4,366 research outputs found

    Endogenous measures for contextualising large-scale social phenomena: a corpus-based method for mediated public discourse

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    This work presents an interdisciplinary methodology for developing endogenous measures of group membership through analysis of pervasive linguistic patterns in public discourse. Focusing on political discourse, this work critiques the conventional approach to the study of political participation, which is premised on decontextualised, exogenous measures to characterise groups. Considering the theoretical and empirical weaknesses of decontextualised approaches to large-scale social phenomena, this work suggests that contextualisation using endogenous measures might provide a complementary perspective to mitigate such weaknesses. This work develops a sociomaterial perspective on political participation in mediated discourse as affiliatory action performed through language. While the affiliatory function of language is often performed consciously (such as statements of identity), this work is concerned with unconscious features (such as patterns in lexis and grammar). This work argues that pervasive patterns in such features that emerge through socialisation are resistant to change and manipulation, and thus might serve as endogenous measures of sociopolitical contexts, and thus of groups. In terms of method, the work takes a corpus-based approach to the analysis of data from the Twitter messaging service whereby patterns in users’ speech are examined statistically in order to trace potential community membership. The method is applied in the US state of Michigan during the second half of 2018—6 November having been the date of midterm (i.e. non-Presidential) elections in the United States. The corpus is assembled from the original posts of 5,889 users, who are nominally geolocalised to 417 municipalities. These users are clustered according to pervasive language features. Comparing the linguistic clusters according to the municipalities they represent finds that there are regular sociodemographic differentials across clusters. This is understood as an indication of social structure, suggesting that endogenous measures derived from pervasive patterns in language may indeed offer a complementary, contextualised perspective on large-scale social phenomena

    OLIG2 neural progenitor cell development and fate in Down syndrome

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    Down syndrome (DS) is caused by triplication of human chromosome 21 (HSA21) and is the most common genetic form of intellectual disability. It is unknown precisely how triplication of HSA21 results in the intellectual disability, but it is thought that the global transcriptional dysregulation caused by trisomy 21 perturbs multiple aspects of neurodevelopment that cumulatively contribute to its etiology. While the characteristics associated with DS can arise from any of the genes triplicated on HSA21, in this work we focus on oligodendrocyte transcription factor 2 (OLIG2). The progeny of neural progenitor cells (NPCs) expressing OLIG2 are likely to be involved in many of the cellular changes underlying the intellectual disability in DS. To explore the fate of OLIG2+ neural progenitors, we took advantage of two distinct models of DS, the Ts65Dn mouse model and induced pluripotent stem cells (iPSCs) derived from individuals with DS. Our results from these two systems identified multiple perturbations in development in the cellular progeny of OLIG2+ NPCs. In Ts65Dn, we identified alterations in neurons and glia derived from the OLIG2 expressing progenitor domain in the ventral spinal cord. There were significant differences in the number of motor neurons and interneurons present in the trisomic lumbar spinal cord depending on age of the animal pointing both to a neurodevelopment and a neurodegeneration phenotype in the Ts65Dn mice. Of particular note, we identified changes in oligodendrocyte (OL) maturation in the trisomic mice that are dependent on spatial location and developmental origin. In the dorsal corticospinal tract, there were significantly fewer mature OLs in the trisomic mice, and in the lateral funiculus we observed the opposite phenotype with more mature OLs being present in the trisomic animals. We then transitioned our studies into iPSCs where we were able to pattern OLIG2+ NPCs to either a spinal cord-like or a brain-like identity and study the OL lineage that differentiated from each progenitor pool. Similar to the region-specific dysregulation found in the Ts65Dn spinal cord, we identified perturbations in trisomic OLs that were dependent on whether the NPCs had been patterned to a brain-like or spinal cord-like fate. In the spinal cord-like NPCs, there was no difference in the proportion of cells expressing either OLIG2 or NKX2.2, the two transcription factors whose co-expression is essential for OL differentiation. Conversely, in the brain-like NPCs, there was a significant increase in OLIG2+ cells in the trisomic culture and a decrease in NKX2.2 mRNA expression. We identified a sonic hedgehog (SHH) signaling based mechanism underlying these changes in OLIG2 and NKX2.2 expression in the brain-like NPCs and normalized the proportion of trisomic cells expressing the transcription factors to euploid levels by modulating the activity of the SHH pathway. Finally, we continued the differentiation of the brain-like and spinal cord-like NPCs to committed OL precursor cells (OPCs) and allowed them to mature. We identified an increase in OPC production in the spinal cord-like trisomic culture which was not present in the brain-like OPCs. Conversely, we identified a maturation deficit in the brain-like trisomic OLs that was not present in the spinal cord-like OPCs. These results underscore the importance of regional patterning in characterizing changes in cell differentiation and fate in DS. Together, the findings presented in this work contribute to the understanding of the cellular and molecular etiology of the intellectual disability in DS and in particular the contribution of cells differentiated from OLIG2+ progenitors

    A direct-laser-written heart-on-a-chip platform for generation and stimulation of engineered heart tissues

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    In this dissertation, we first develop a versatile microfluidic heart-on-a-chip model to generate 3D-engineered human cardiac microtissues in highly-controlled microenvironments. The platform, which is enabled by direct laser writing (DLW), has tailor-made attachment sites for cardiac microtissues and comes with integrated strain actuators and force sensors. Application of external pressure waves to the platform results in controllable time-dependent forces on the microtissues. Conversely, oscillatory forces generated by the microtissues are transduced into measurable electrical outputs. After characterization of the responsivity of the transducers, we demonstrate the capabilities of this platform by studying the response of cardiac microtissues to prescribed mechanical loading and pacing. Next, we tune the geometry and mechanical properties of the platform to enable parametric studies on engineered heart tissues. We explore two geometries: a rectangular seeding well with two attachment sites, and a stadium-like seeding well with six attachment sites. The attachment sites are placed symmetrically in the longitudinal direction. The former geometry promotes uniaxial contraction of the tissues; the latter additionally induces diagonal fiber alignment. We systematically increase the length for both configurations and observe a positive correlation between fiber alignment at the center of the microtissues and tissue length. However, progressive thinning and “necking” is also observed, leading to the failure of longer tissues over time. We use the DLW technique to improve the platform, softening the mechanical environment and optimizing the attachment sites for generation of stable microtissues at each length and geometry. Furthermore, electrical pacing is incorporated into the platform to evaluate the functional dynamics of stable microtissues over the entire range of physiological heart rates. Here, we typically observe a decrease in active force and contraction duration as a function of frequency. Lastly, we use a more traditional ?TUG platform to demonstrate the effects of subthreshold electrical pacing on the rhythm of the spontaneously contracting cardiac microtissues. Here, we observe periodic M:N patterns, in which there are ? cycles of stimulation for every ? tissue contractions. Using electric field amplitude, pacing frequency, and homeostatic beating frequencies of the tissues, we provide an empirical map for predicting the emergence of these rhythms

    Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico

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    Valve replacement remains as the standard therapeutic option for aortic stenosis patients, aiming at abolishing pressure overload and triggering myocardial reverse remodeling. However, despite the instant hemodynamic benefit, not all patients show complete regression of myocardial hypertrophy, being at higher risk for adverse outcomes, such as heart failure. The current comprehension of the biological mechanisms underlying an incomplete reverse remodeling is far from complete. Furthermore, definitive prognostic tools and ancillary therapies to improve the outcome of the patients undergoing valve replacement are missing. To help abridge these gaps, a combined myocardial (phospho)proteomics and pericardial fluid proteomics approach was followed, taking advantage of human biopsies and pericardial fluid collected during surgery and whose origin anticipated a wealth of molecular information contained therein. From over 1800 and 750 proteins identified, respectively, in the myocardium and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated proteins were detected. Gene annotation and pathway enrichment analyses, together with discriminant analysis, are compatible with a scenario of increased pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by complement activity and other extrinsic factors, such as death receptor activators), acute-phase response, immune system activation and fibrosis. Specific validation of some targets through immunoblot techniques and correlation with clinical data pointed to complement C3 β chain, Muscle Ring Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation regulated kinase 1A (DYRK1A) as potential markers of an incomplete response. In addition, kinase prediction from phosphoproteome data suggests that the modulation of casein kinase 2, the family of IκB kinases, glycogen synthase kinase 3 and DYRK1A may help improve the outcome of patients undergoing valve replacement. Particularly, functional studies with DYRK1A+/- cardiomyocytes show that this kinase may be an important target to treat cardiac dysfunction, provided that mutant cells presented a different response to stretch and reduced ability to develop force (active tension). This study opens many avenues in post-aortic valve replacement reverse remodeling research. In the future, gain-of-function and/or loss-of-function studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic targets. Besides, clinical studies in larger cohorts will bring definitive proof of complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de referência para doentes com estenose aórtica e visa a eliminação da sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica. Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes apresentam regressão completa da hipertrofia do miocárdio, ficando com maior risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os mecanismos biológicos subjacentes a uma remodelagem reversa incompleta ainda não são claros. Além disso, não dispomos de ferramentas de prognóstico definitivos nem de terapias auxiliares para melhorar a condição dos pacientes indicados para substituição da válvula. Para ajudar a resolver estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica para a caracterização, respetivamente, do miocárdio e do líquido pericárdico foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em ambiente cirúrgico. Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90 proteínas desreguladas foram detetadas. As análises de anotação de genes, de enriquecimento de vias celulares e discriminativa corroboram um cenário de aumento da expressão de genes pro-hipertróficos e de síntese proteica, um sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular (potencialmente acelerada pela atividade do complemento e por outros fatores extrínsecos que ativam death receptors), com ativação da resposta de fase aguda e do sistema imune, assim como da fibrose. A validação de alguns alvos específicos através de immunoblot e correlação com dados clínicos apontou para a cadeia β do complemento C3, a Muscle Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma, sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição dos pacientes indicados para intervenção. Em particular, a avaliação funcional de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes responderam de forma diferente ao estiramento e mostraram uma menor capacidade para desenvolver força (tensão ativa). Este estudo levanta várias hipóteses na investigação da remodelagem reversa. No futuro, estudos de ganho e/ou perda de função realizados em cardiomiócitos isolados ou em modelos animais de banding-debanding da aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos encontrados. Além disso, estudos clínicos em coortes de maior dimensão trarão conclusões definitivas quanto ao valor de prognóstico do complemento C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin

    How to Be a God

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    When it comes to questions concerning the nature of Reality, Philosophers and Theologians have the answers. Philosophers have the answers that can’t be proven right. Theologians have the answers that can’t be proven wrong. Today’s designers of Massively-Multiplayer Online Role-Playing Games create realities for a living. They can’t spend centuries mulling over the issues: they have to face them head-on. Their practical experiences can indicate which theoretical proposals actually work in practice. That’s today’s designers. Tomorrow’s will have a whole new set of questions to answer. The designers of virtual worlds are the literal gods of those realities. Suppose Artificial Intelligence comes through and allows us to create non-player characters as smart as us. What are our responsibilities as gods? How should we, as gods, conduct ourselves? How should we be gods

    Industry 4.0: product digital twins for remanufacturing decision-making

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    Currently there is a desire to reduce natural resource consumption and expand circular business principles whilst Industry 4.0 (I4.0) is regarded as the evolutionary and potentially disruptive movement of technology, automation, digitalisation, and data manipulation into the industrial sector. The remanufacturing industry is recognised as being vital to the circular economy (CE) as it extends the in-use life of products, but its synergy with I4.0 has had little attention thus far. This thesis documents the first investigating into I4.0 in remanufacturing for a CE contributing a design and demonstration of a model that optimises remanufacturing planning using data from different instances in a product’s life cycle. The initial aim of this work was to identify the I4.0 technology that would enhance the stability in remanufacturing with a view to reducing resource consumption. As the project progressed it narrowed to focus on the development of a product digital twin (DT) model to support data-driven decision making for operations planning. The model’s architecture was derived using a bottom-up approach where requirements were extracted from the identified complications in production planning and control that differentiate remanufacturing from manufacturing. Simultaneously, the benefits of enabling visibility of an asset’s through-life health were obtained using a DT as the modus operandi. A product simulator and DT prototype was designed to use Internet of Things (IoT) components, a neural network for remaining life estimations and a search algorithm for operational planning optimisation. The DT was iteratively developed using case studies to validate and examine the real opportunities that exist in deploying a business model that harnesses, and commodifies, early life product data for end-of-life processing optimisation. Findings suggest that using intelligent programming networks and algorithms, a DT can enhance decision-making if it has visibility of the product and access to reliable remanufacturing process information, whilst existing IoT components provide rudimentary “smart” capabilities, but their integration is complex, and the durability of the systems over extended product life cycles needs to be further explored

    Image-Based Rendering Of Real Environments For Virtual Reality

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    ‘We the People: Supporting Food SMEs towards a Circular Food Economy’

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    This single Case Study locates SME (small and medium-size enterprise) hospitality and food services (HaFS) within a complex food waste system. It examines collaborative support for business change from linear resource wastage (‘take, use, dump), towards a circular food economy (CfE)- where ‘designing out’ food waste may reap savings. The objective is to support SME uptake of waste aversion practices so that they may thrive. The qualitative research centers on a London-based project promoting food waste valorization and healthy nutrition, in 15 boroughs. That project’s outreach for broad-based, collective impact included HaFS that are SMEs. Cross-sector liaison was the research focus for this Case Study which utilizes a hybrid philosophy and meta-framework, based on Critical Realism and Systemic Thinking. Some reference to Interpretivism highlights stewardship values for transforming individual behaviour. The Study also uses a multi-method design, borrowing soft systems from Management Science and Operational Research. Its blended approach includes: participant observation, mapping and rich picture techniques, semi-structured interviews and focus groups. The main research questions align concepts such as: circular economy, cross-sector collaboration and food waste management- with HaFS that are SMEs. A framework method and Leximancer software supported coding and qualitative thematic analysis. Primary findings include interesting categories of analytical, NGO and policy literature. Although conversations flagged up pivotal roles for our health and education sectors, the food SME element still seems peripheral in this transition to regenerative business. A ‘people vibe’ is enabling some HaFS’ kitchen waste action and food redistribution and, academia is a potential contributor to this information resource flow among stakeholders. The Study’s unique onto-epistemological framework enhances philosophical and theoretical knowledge about promoting SME resource stewardship. It spans Systemic Thinking (overt connections and acute complexities) and Critical Realism (deep mechanisms and institutional power differentials, impacting change). As an interpretive lens, the framework’s contribution to praxis was tested by shadowing the London TRiFOCAL project. This research could inform a business policy shift from traditional supply chain thinking, towards active UK food citizenship

    Analysis of chromatin accessibility to characterize transcription factor activities in malignancies

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    In the context of the study of human disorders, exploring the chromatin accessibility applying the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) in combination with the study of certain histone markers via chromatin-immunoprecipita-tion followed by sequencing (ChIP-seq) has proven to be a robust approach. It allows to unravel essential transcriptional regulatory circuitry, as well as to identify genes or genetic pathways, not necessarily presenting mutations, but relevant for any aspect of the disorder, from disease progression to relapse, or even the appearance of therapy resistance. In the course of this work, three different human disorders were investigated. Our main objective was the study of Acute Myeloid Leukemia (AML), for which both experiments, ATAC-seq and ChIP-seq of the acetylation of lysine 27 of histone H3 (H3K27ac - a marker for active enhancers and super-enhancers) were performed. AML is a hematopoietic malignancy characterized by a broad genetic heterogeneity and the frequent occurrence of relapses, which compromises patient survival. In collaboration with other research groups, we additionally explored on the one hand, the mechanisms involved in the emergence of human breast cancer metastasis, and on the other hand, the response of the immune system in the context of severe autoimmune diseases using a mouse model commonly employed in the investigation of human multiple sclerosis. To deeply cover all relevant aspects of the AML disease concerning our main goal, I studied AML cell lines as in vitro model, an AML patient-derived xenograft (PDX) mouse model as in vivo model and, most importantly, paired patient-derived samples at the stages of primary diagnosis and relapse. The analysis of patient samples was of great interest to capture the nature of the disorder in its whole complexity, free of the limitations intrinsic to the two aforementioned models. The epigenetic landscape in terms of chromatin accessibility and enhancers was characterized based on 18 leukemic cell lines. They exhibited, as expected, a vast heterogeneity, setting the basis for an in vitro model to work with and validate hypothesis derived from the study of human samples. To explore the effects caused by the standard therapy over time in vivo we used PDX samples. Xenografted mice were subjected to several cycles of therapy. The derived samples were processed at three different time points to analyze the development of chromatin accessibility. Our experiments showed that at the beginning of the treatment chromatin changes barely occurred but as the therapy progressed, the effects accumulated, causing chromatin to significantly open up. The exploration and analysis performed on paired patient-derived samples clearly revealed a larger similarity with regard to the epigenetic landscape for the relapse stage among all patients analyzed. Especially apoptotic-related pathways, although primarily nonexistent in diagnosis, appeared to be commonly active in relapse. Nevertheless, due to the heterogeneity characterizing this disorder, no common pathways or genes could be identified for the whole patient cohort. Notably, for a patient subgroup, we could determine a bunch of relapse-associated relevant genes, some of which have been recently documented in the literature as playing an important role in the disease progression and even in therapy resistance, thus validating our approach.Im Rahmen der Erforschung menschlicher Erkrankungen, die Untersuchung der Zugänglichkeit des Chromatins mittels der Assay for Transposase Accessible Chromatin gefolgt von Sequenzierung (ATAC-seq) kombiniert mit der Untersuchung bestimmte Histonmodifikationen durch Chromatin Immunoprecipitation gefolgt von Sequenzierung (ChIP-seq) hat sich als robuster Ansatz erwiesen. Diese Strategie ermöglicht sowohl wesentliche transkriptionelle Regulationsschaltkreise als auch Gene oder genetische Pfade zu identifizieren. Diese weisen nicht unbedingt Mutationen auf, sind aber für manche Aspekte der Erkrankung relevant: von der Krankheitsprogression bis zum Rezidiv oder sogar dem Auftreten von Therapieresistenz. In dieser Arbeit wurden drei verschiedene Erkrankungen untersucht. Unser Hauptziel war dabei die Untersuchung der menschlichen Akuten Myeloischen Leukämie (AML) und dafür führte ich sowohl ATAC-seq als auch ChIP-seq für Acetylierung des Lysins 27 am Histon H3 (H3K27ac - ein Marker für aktive Enhancers und Super-enhancers) durch. AML ist eine hämatopoetische Malignität, die durch eine breite genetische Heterogenität und das häufige Auftreten von Rezidiven gekennzeichnet ist, wodurch das Überleben der Patienten beeinträchtigt wird. In Zusammenarbeit mit anderen Forschungsgruppen haben wir zwei zusätzliche menschliche Erkrankungen untersucht. Zum einen waren es die Mechanismen, die an der Entstehung von Brustkrebsmetastasen beteiligt sind. Zum anderen, die Reaktion des Immunsystems im Kontext schwerer Autoimmunerkrankungen. Dafür wurde ein Mausmodell angewendet, das häufig für die Erforschung menschlichen Multiplen Sklerose benutzt wird. Um alle relevanten Aspekte der AML umfassend abzudecken, untersuchte ich drei verschiedene Modelle: erstens, AML-Zelllinien als in-vitro-Modell; zweitens, ein von AML-Patienten abgeleitetes Xenograft (PDX)-Mausmodell als in vivo-Modell; und drittens, gepaarte Patientenproben in den Stadien der Erstdiagnose und des Rezidives. Die Analyse der Patientenproben war vom großen Interesse um die Natur der Störung in ihrer ganzen Komplexität zu erfassen, frei von den Einschränkungen, die in den zuvor genannten Modellen implizit enthalten sind. Die epigenetische Landschaft bezüglich der Chromatinzugänglichkeit und der Enhancer wurden an 18 Leukemie-Zelllinien charakterisiert. Diese Zelllinien wiesen erwartungsgemäß eine große Heterogenität auf. Das bildete die Grundlage für das in vitro-Modell, mit dem Hypothesen validiert werden können, die aus der Untersuchung menschlicher Proben abgeleitet worden sind. Mithilfe von PDX-Proben wurden die Auswirkungen der Standardtherapie über die Zeit in vivo untersucht. Dafür wurden xenotransplantierte Mäuse mehreren Therapiezyklen unterzogen. Zu bestimmten Zeitpunkten wurden die von Mäusen abgeleiteten Proben verarbeitet, um die Entwicklung der Chromatinzugänglichkeit zu analysieren. Die Ergebnisse der Experimente haben gezeigt, dass zu Beginn der Behandlung kaum Chromatinveränderungen auftraten, sich jedoch im Verlauf der Therapie die Wirkungen akkumulierten, wodurch sich das Chromatin deutlich öffnete. Die Analyse von gepaarten Patientenproben zeigte eine deutliche Ähnlichkeit in Bezug auf die epigenetische Landschaft für das Rezidivstadium bei allen analysierten Patienten. Insbesondere schienen apoptotisch bedingte Signalwege beim Rezidiv häufig aktiv zu sein, obwohl sie in der Diagnose nicht vorhanden waren. Jedoch aufgrund der Heterogenität, die diese Erkrankung charakterisiert, konnten für die gesamte Patientenkohorte keine gemeinsamen Signalwege oder Gene bestimmt werden. Nichtsdestotrotz konnten wir für eine Patientenuntergruppe eine Reihe von rezidivassoziierten relevanten Genen identifizieren, wobei einige von denen vor kurzem in der Literatur als wichtig für die Krankheitsprogression und auch für die Therapieresistenz dokumentiert wurden. Dadurch ist unser Ansatz grundsätzlich validiert

    Exploiting Novel Deep Learning Architecture in Character Animation Pipelines

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    This doctoral dissertation aims to show a body of work proposed for improving different blocks in the character animation pipelines resulting in less manual work and more realistic character animation. To that purpose, we describe a variety of cutting-edge deep learning approaches that have been applied to the field of human motion modelling and character animation. The recent advances in motion capture systems and processing hardware have shifted from physics-based approaches to data-driven approaches that are heavily used in the current game production frameworks. However, despite these significant successes, there are still shortcomings to address. For example, the existing production pipelines contain processing steps such as marker labelling in the motion capture pipeline or annotating motion primitives, which should be done manually. In addition, most of the current approaches for character animation used in game production are limited by the amount of stored animation data resulting in many duplicates and repeated patterns. We present our work in four main chapters. We first present a large dataset of human motion called MoVi. Secondly, we show how machine learning approaches can be used to automate proprocessing data blocks of optical motion capture pipelines. Thirdly, we show how generative models can be used to generate batches of synthetic motion sequences given only weak control signals. Finally, we show how novel generative models can be applied to real-time character control in the game production
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