to be dependent on CTA- than ERE-derived MAP presentation. AZA-induced EREs produced at the RNA level still contributed to immune responses by forming double-stranded RNA leading to a state of viral mimicry. However, AZA incorporation into RNA and subsequent DNMT2-inhibition led to protein aggregation and autophagy responses. These responses were responsible for degrading EREs, which limited their upregulation. We further demonstrate that the immune effects of AZA can be enhanced by the combination of AZA with autophagy inhibitors. Additionally, the work in this thesis has shown that although a practical model, cell lines have their caveats and must be used with caution. This work has highlighted the grave discrepancies between supposedly identical cell lines supplied by established repositories. Moreover, our analyses determine which of the two is closer to the parental cell line. Finally, this work provides recommendations for improving the current guidelines for cell line-based research

    The genetic interactions of PKHD1 and ATMIN in autosomal recessive polycystic kidney disease (ARPKD)

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    A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.The main gene associated with Autosomal Recessive Polycystic Kidney Disease (ARPKD) is PKHD1 which encodes a ciliary protein associated with planar cell polarity. In mice, mutations in the transcription factor Atmin can present with an ARPKD-like phenotype with kidney disease similar to an early manifestation of ARPKD. Like the mouse gene Pkhd1, mutations in Atmin are associated with altered WNT/PCP expression. Previous work has suggested that Atmin and Pkhd1 do not physically interact, but Atmin may modulate Pkhd1 expression. However, the mechanisms governing this relationship are unknown. ARPKD is a rare disorder typically associated with severe kidney and liver disease in children. The disease has considerable clinical and familial variability, but little is known regarding genotype-phenotype relationships. It has been proposed that genetic modifiers may influence disease severity. Next-generation sequencing (NGS) using ChIP-Seq and RNA-Seq techniques in mouse kidneys and intermedullary collecting duct (mIMCD3) cells identified new transcriptional targets of Atmin, which did not include Pkhd1 but included genes associated with cystic kidneys in animal models (Camk2g and G6pc). NGS in Atmin and Pkhd1 KDs identified a common transcriptional network between the two genes. Gene enrichment analysis suggests this common network is associated with immune system processes. Dysregulated genes associated with double KDs showed greater enrichment of processes associated with the actin cytoskeleton, cell cycle and energy metabolism. Loss of Atmin expression negatively impacts the ciliary localisation of Fibrocystin, suggesting that Atmin may be needed for the proper localisation of Fibrocystin to the cilium. NGS in ARPKD kidneys highlights mutations in ATMIN as a potential regulator of disease severity, associated with reduced ARPKD severity. Expression differences in WNT genes may be present between severe and moderate ARPKD and transcriptomic profiling identified candidate diagnostic markers in ARPKD which included MSC, FGA, WNT4, WNT9B and KIF26B. This work indicates that Atmin and Pkhd1 interact in a similar transcriptional network in mice. Atmin is not a transcription factor of Pkhd1 but may modulate its function by governing its ciliary localisation by a yet unknown mechanism. Additionally, ATMIN mutations may modulate ARPKD disease severity, and the amount of differential expression in WNT/PCP genes may be a marker of disease severity.PKD Charity, Arran Brown Rainbow Foundation, and the University of Wolverhampton

    Design and application of supramolecular solvents for the development of rapid sample treatment and detection platforms

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    This Doctoral Thesis has been structured in several sections. Firstly, in the Introduction the different studied groups of contaminants and the investigated matrices are discussed. Then, theorical and practical aspects of supramolecular solvents (SUPRASs) are described, and finally, the emerging technique of ambient mass spectrometry (AMS), used in some studies of this Thesis, is presented. Secondly, Blocks I and II are exposed, composed by the different chapters which correspond to the scientific articles derived from the performed research in this Thesis. Finally, the most relevant conclusions from the different studies are exposed, followed by the Annexes which contain other scientific and divulgation publications, as well as the communications presented in scientific congresses.La memoria de esta Tesis Doctoral se ha estructurado en varias secciones. En primer lugar, se expone la Introducción, donde se describen los diferentes grupos de contaminantes estudiados, así como las distintas matrices que se han investigado. También se describen aspectos teóricos y pråcticos de los disolventes supramoleculares (SUPRASs), y, finalmente, se discute la técnica de espectrometría de masas ambiental (AMS, de sus siglas en inglés Ambient Mass Spectrometry). A continuación, se exponen los contenidos de los Bloques I y II, donde se describen los distintos Capítulos que se corresponden con los artículos científicos derivados de las investigaciones realizadas. Finalmente, se exponen las conclusiones mås relevantes de los distintos estudios, seguidas de los Anexos donde se recogen otras publicaciones científicas y de divulgación, así como las comunicaciones presentadas en congresos científicos

    Molecular Motor Based on Single Chiral Tripodal Molecules Studied with STM

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    This work presents a single molecular motor driven by the current in an STM. Its chiral functional group is supposed to perform a rotation in a preferred direction, proven by Binomial tests to be statistically significant. The rotation is proposedly driven by the chiral-induced spin selectivity effect (CISS). However, the studies of the rotation on the dependence on the lateral tip position, voltage and current indicate that he CISS is unlikely to cause the preferred rotation direction

    Platforms for the development of electrochemiluminescent biosensors

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    Electrochemiluminescence (ECL) based biosensors has attracted much attention since they provide high selectivity, controllability, and sensitivity. Therefore, the goal of this work was to study novel gold-based materials for the development ECL platforms using ruthenium based luminophores for future application in bacteria detection. Firstly, 3D Ti electrodes, printed using Ti alloy (Ti-6AI-4V) powder were studied and functionalized with a thin layer of gold and ECL generation was investigated with [Ru(bpy)3]2+ and the co-reactant tri-propyl amine. Results demonstrated that the presence of gold improved the diffusion on the electrode surface as well as ECL intensity, suggesting it can provide a unique and optimizable platform for their potential application for biosensors. Gold has very interesting electrochemical applications, but it also presents optical properties that can be exploited for sensing purpose, such as ECL signal amplification through optically driven plasmon excitation. With this purpose, 10 nm gold nanoparticles (AuNPs) were investigated in solution with different luminophores of [Ru(bpy)3]2+, [Ru(bpy)3-NH2]2+ and [Ru(bpy)2(phen)-NH2]2+ (separately), for the development of a SPR-ECL system. According to the fluorescence emission results, [Ru(bpy)3-NH2]2+ was chosen as the most suitable dye to develop an ECL biosensor for the DNA detection UTI causing Escherichia coli. For this, gold nanoparticles coated glassy carbon electrodes were analyse using impedance and cyclic voltammetry technique in order to investigate the suitability of the system for DNA bacterial detection. Finally, Ferromagnetic-Core/Gold-Shell NPs synthesized by thermal decomposition method were also characterised. Results confirmed that the particles were successfully synthesized and covered with gold, however, SEM images shown an aggregate size >200nm and a heterogenous shape, indicating that the synthesis protocol should be further optimized to achieve better particle properties for a magnetic ECL based biosensor. In conclusion. this thesis demonstrated the how novel platforms and luminophores could be used in conjunction with gold to develop ECL sensing systems. SPR of AuNPs coupled ECL of luminophores can be exploited to amplify the ECL signal, and overall, the analytical performance of the sensing platforms and undoubtedly, the development of highly selective and sensitive biosensors for correct detection and diagnosis of diseases such as bacterial infections
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