8,201 research outputs found

    Studies on genetic and epigenetic regulation of gene expression dynamics

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    The information required to build an organism is contained in its genome and the first biochemical process that activates the genetic information stored in DNA is transcription. Cell type specific gene expression shapes cellular functional diversity and dysregulation of transcription is a central tenet of human disease. Therefore, understanding transcriptional regulation is central to understanding biology in health and disease. Transcription is a dynamic process, occurring in discrete bursts of activity that can be characterized by two kinetic parameters; burst frequency describing how often genes burst and burst size describing how many transcripts are generated in each burst. Genes are under strict regulatory control by distinct sequences in the genome as well as epigenetic modifications. To properly study how genetic and epigenetic factors affect transcription, it needs to be treated as the dynamic cellular process it is. In this thesis, I present the development of methods that allow identification of newly induced gene expression over short timescales, as well as inference of kinetic parameters describing how frequently genes burst and how many transcripts each burst give rise to. The work is presented through four papers: In paper I, I describe the development of a novel method for profiling newly transcribed RNA molecules. We use this method to show that therapeutic compounds affecting different epigenetic enzymes elicit distinct, compound specific responses mediated by different sets of transcription factors already after one hour of treatment that can only be detected when measuring newly transcribed RNA. The goal of paper II is to determine how genetic variation shapes transcriptional bursting. To this end, we infer transcriptome-wide burst kinetics parameters from genetically distinct donors and find variation that selectively affects burst sizes and frequencies. Paper III describes a method for inferring transcriptional kinetics transcriptome-wide using single-cell RNA-sequencing. We use this method to describe how the regulation of transcriptional bursting is encoded in the genome. Our findings show that gene specific burst sizes are dependent on core promoter architecture and that enhancers affect burst frequencies. Furthermore, cell type specific differential gene expression is regulated by cell type specific burst frequencies. Lastly, Paper IV shows how transcription shapes cell types. We collect data on cellular morphologies, electrophysiological characteristics, and measure gene expression in the same neurons collected from the mouse motor cortex. Our findings show that cells belonging to the same, distinct transcriptomic families have distinct and non-overlapping morpho-electric characteristics. Within families, there is continuous and correlated variation in all modalities, challenging the notion of cell types as discrete entities

    Social plasticity and limited resilience of coral-dwelling gobies (genus Gobiodon) to climate change: outlook for coral-fish mutualisms in a changing world

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    Climate change is rapidly altering ecosystems on a global scale, and coral reefs are particularly vulnerable to climate-induced disturbances. Coral reefs depend on mutualisms with their foundation species, i.e. corals, and yet most of the literature has focused on their mutualisms with only one type of symbiont (algae). Little is known about how coral-fish mutualisms respond to climatic disturbances, and yet cyclones and heatwaves are increasingly devastating coral reefs. We urgently need to assess how coral-fish mutualisms respond to disturbances as changes in mutualisms have the potential for causing ecosystem-level changes. Yet fish in coral-fish mutualisms have often been overlooked in studies regarding environmental disturbances. There are multiple aspects of the life history, behaviour, and movement of fish that may impact their mutualisms with corals. Here, I investigated (1) whether both symbionts in coral-fish mutualisms respond similarly to climatic disturbances, and (2) what mechanisms from the fish perspective are likely responsible for how coral-fish mutualisms respond to climatic disturbances. I used a model coral-fish mutualism between coral hosts from the genus Acropora and coral-dwelling gobies from the genus Gobiodon in which both organisms provide important benefits for the resilience of each partner. I implemented a comparative approach by investigating multiple goby and coral species encountered in study locations to provide genus-wide understandings of how their coral-goby mutualisms are impacted by climatic disturbances. Particularly important is that gobies can live in social groups and living in groups can improve coral maintenance. Accordingly, first I provided a comprehensive review on how climate change is impacting the sociality of coral reef fish as the sociality of these taxa have only recently been investigated. Studies have shown that climate change affected the habitat and physiology of fishes, and each of these effects impacted their sociality. The review highlighted key changes to the sociality of these fish depending on how corals respond to disturbances, like reduction in coral size, shifts in coral communities, and health of corals. Secondly, I set the scene by monitoring coral-goby mutualisms throughout four extreme disturbances in the northern Great Barrier Reef (GBR): two cyclones and two heatwaves that caused mass bleaching events. In the aftermath and after a few years of recovery, there were more coral species, but corals were almost three times smaller. For gobies though, there were two times fewer coral species, there were fewer gobies, and most corals became absent of gobies when previously most were occupied. Alarmingly, this study highlighted that gobies declined far more than corals and were far slower to recover than their hosts. Finally, I used a combination of observational and manipulative studies to investigate the potential for coral gobies to exhibit plasticity in their host use, sociality, and movement in relation to disturbances. Following the same four extreme disturbances, I found that gobies shifted hosts to the newly abundant coral species. Although exhibiting host plasticity may be an advantage in the short-term, using alternative coral hosts may reduce the fitness of gobies, i.e. their growth rates. I then investigated whether gobies shifted their social tendencies to live in groups or in pairs following these four extreme disturbances in the northern GBR and following a single extreme disturbance in the southern GBR. Gobies no longer lived in groups, rarely in pairs, and primarily lived as solitary individuals after the four disturbances, whereas there was relatively little change in their social tendencies after the single disturbance. This study suggests that if consecutive disturbances become the norm, gobies may continue to decline if they primarily stay solitary as they need to live in pairs to breed. I then completed another study to investigate how predation risk, coral size and health, and number of group members affected the movement of gobies. I translocated gobies in situ into corals with varying sizes, number of individuals, and health. I replicated the study in a relatively undisturbed environment in Papua New Guinea, and in the highly disturbed environment following the four extreme disturbances in northern GBR. Regardless of the disturbance state, gobies preferred to face high costs of predation and did alter their movement based on coral size, health, or number of group members, even when predation risk was higher in disturbed environments. This suggests that gobies do not alter their movement plasticity based on environmental disturbances even though predation risk is heightened. This means that gobies exhibited host and social plasticity, but they did not exhibit movement plasticity to disturbances. I found that each mechanism of plasticity was likely responsible for a reduced recovery potential of gobies compared to their coral hosts. By combining the findings from each chapter of the thesis, I suggest that coral-fish mutualisms are highly vulnerable to climate change as fish experience barriers to recovery via host, social, and movement plasticity. Future conservation strategies should address declines in fish in order to maintain coral-fish mutualisms important for coral health

    KYT2022 Finnish Research Programme on Nuclear Waste Management 2019–2022 : Final Report

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    KYT2022 (Finnish Research Programme on Nuclear Waste Management 2019–2022), organised by the Ministry of Economic Affairs and Employment, was a national research programme with the objective to ensure that the authorities have sufficient levels of nuclear expertise and preparedness that are needed for safety of nuclear waste management. The starting point for public research programs on nuclear safety is that they create the conditions for maintaining the knowledge required for the continued safe and economic use of nuclear energy, developing new know-how and participating in international collaboration. The content of the KYT2022 research programme was composed of nationally important research topics, which are the safety, feasibility and acceptability of nuclear waste management. KYT2022 research programme also functioned as a discussion and information-sharing forum for the authorities, those responsible for nuclear waste management and the research organizations, which helped to make use of the limited research resources. The programme aimed to develop national research infrastructure, ensure the continuing availability of expertise, produce high-level scientific research and increase general knowledge of nuclear waste management

    Making friends with failure in STS

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    Intelligent computing : the latest advances, challenges and future

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    Computing is a critical driving force in the development of human civilization. In recent years, we have witnessed the emergence of intelligent computing, a new computing paradigm that is reshaping traditional computing and promoting digital revolution in the era of big data, artificial intelligence and internet-of-things with new computing theories, architectures, methods, systems, and applications. Intelligent computing has greatly broadened the scope of computing, extending it from traditional computing on data to increasingly diverse computing paradigms such as perceptual intelligence, cognitive intelligence, autonomous intelligence, and human computer fusion intelligence. Intelligence and computing have undergone paths of different evolution and development for a long time but have become increasingly intertwined in recent years: intelligent computing is not only intelligence-oriented but also intelligence-driven. Such cross-fertilization has prompted the emergence and rapid advancement of intelligent computing

    A Framework for Size-dependent Structural Analysis of Smart Micro/nanoplates

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    This age has witnessed a proliferation of technological advancements that affected all facets of civilisation. Driven by the joint force of the evolution of sophisticated design tools, tailored material characteristics, and robust mechanics-based analyses, smart composite materials are widely used in high-performance engineering applications. Meanwhile, there is a growing interest in micro/nanoscopic structures in academia and industry due to the overwhelming trend toward portability, miniaturisation and integration in engineering. Therefore, the theoretical, computational, and experimental research communities have developed various effective methodologies to understand the structural behaviour of smart small-scale structures comprehensively. This dissertation introduces two size-dependent continuum theories, modified strain gradient and nonlocal strain gradient theories, to build the analytical framework for exploring application-driven micro/nanoplates made of smart composite materials. As examples of promising candidates for power supply and nano/microelectromechanical systems, organic solar cells and thermo-magneto-elastic sandwich nanoplates are studied. Size-dependent continuum models combined with various shear deformation plate theories are adopted to derive the governing equations. The size-sensitive static and dynamic mechanical responses, including bending, buckling, and free vibration behaviours of these ultra-fine-size structures, are predicted by capturing the size effect with material length scale or nonlocal parameters. The numerical results underlying size-dependent theories pose a new insight into the structural analysis of functional micro/nanoscopic plate-like structures. Some typical size-involving mechanical characteristics are revealed by comparing the present estimation with those from size-independent models. Moreover, the simulation outcomes thoroughly investigate several practical factors, such as boundary conditions, geometric configuration, and elastic foundation modelling parameters. In this endeavour, taking advantage of the computational efficiency and accessible operation of nonclassical continuum-based theories, the current analytical framework is suitable for exploring the size-tendency of the smart micro-/nanosized structures. The present work may serve as a benchmark for following numerical simulations and as a guide for evolving new engineering tools for modelling relevant responses by designers and manufacturers

    Efficient finite element methods for solving high-frequency time-harmonic acoustic wave problems in heterogeneous media

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    This thesis focuses on the efficient numerical solution of frequency-domain wave propagation problems using finite element methods. In the first part of the manuscript, the development of domain decomposition methods is addressed, with the aim of overcoming the limitations of state-of-the art direct and iterative solvers. To this end, a non-overlapping substructured domain decomposition method with high-order absorbing conditions used as transmission conditions (HABC DDM) is first extended to deal with cross-points, where more than two subdomains meet. The handling of cross-points is a well-known issue for non-overlapping HABC DDMs. Our methodology proposes an efficient solution for lattice-type domain partitions, where the domains meet at right angles. The method is based on the introduction of suitable relations and additional transmission variables at the cross-points, and its effectiveness is demonstrated on several test cases. A similar non-overlapping substructured DDM is then proposed with Perfectly Matched Layers instead of HABCs used as transmission conditions (PML DDM). The proposed approach naturally considers cross-points for two-dimensional checkerboard domain partitions through Lagrange multipliers used for the weak coupling between subproblems defined on rectangular subdomains and the surrounding PMLs. Two discretizations for the Lagrange multipliers and several stabilization strategies are proposed and compared. The performance of the HABC and PML DDM is then compared on test cases of increasing complexity, from two-dimensional wave scattering in homogeneous media to three-dimensional wave propagation in highly heterogeneous media. While the theoretical developments are carried out for the scalar Helmholtz equation for acoustic wave propagation, the extension to elastic wave problems is also considered, highlighting the potential for further generalizations to other physical contexts. The second part of the manuscript is devoted to the presentation of the computational tools developed during the thesis and which were used to produce all the numerical results: GmshFEM, a new C++ finite element library based on the application programming interface of the open-source finite element mesh generator Gmsh; and GmshDDM, a distributed domain decomposition library based on GmshFEM.Cette thèse porte sur la résolution numérique efficace de problèmes de propagation d'ondes dans le domaine fréquentiel avec la méthode des éléments finis. Dans la première partie du manuscrit, le développement de méthodes de décomposition de domaine est abordé, dans le but de surmonter les limitations des solveurs directs et itératifs de l'état de l'art. À cette fin, une méthode de décomposition de domaine sous-structurée sans recouvrement avec des conditions absorbante d'ordre élevé utilisées comme conditions de transmission (HABC DDM) est d'abord étendue pour traiter les points de jonction, où plus de deux sous-domaines se rencontrent. Le traitement des points de jonction est un problème bien connu pour les HABC DDM sans recouvrement. La méthodologie proposée mène à une solution efficace pour les partitions en damier, où les domaines se rencontrent à angle droit. La méthode est basée sur l'introduction de variables de transmission supplémentaires aux points de jonction, et son efficacité est démontrée sur plusieurs cas-tests. Une DDM sans recouvrement similaire est ensuite proposée avec des couches parfaitement adaptées au lieu des HABC (DDM PML). L'approche proposée prend naturellement en compte les points de jonction des partitions de domaine en damier par le biais de multiplicateurs de Lagrange couplant les sous-domaines et les couches PML adjacentes. Deux discrétisations pour les multiplicateurs de Lagrange et plusieurs stratégies de stabilisation sont proposées et comparées. Les performances des DDM HABC et PML sont ensuite comparées sur des cas-tests de complexité croissante, allant de la diffraction d'ondes dans des milieux homogènes bidimensionnelles à la propagation d'ondes tridimensionnelles dans des milieux hautement hétérogènes. Alors que les développements théoriques sont effectués pour l'équation scalaire de Helmholtz pour la simulation d'ondes acoustiques, l'extension aux problèmes d'ondes élastiques est également considérée, mettant en évidence le potentiel de généralisation des méthodes développées à d'autres contextes physiques. La deuxième partie du manuscrit est consacrée à la présentation des outils de calcul développés au cours de la thèse et qui ont été utilisés pour produire tous les résultats numériques : GmshFEM, une nouvelle bibliothèque d'éléments finis C++ basée sur le générateur de maillage open-source Gmsh ; et GmshDDM, une bibliothèque de décomposition de domaine distribuée basée sur GmshFEM

    Stabilization of Recurrent Fuzzy Systems via Sum of Squares-based Hybrid Control

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    This paper presents an approach for stabilization of equilibria in recurrent fuzzy systems. This type of dynamic fuzzy systems being defined via linguistic rules can be interpreted as interpolation between constant gradients, and therefore as hybrid dynamical system. It is shown that the latter viewpoint allows for a precise description of the system dynamics, but on the other hand lacks transparency. In order to render a given equilibrium of the recurrent fuzzy system globally asymptotically stable, local polynomial controllers are computed via sum of squares optimization to allow only for deterministic mode transitions on a micro level. In addition, the controlled recurrent fuzzy system can then be interpreted as finite deterministic automaton, thus allowing for analysis of system properties on a more abstract macro level. Relaxations are proposed in cases where recurrent fuzzy systems may not be rendered deterministic and the method is applied to two examples
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