The master's thesis deals with the restoration of audio signals that have been damaged by clipping. Used methods are based on sparse representations of signals. The introduction of the thesis explains the issue of clipping and mentions the list of already existing methods that solve declipping, which are followed by the thesis. In the next chapter, the necessary theory of sparse representations and the proximal algorithms is described, including specific representatives from the category of convex optimization problems. The thesis contains declipping algorithm implemented in Matlab software environment. Chosen method for solving the task uses the Condat algorithm or Generic proximal algorithm for convex optimization and solves minimization of sum of three convex functions. The result of the thesis is five versions of algorithm and three of them have implemented psychoacoustic model for results improvement. For each version has been found optimal setting of parameters. The restoration quality results are evaluated using objective measurements like SDR and PEMO-Q and also using subjective listening test.

La thérapie génique consiste à introduire du matériel génétique dans des cellules dans l’objectif de traiter une pathologie. Le plus souvent, la thérapie génique s’effectue au moyen d’un vecteur viral, transportant le gène jusque dans les cellules cibles. Dans le cas des maladies monogéniques, l’adeno-associated virus (AAV) s’est imposé progressivement comme un vecteur de choix. Son absence de pathogénicité, son large tropisme et sa capacité à transduire des cellules quiescentes sont autant d’avantages comparés à d’autres vecteurs utilisés en thérapie génique. L’utilisation d’AAV est approuvé en Europe pour le traitement d’un déficit rare en lipoprotéine lipase et vient récemment d’être approuvé par les autorités américaines pour le traitement d’un déficit de la vision. Toutefois, les essais de thérapies géniques se heurtent souvent aux réponses immunitaires dirigées contre l’AAV. En effet, les différents composants de ce vecteur viral ont été identifiés comme pouvant déclencher des réponses immunitaires s’opposant à l’efficacité à long terme de la thérapie génique. De plus, la protéine transgénique peut s’avérer immunogène, ce qui conduit au déclenchement de réponses immunitaires, à la destruction des cellules transduites et in fine à l’échec de la thérapie génique. En clinique, des immunosuppresseurs sont utilisés pour palier à ses effets indésirables. Toutefois, de par leurs effets secondaires infectieux et tumorigènes, des stratégies visant plutôt à induire de la tolérance vis-à-vis de la protéine transgénique, associées à un bénéfice pour la santé des patients, se sont développées.L’objectif de ce travail de thèse a été d’implémenter une nouvelle stratégie visant à étudier l’effet immunorégulateur et tolérogène de protéines de fusion dérivées de CTLA-4/Fc et de PD-L1/Fc. Pour cela, nous avons utilisé un modèle murin récapitulant les réponses immunitaires induites par un AAV permettant l’expression d’une protéine modèle fortement immunogène, l’ovalbumine (Ova). Ensuite, des AAV codant pour les protéines au potentiel immunorégulateur ont été synthétisés et injectés aux souris conjointement à l’AAV-Ova. Cette stratégie d’immunorégulation vectorisée (VIR) nous a permis d’évaluer la capacité de chacune des protéines à moduler les réponses immunitaires dirigées contre l’Ova directement in vivo. Au total, ce travail a permis de mettre en évidence i) l’intérêt et les limites de la stratégie VIR, ii) celui du rôle délétère de CTLA-4/Fc au long terme sur les lymphocytes Tregs CD4+FoxP3+, périphériques et centraux, iii) et de démontrer l’intérêt de 2 nouvelles molécules dérivées PD-L1/Fc sur la persistance de l’Ova. / Gene therapy consist into introducing genetic material into cells to treat genetic disorders. Most gene therapies use viral vectors to carry the gene within target cells. In case of monogenic disorders, adeno-associated viruses (AAV) has become a vector of choice because of its lack of pathogenicity, its large tropism and its capacity to transduce quiescent cells. The use of AAV is approved in Europe to treat a rare lysosomal storage disease and has recently been approved by the FDA to treat a genetic cause of blindness. However, most clinical trials face immune responses directed against AAV components which may be highly immunogenic. This deleterious immunogenicity often lead to the trial failure. In addition, transgenic protein can also be immunogenic, aimaing to the destruction of transduced cells and ultimatly to gene therapy failure. In clinic, immunosuppressive drug remain the only option to counteract unwanted immune responses. These drugs possess infectious and tumorigenic side effects, therefore strategies aiming to rather capable to induce tolerance toward the transgenic protein are being developped and needed. The objectif of this work was to implement a new strategy aiming to study the immunoregulatory and tolerogenic effect of fusion proteins derived from CTLA-4 and PD-L1. We used a murin model recapitulating the immunes responses induced by an AAV coding for an immunogenic model protein, ovalbumin (Ova) presented in previous studies by our group and others. Then, we synthesized AAV coding for our newly designed immunoregulatory protein and injected them into mice along with AAV-Ova. This strategy of vectorized immunoregulation (VIR) allowed to evaluate the intrinsic capacity of each individual proteins to modulate immune responses against Ova directly in vivo. Eventually, this work allow to 1) assess the benefits and limits of the VIR strategy, 2) the deletrious long-term effects of CTLA-4/Fc on central and peripheral Tregs in mice, 3) to demonstrate the interest of new molecules specifically derived from PD-L1/Fc over the immune tolerance through the long-term persistance of Ova transgene.

Eines der prävalentesten humanen Pathogene ist das Magenbakterium Helicobacter pylori, welches ca. die Hälfte der Weltbevölkerung infiziert. Die Persistenz geht mit einer chronischen Gastritis einher, welche bis zu Magenkrebs fortschreiten kann. H.pylori bedient sich diverser Mechanismen um sich der Erkennung des Immunsystems zu entziehen und somit eine chronische Infektion zu ermöglichen. Erhöhte Expression des Immunzellinhibitors PD-L1 wurde in Magenepithelzellen gefunden, welche mit diesem Gram-negativen Erreger infiziert wurden. In dieser Arbeit wurde die Regulation auf in vitro Ebene untersucht, wobei zwei unterschiedliche Mechanismen identifiziert wurden. Ursächlich für die frühe PD-L1-Induktion ist die ADP-heptose/ALPK1 Signalkaskade. Der bakterielle Metabolit ADP-heptose, welcher für die Bildung von LPS benötigt wird, wurde als PAMP identifiziert, welcher durch das Sekretionssystems cagT4SS in die infizierte transportiert und anschließend von der Host Kinase ALPK1 erkannt wird. Gegensätzlich hierzu, wurde festgestellt, dass die zweite PD-L1-Hochregulation auf der metabolischen Reprogrammierung des Wirts beruht. Ein Merkmal von H. pylori ist dessen Bedarf an Cholesterin, welches es aus dem Medium oder aus membranösen Lipidregionen des Wirts extrahiert wird. Es konnte bewiesen werden, dass dieser Sterol-Abbauprozess zu einer erhöhten Stoffwechselaktivität führt, die spezifisch mit einer Zunahme der Glykolyse verbunden ist und mit einer Expressionsverschiebung des ersten Glykolyseenzyms Hexokinase von der Isoform 1 zu 2 einhergeht. Knockdown und Knockout- Experimente wiesen auf einen Zusammenhang mit der Regulation des Immunzellinhibitoren PD-L1 hin. / One of the most prevalent bacteria is the gastric bacterium Helicobacter pylori, which infects half of the world’s population. Persistence is accompanied with chronic gastritis which can progress towards gastric cancer. Several strategies are used by H.pylori to evade the immune system, enabling chronic infection. Heightened expression of the immune cell inhibitor PD-L1 was found in gastric epithelial cells, infected with this Gram-negative pathogen. Within this thesis, upregulation was studied in in vitro models, revealing two distinct mechanism. Causative for early PD-L1 induction is the ADP heptose/ALPK1 signaling axis. The bacterial metabolite ADP heptose, which is needed for LPS synthesis, was identified as PAMP, which is transported through the secretion system cagT4SS into the infected cell and is recognized by the host kinase ALPK1. In contrast, late upregulation of PD-L1 was found to be linked to metabolic reprogramming upon infection. Characteristic to H.pylori is its need of cholesterol, which it has to extract from the surrounding medium or lipid-rich regions within the host membrane. It could be shown that this sterol extraction process is accompanied with an increased metabolic activity which is linked with enhanced glycolysis and an expression shift of the glycolytic enzyme hexokinase isoform 1 to 2. Knockdown and knockout experiments showed a link between HK2 and regulation of the immune checkpoint PD-L1.

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[pt] A presente dissertação aborda a escrita bilíngue – Português como L1 e Inglês como L2, a partir de uma perspectiva cognitiva, com vistas a buscar caracterizar, de forma integrada, o processo e o produto da escrita, e possíveis correlações entre desempenho em escrita e aspectos atencionais. Participam da pesquisa 15 professores de língua inglesa (10 mulheres e 5 homens), idade média de 43,5 anos (DP 13,25), nativos do Português brasileiro. No estudo, foram empregadas ferramentas computacionais que possibilitam o registro das ações de escrita no curso da produção textual de textos argumentativos (programa Inputlog), a análise automática de características linguísticas do texto final (Nilc-Metrix (L1) e Coh-Metrix (L2) e a verificação de padrões de conectividade no texto final, por meio de atributos de grafos (SpeechGraphs). Adotou-se também o teste ANT - Attention Network Test com o intuito de ampliar a reflexão a respeito de fatores cognitivos e possíveis influências na produção textual. Na análise do processo de escrita, foram examinados tanto padrões de pausa como operações de escrita ativa e ações de revisão (inserções e apagamentos). Na análise do produto, consideraram-se parâmetros ligados a aspectos vocabulares, semânticos, sintáticos e índices de legibilidade, e informações sobre recorrência lexical e conectividade entre palavras. No que tange ao processo, os resultados do estudo revelaram diferenças entre as duas línguas, com valores mais altos associados à escrita em Inglês, para (i) pausas no interior de palavras - possivelmente sinalizando uma demanda de ordem ortográfica - e (ii) percentual de escrita ininterrupta, indicando uma escrita com menos interrupções, com menor número de alterações/revisões. O estudo de correlação revelou que os participantes apresentam o mesmo perfil de escrita na L1 e na L2. Na análise do produto por meio do Coh-Metrix (Inglês) e Nilc-Metrix (Português), verificou-se, por meio de índice de legibilidade, que os textos apresentam complexidade moderada nas duas línguas. A despeito de diferenças em como as métricas são definidas em cada Programa, os resultados sugerem que os textos em Português apresentam graus de complexidade que se correlacionam com aspectos sintáticos (como número de palavras antes do verbo principal e índice de Flesch) e semânticos (grau de concretude). Na L2, destaca-se que a diversidade lexical permanece sendo um dos indicadores mais confiáveis de proficiência e graus de complexidade, correlacionando-se com comportamentos de pausas (antes de palavras) e revisão (normal production). Em relação ao SpeechGraphs, foram observadas diferenças significativas entre os textos na L1 e na L2 para quase todos os atributos de grafos analisados, o que é interpretado como um reflexo da forma como o programa lida com características morfológicas das duas línguas. Não foram observadas correlações entre o comportamento dos falantes na L1 e na L2. Foram ainda conduzidos estudos de correlação entre os dados do Inputlog e os das ferramentas Coh-Metrix e Nilc-Metrix e entre estas e os dados do SpeechGraphs. Nos dois estudos, observou-se uma correspondência entre parâmetros indicativos de complexidade das ferramentas utilizadas, sugerindo um caminho relevante de exploração de análise integrada processo-produto para trabalhos futuros. Em relação ao estudo de correlação entre dados do Inputlog e do ANT, destacaram-se as correlações entre acurácia e tempo de reação nas condições experimentais e os percentuais de apagamentos. Os presentes achados abrem caminho e trazem contribuições significativas para o campo da psicolinguística no âmbito da pesquisa entre L1 e L2. / [en] This dissertation addresses bilingual writing – Portuguese as L1 and English as L2 – from a cognitive perspective, aiming to characterize both the writing process and the final product in an integrated manner and explore correlations between writing performance and attentional aspects. The research involves 15 English language teachers (10 women and 5 men) with an average age of 43.5 years (SD 13.25), native speakers of Brazilian Portuguese. The study utilized computational tools to record writing actions during the production of argumentative texts (Inputlog program), automatically analyzed linguistic aspects from the text (Nilc-Metrix program for Portuguese and Coh-Metrix for English) and verify connectivity patterns in the final text using graph attributes (SpeechGraphs program). The Attention Network Test (ANT) was also adopted. In the analysis of the writing process, patterns of pauses, active writing operations, and revision actions (insertions and deletions) were examined. In the product analysis, parameters related to vocabulary, semantics, syntax, readability índices, as well as information on lexical recurrence and word connectivity, were considered. Regarding the writing process, the results of the study revealed differences between the two languages, with higher values associated with writing in English, particularly in terms of (i) pauses within words, indicating orthographic demands, and (ii) the percentage of uninterrupted writing, suggesting less interruption and fewer alterations/revisions. Correlation analysis indicated that participants exhibited a similar writing profile in both L1 and L2. In the product analysis using Coh-Metrix (English) and Nilc-Metrix (Portuguese), it was found, through readability índices, that the texts exhibited moderate complexity in both languages. Despite differences in how metrics are defined in each program, the results suggest that texts in Portuguese show a higher level of complexity when considering syntactic aspects (such as the number of words before main verbs) and semantic aspects (concreteness degree). For L2, lexical diversity remains one of the most reliable proficiency indicators, correlating with pause behavior (before words) and revision (normal production). Regarding SpeechGraphs, significant differences were observed between texts in L1 and L2 for almost all analyzed graph attributes, reflecting how the program deals with morphological characteristics of the two languages. No correlations were observed between the behavior of speakers in L1 and L2. Additionally, correlation studies were conducted between Inputlog data and Coh-Metrix and Nilc-Metrix tools, as well as between these tools and Speech Graph data. In both studies, a correspondence was observed between parameters indicative of complexity in the tools used, suggesting a relevant path for exploring integrated process-product analysis in future research. Regarding the correlation study between Inputlog and ANT data, notable correlations emerged between accuracy and reaction time in experimental conditions and percentages of deletions. These findings pave the way for significant contributions to the field of psycholinguistics in the context of research between L1 and L2.

Not many studies exist in the literature on reading in South Africa which examine the differences between the reading performance of first (L1) and second (L2) language English speaking learners, particularly those who experience barriers to learning. Using archival material from the Education Clinic of the University of the Witwatersrand, this study compared the results on the Stanford Diagnostic Reading Test (Brown Level) for a group of 43 high school L1 (20) and L2 (23) learners identified as experiencing barriers to learning. In line with international research on reading difficulties skills (Ben-Zeev, 1984; Baker, 1988; Drucker, 2003; Cummins, 1989,1991; Miller, 1984; Droop and Verhoeven, 1998), it was found that the L2 students performed significantly below the level of their L1 counterparts in Auditory Vocabulary and Reading Comprehension. The results on the Phonetic Analysis were found to be similar for both groups.

A presente dissertação teve como finalidade avaliar a precisão e a discrepância das coordenadas (acurácia) obtidas por meio das observações GPS, no modo estático rápido, medidas com receptores de uma freqüência, empregando-se a técnica de suavização do código C/A pela fase da portadora para diferentes comprimentos de linha base (20, 50, 75, 100, 150, 200 e 300 Km), a partir da estação de monitoramento contínuo da EESC/USP. Essa técnica obteve boa repercussão no Brasil, a partir do momento em que foi permitida sua utilização para fins de georreferenciamento de imóveis rurais, conforme a norma técnica do INCRA, que permite a utilização da suavização do código pela fase da portadora, desde que esta apresente acurácia com valores iguais ou inferiores a 50 cm. Atualmente, trabalhos com tal técnica estão sendo desenvolvidos e aceitos para compor o banco de dados do cadastro rural nacional. Pelos resultados obtidos nesta dissertação, foi possível avaliar que a aplicação dessa técnica não atende à exigência requerida em 100% das medições e, ao mesmo tempo, verificar a diferença entre a precisão do pós-processamento, indicada pelos softwares comerciais e a acurácia dos pontos medidos comparados com os pontos de controle estabelecidos para esse fim. / The present dissertation has as objective to evaluate precision and discrepancies of coordinates (accuracy) obtained through GPS observations, in a rapid static method, measured by single frequency, which applies carrier-smoothed-code for different baseline length (20, 50, 75, 100, 150, 200 and 300 km), since continuous monitoring station from EESC/USP. This technique obtained a good repercussion in Brazil, since when its use was legitimate in rural property georeferencing, according to INCRA\'s norma técnica (technical rule), which allows the use of carrier-smoothed-code in view of the fact that presents accuracy with equal or inferior values to 50 cm. Currently, works using such technique are developed and accepted in order to compound database of national rural survey in Brazil. Based on the obtained results it was possible to evaluate that the technique does not guaranteed to requested requirement in 100% of measurements, and at the same time to verify the difference between post-processing precision, indicated by commercial software, as well as measured point accuracy compared with points established for this purposed.

Este texto apresenta um método alternativo de regressão que é denominado regressão L1. Este método é robusto com relação a outliers na variável Y enquanto o método tradicional, mínimos quadrados, não oferece robustez a este tipo de outlier. Neste trabalho reanalisaremos os dados sobre imóveis apresentados por Narula e Wellington (1977) à luz da regressão L1. Ilustraremos os principais resultados inferenciais como: interpretação do modelo, construção de intervalos de confiança e testes de hipóteses para os parâmetros, análise de medidas de qualidade do ajuste do modelo e também utilizaremos medidas de diagnóstico para destacar observações influentes. Dentre as medidas de influência utilizaremos a diferença de verossimilhanças e a diferença de verossimilhanças condicional. / This text presents an alternative method of regression that is called L1 regression. This method is robust to outliers in the Y variable while the traditional least squares method does not provide robustness to this type of outlier. In this work we will review the data about houses presented by Narula and Wellington (1977) in the light of the L1 regression. We will illustrate the main inferential results such as: model interpretation, construction of confidence intervals and hypothesis tests for the parameters, analysis of quality measures of model fit and also use diagnostic measures to highlight influential observations. Among the measures of influence we will use the likelihood displacement and the conditional likelihood displacement.

The present study aims to capture linguistic variation in subject distribution of two typologically similar languages, Greek and Chilean Spanish, considering adult monolingual and bilingual speakers of Greek as a heritage/minority language in Chile. The focus is on null and overt third-person subjects in topic-continuity and topic-shift contexts. Such structures involve the interface between syntax and discourse/pragmatics, a vulnerable domain in bilingualism. Previous research has shown overextension of the scope of the overt subject pronoun in contexts where null subjects are discursively expected (e.g. Tsimpli, Sorace, Heycock & Filiaci 2004). The Interface Hypothesis (IH) (Sorace 2011) was formulated to account for such findings, which obtain even in pairs of two null subject languages (Sorace, Serratrice, Filiaci & Baldo 2009). The key question as to the language-contact effects on subject distribution in pairs of two null subject languages requires further exploration while the combination of Greek and Spanish has been so far understudied. The IH is evaluated with new empirical data from a bilingual situation not studied before. Data from oral narratives and aural pronominal anaphora resolution were elicited from monolinguals and three types of bilinguals, namely first-generation immigrants, heritage speakers and L2 speakers of Greek residing in Chile. The monolingual data revealed differences in the use and interpretation of overt subject pronouns between Greek and Chilean Spanish. The crosslinguistic difference lies in the strong deictic properties of the Greek pronoun compared to its Spanish counterpart; hence differences obtain because of the relative strength of the two pronominal forms. No overextension of the scope of overt pronouns was found in bilinguals, against predictions stemming from the Interface Hypothesis. This may relate to the typological similarity between Greek and Spanish as well as to the nature of the Greek pronoun, which makes its use relatively categorical. Such findings lend support to the Representational account (Tsimpli et al. 2004). On the contrary, null subjects gave rise to optionality presumably due to their complexity, which demands higher degrees of computational efficiency. The Vulnerability Hypothesis (Prada Pérez 2018) may also account for the findings.

Ce travail porte sur l’inscription de la notion extralinguistique de mouvement dans deux langues typologiquement différentes, et examine l’impact de ces différences sur les premiers développements langagiers. Les travaux récents sur la question montrent en effet qu’il existe des contraintes proprement linguistiques, en plus de contraintes générales liées à l’empreinte particulière qu’apporte la perception de l’espace et du mouvement à la cognition. Notre objectif est d’analyser la place de ces contraintes dans l’acquisition du langage, à partir de suivis longitudinaux d’enfants francophones et anglophones filmés dès les débuts du langage. Nous présentons d’abord plusieurs illustrations des hypothèses sur la précocité du mouvement, repérées dans les premières formes de communication : celles-ci dessinent des liens très précoces entre mouvement et langage, qui ne semblent pas dépendre de la langue adressée à l’enfant. Nous nous penchons ensuite sur l’impact des contraintes proprement linguistiques, que l’expression du déplacement fait apparaître. L’analyse du discours adressé à l’enfant permet de souligner l’importance des contextes de production, et de variations reflétant des choix énonciatifs différents : leur prise en compte atténue les différences inter-langues observées dans la littérature. Cependant, des contrastes plus marqués apparaissent dans les premières expressions du déplacement : ils montrent une prise en compte précoce des contraintes linguistiques. L’analyse de l’expression du déplacement en français révèle aussi une focalisation peut-être excessive de la typologie sémantique sur les valeurs spatiales. Pour montrer que la prise en compte des valeurs non spatiales importe y compris pour l’analyse de l’anglais, nous interrogeons l’articulation des valeurs spatiales et non spatiales dans l’acquisition des premières constructions, à partir d’un des premiers marqueurs utilisés par les enfants anglophones : up. / This dissertation starts from the expression of motion (an extralinguistic notion) in two typologically different languages, and analyses the impact of those differences in early language acquisition. Recent studies have highlighted the importance of linguistic constraints, in addition to general constraints linking our perception of space and motion with general cognitive processes. Our aim is to situate those constraints within a general understanding of first language acquisition: this will be achieved through analyses of longitudinal follow-ups of French and English-speaking children from early communication onwards. We start by isolating and discussing some features of early communication in which the primacy of motion is best illustrated. They are evidence for the existence of early links between motion and language, which do not seem to depend on the characteristics of the language acquired. We then examine the impact of linguistic constraints, as they appear in the expression of location changes. Child-directed speech shows important variations in context, but also in each speaker’s linguistic choices and strategies: cross-linguistic differences thus need to be reconsidered. However, more marked contrasts are seen in how children first express location changes: they are evidence for an early integration of linguistic constraints. Our analyses also underline the overrated status of spatial semantics in typology and cross-linguistic comparisons. In order to show that non spatial meaning matters, we finally question how both spatial and non-spatial semantics are implied in the acquisition of syntactic constructions with one of the first markers used by English-speaking children: up.