11,443 research outputs found

    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

    Passive Radio Frequency-based 3D Indoor Positioning System via Ensemble Learning

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    Passive radio frequency (PRF)-based indoor positioning systems (IPS) have attracted researchers' attention due to their low price, easy and customizable configuration, and non-invasive design. This paper proposes a PRF-based three-dimensional (3D) indoor positioning system (PIPS), which is able to use signals of opportunity (SoOP) for positioning and also capture a scenario signature. PIPS passively monitors SoOPs containing scenario signatures through a single receiver. Moreover, PIPS leverages the Dynamic Data Driven Applications System (DDDAS) framework to devise and customize the sampling frequency, enabling the system to use the most impacted frequency band as the rated frequency band. Various regression methods within three ensemble learning strategies are used to train and predict the receiver position. The PRF spectrum of 60 positions is collected in the experimental scenario, and three criteria are applied to evaluate the performance of PIPS. Experimental results show that the proposed PIPS possesses the advantages of high accuracy, configurability, and robustness.Comment: DDDAS 202

    High-Dimensional Private Empirical Risk Minimization by Greedy Coordinate Descent

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    In this paper, we study differentially private empirical risk minimization (DP-ERM). It has been shown that the worst-case utility of DP-ERM reduces polynomially as the dimension increases. This is a major obstacle to privately learning large machine learning models. In high dimension, it is common for some model's parameters to carry more information than others. To exploit this, we propose a differentially private greedy coordinate descent (DP-GCD) algorithm. At each iteration, DP-GCD privately performs a coordinate-wise gradient step along the gradients' (approximately) greatest entry. We show theoretically that DP-GCD can achieve a logarithmic dependence on the dimension for a wide range of problems by naturally exploiting their structural properties (such as quasi-sparse solutions). We illustrate this behavior numerically, both on synthetic and real datasets

    Learning disentangled speech representations

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    A variety of informational factors are contained within the speech signal and a single short recording of speech reveals much more than the spoken words. The best method to extract and represent informational factors from the speech signal ultimately depends on which informational factors are desired and how they will be used. In addition, sometimes methods will capture more than one informational factor at the same time such as speaker identity, spoken content, and speaker prosody. The goal of this dissertation is to explore different ways to deconstruct the speech signal into abstract representations that can be learned and later reused in various speech technology tasks. This task of deconstructing, also known as disentanglement, is a form of distributed representation learning. As a general approach to disentanglement, there are some guiding principles that elaborate what a learned representation should contain as well as how it should function. In particular, learned representations should contain all of the requisite information in a more compact manner, be interpretable, remove nuisance factors of irrelevant information, be useful in downstream tasks, and independent of the task at hand. The learned representations should also be able to answer counter-factual questions. In some cases, learned speech representations can be re-assembled in different ways according to the requirements of downstream applications. For example, in a voice conversion task, the speech content is retained while the speaker identity is changed. And in a content-privacy task, some targeted content may be concealed without affecting how surrounding words sound. While there is no single-best method to disentangle all types of factors, some end-to-end approaches demonstrate a promising degree of generalization to diverse speech tasks. This thesis explores a variety of use-cases for disentangled representations including phone recognition, speaker diarization, linguistic code-switching, voice conversion, and content-based privacy masking. Speech representations can also be utilised for automatically assessing the quality and authenticity of speech, such as automatic MOS ratings or detecting deep fakes. The meaning of the term "disentanglement" is not well defined in previous work, and it has acquired several meanings depending on the domain (e.g. image vs. speech). Sometimes the term "disentanglement" is used interchangeably with the term "factorization". This thesis proposes that disentanglement of speech is distinct, and offers a viewpoint of disentanglement that can be considered both theoretically and practically

    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

    Monitoring genotypic and phenotypic progression of systemic melanoma by cell lineage tree analysis and for molecular disease staging

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    A recent study on metastatic seeding in melanomas showed that lymphatic dissemination occurs very early. Disseminated cancer cells (DCCs) of melanoma patients can leave the primary tumor (PT) in a genomically immature state, then evolve within the lymph nodes (LNs) and adapt to the ectopic site until they start to proliferate and form metastasis. Since the PT and the metastasis are often genetically disparate, the focus for treating metastases should be on the DCCs. The molecular characterization of the DCCs that left the PT at an early stage could reveal new therapeutic targets against metastasis. After routine LN removal in melanoma patients, staining of LNs against the tumour marker MCSP identified two different phenotypes: small MCSP-positive and large MCSP-positive DCCs. While the small phenotype appears mostly in LNs with a low DCCD (DCC-density; number of DCCs per million mononuclear cells), the large phenotype could be found in LNs with a higher DCCD. Furthermore, we also observed LNs with both small and large DCCs, that had a medium DCCD. Based on these findings we hypothesized that small MCSP-DCCs are precursors of large MCSP-DCCs and represent very early DCCs. In addition, we wanted to have a closer look at the two most common BRAF mutations in malignant melanoma and its association with the DCCD of the LNs. We hypothesized that acquisition of BRAF mutations marks the transition from pre-colonizing DCCs to colonizing DCCs and hence a significant progression step in systemic cancer development. The hypothesis if small MCSP-positive DCCs are the precursors of large MCSP-positive DCCs should be investigated with the help of a cell lineage tree reconstruction based on short tandem repeats (STRs). To study the incidence of the BRAF mutations we established an allele-specific PCR with a blocking reagent (ASB-PCR) for DCCs. The cell lineage tree reconstruction of patient MM15-127 resulted in three distinct clusters of DCCs. Two of the clusters were found in close proximity to the PT, while one DCC cluster was closer to the metastatic tumour cells than the PT. Both small and large MCSP-positive DCCs were found in the two clusters close to the PT. The cluster closer to the metastatic tumour cells only contained large MCSP-positive DCCs. Retrospective testing of 80 DCCs with the established ASB-PCR resulted in the correct identification of wild type and mutant DCCs in 98% and 96% of the samples, respectively. From patient MM16-423, DCCs were isolated from the sentinel lymph node (SLN) and the non-SLNs and tested for BRAF mutations by the ASB-PCR. While the PT and the DCCs isolated from the SLN at primary diagnosis were wild type, the DCCs isolated from non-SLNs after LN relapse harboured a BRAF mutation. Testing a cohort of 150 malignant melanoma patients for BRAF mutations in DCCs, showed that 19.8% patients with a pathologically negative LN and 59.4% with a pathologically positive LN harboured a mutation. However, studying the incidence of the BRAF mutation depending on the DCCD, we found out that there is a large increase of the BRAF mutation from 14.9% in LNs with a DCCD>1≤10 to 62.5% in LNs with a DCCD>10≤30. Based on the result of the cell lineage tree reconstruction of patient MM15-127 our hypothesis that small MCSP-positive DCCs are the precursors of large MCSP-positive DCCs could neither be confirmed nor rejected. The resolution of the cell lineage tree is no yet good enough 8 to provide such accurate insights. However, three distinct clusters of DCCs were identified which could be an indication that DCCs disseminated at different time points. The ASB-PCR of DCCs from patient MM16-423 showed that BRAF mutations were acquired outside of the PT at a later time point of disease progression, when metastases were detected in the non-SLN. However, 62.5% of patients with a DCCD>10≤30 harboured a BRAF mutation, indicating that the BRAF mutation could be acquired early before colonisation of the DCCs
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