La langue maternelle (L1) peut faciliter l’apprentissage du genre grammatical (GG) en langue seconde (L2), d’autant plus si, d’après certains chercheurs, les deux systèmes de genre présentent des similitudes. Les études – relativement peu nombreuses (par ex. Sabourin et al. 2006, Ellis et al. 2012, et Ragnhildstveit 2017) – comparant l’appropriation du genre en L2 à partir de plus de deux groupes d’apprenants avec différentes L1, appréhendent souvent différents phénomènes morphosyntaxiques sous la même rubrique d’« accord grammatical » en genre. Aussi s’attardent-elles peu sur les critères utilisés pour déterminer le degré de proximité ou d’éloignement de la L1 à la L2. La présente recherche applique une approche différente des études précédentes en distinguant la maîtrise de trois sous-systèmes du GG en français langue seconde (FL2), à savoir l’assignation (SA), l’accord (SAC) et la reprise pronominale (SRP) du GG, et elle étudie la maîtrise du genre en français L2 à partir de plusieurs L1 à l’aide d’une grille paramétrique définissant le degré de proximité ou d’éloignement des langues considérées pour chaque sous-système. Notre recherche porte sur un corpus de productions orales de trois groupes d’apprenants âgés entre 9 et 11 ans (n=75) de L1 différentes, à savoir l’allemand (25), l’anglais (25) et l’espagnol (25). Tous ont bénéficié d’un input comparable en français comme première langue étrangère et sont scolarisés dans un contexte d’apprentissage plurilingue identique. Les résultats globaux, qui se concentrent sur la maîtrise de ces trois sous-systèmes du GG en FL2, indiquent qu’il existe un lien entre le degré de précision atteint pour ces sous-systèmes en FL2 et les différences paramétriques observées entre le système de GG de la L1 et celui du français. Les données confirment néanmoins que l’étendue de l’impact de la L1 sur les taux de précision du GG en FL2 n’est pas parallèle selon le sous-système envisagé pour chaque groupe d’apprenants. / Doctorat en Langues, lettres et traductologie / info:eu-repo/semantics/nonPublished

In Czechia, teaching L2 English pronunciation is underestimated, which might lead to potential production slips and affect the intelligibility of the learners. This study investigates accuracy in L2 English pronunciation of checked vowels (/ʌ, ɛ, ɪ, ɒ, ʊ, æ/) as produced by Czech students. I applied cross-sectional approach and analysed participants from two distinct school classes who are divided by an 8-year study period. The pronunciation accuracy is analysed with the help of the computer program Praat, which generates frequencies for both Czech and English vowel phonemes produced by the participants reading out loud a set of monosyllabic citation words. The formant frequencies are later compared to a reference set of SSBE frequency values, which represents the targeted native language model. The results of this work show that the L2 English values are influenced by the students’ inventories of L1 Czech, leading to inaccuracy in production of the phonemes /ʌ, ɛ, ɪ, ɒ, ʊ/ and setting constraints to the L2 /æ/ acquisition.

The importance of vocabulary knowledge gained through incidental learning is well documented. The growth of incidental vocabulary knowledge is especially crucial for middle school students due to the complex words encountered in their studies. However, research on incidental vocabulary acquisition for middle school students is lacking. The purpose of this study was to compare the relative effectiveness of three instructional conditions (reading, writing, and reading and writing) on incidental vocabulary acquisition and retention with middle school students in an English as a first language (L1) environment. In this within subjects repeated measure study, 263 eighth-grade participants received treatment in three instructional conditions with three differing levels of involvement load. Data from 2,893 individual student measures were used to evaluate the influence of instructional conditions on incidental vocabulary acquisition and retention. Analysis of mixed-effects models showed that participant scores on the reading and writing condition were consistently higher than the writing only or the reading only condition. These results indicate that instructional tasks with higher involvement loads (e.g., reading and writing or writing) offer benefits to L1 middle school students for the incidental vocabulary acquisition necessary to be academically successful.

Institutional factors affecting implementation of policies are a reflection of the larger political context and setting of money in education. This has an impact on implementing accommodations for English Language Learners in standardized testing under No Child Left Behind. To see if this is true, four states: Indiana, New York, Tennessee and Wisconsin were chosen as examples of state policy adoption and their test contracts were collected from a test company. State accommodations for ELL in testing policy and state costs for standardized tests were analyzed in a comparative review. The diversity of methods in accommodation and lack of correlation between state standardized test costs to product illustrates institutional factors affecting NCLB implementation. Therefore it becomes essential for professional development to support states in implementing NCLB within an institutional context. Addressing these factors will lead to greater educational progress in U.S. federal policies.

The immune checkpoint blockade is a novel approach of cancer therapy, which markedly enhanced treatment efficacy of several cancer types. However, the frequency of cancer patients non-responding to this treatment is high. Establishment of predictive markers to distinguish patients suitable for the immune checkpoint blockade would enhance the number of patients receiving benefit from the therapy. This dissertation thesis focuses on the enhancement of efficacy of immune checkpoint inhibitors (ICIs) and predictive markers in experimental models of mouse tumours induced by TC-1 and TC-1/A9 cell lines and its clones with deactivation of interferon (IFN)-γ signalling (TC-1/dIfngr1 and TC-1/A9/dIfngr1), or CD80 molecule (TC-1/dCD80-1). IFN-γ is presumed to be the main inducer of programmed death ligand 1 (PD-L1) and a major histocompatibility complex I (MHC-I). Moreover, PD-L1 expression may predict sensitivity to PD-1/PD-L1 blockade. Non-functional IFN-γ signalling or downregulated MHC-I expression has been associated with resistance to ICIs in some patients. We found that IFNs type I (IFN-α and IFN-β) induced the expression of PD-L1 and MHC-I on TC-1/A9/dIfngr1 tumour cells with reversible downregulation of both molecules. We also showed that deactivation of IFN-γ signalling in TC-1/A9 cells was not a...

Programmed death-ligand 1 (PD-L1) is a type 1 transmembrane protein that has been reported to play a vital role in mediating suppressed immunity. The interaction between PD-L1 and PD-1 delivers a negative signal that reduces the proliferation of these T cells and induces apoptosis at the same time. Antibodies that can block the Programmed death-ligand 1 (PD-L1) on tumor cells have been shown to alleviate cancer-induced immunosuppression. While antibodies have a great potential in various therapeutic uses, many drawbacks such as the high cost of production, huge molecular size, and poor permeability impose restrictions on the extensive use of full-length antibodies. These limitations have necessitated research for finding alternatives to antibodies, such as peptides, that have lower molecular weight and similar properties as antibodies but do not have the lengthy and complicated approach of producing antibodies. In this study, a novel approach based on molecular interactions of the PD1-PD-L1 complex was developed to design peptides against PD-L1 using Knob-Socket model as basis. Three generations of peptides, α-helix, over-packed and salt bridge function peptides, were designed. All designed peptides were docked in the Molecular Operating Environment (MOE) and the AutoDock Vina software for the docking energy and the detail interaction information. Synthesis and characterization of selected peptides were performed after simulation studies. Surface Plasmon Resonance (SPR) studies showed that α-helix and over-packed peptides can’t bind to the PD-L1 protein with no response on sensorgrams, while peptides with salt bridge function had a higher binding response than those two generations of peptides. In confocal microscopic studies, PD-L1 positive breast cancer cell line MDA-MB-231 was used to determine the binding specificity of the salt bridge function peptides to PD-L1 in vitro, while another breast cancer cell line (MCF-7, without PD-L1) was used as a control. After incubation with peptides, significant fluorescence intensities were detected on the MDA-MB-231 cells, while only background fluorescence was observed on MCF-7 cells. In conclusion, this study demonstrated that peptides against PD-L1 designed using the Knob-Socket model and molecular interaction between PD-L1-PD1 complex showed feasibility to bind specifically with PD-L1 receptors.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18883号 / 医博第3994号 / 新制||医||1009(附属図書館) / 31834 / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩井 一宏, 教授 野田 亮, 教授 藤田 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21302号 / 医博第4391号 / 新制||医||1030(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 椛島 健治, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Abscisic acid is an important plant hormone in the responses to biotic and abiotic stresses, which also regulates various growth and developmental processes in plants. Three major components-receptors (PYRs), the PP2C type phosphatases and the SnRK2 subtype kinases form a double negative regulatory system: PYR/PYL/RCARs inhibit the activity of PP2Cs while PP2Cs inhibit that of SnRK2s in ABA signaling pathway. The results of my studies showed that ABA would directly affect the interaction between SnRK2.2 and ABI1 in absence of PYRs. Furthermore, ABA can inhibit the catalytic activity of the SnRK2.2 kinase. These findings indicated that ABA may directly interact with SnRK2.2. Posttranslational modifications play a key role in signal transduction. Phosphorylation is the most important posttranscriptional modification in ABA signal transduction. To dissect new components in ABA signaling network in plants, proteomics studies were carried out in Arabidopsis for identifying ABA- responsive phosphoproteins. Ten phosphoproteins, ATPB, ATPC1, FBA1, CTIMC, GGAT1, GAPC1, GAPC2, GAPA1 and ALDH11A3, were identified by 2-DE proteomic approach and LC-MS/MS analysis. These proteins are likely to be the potential phosphorylated targets of SnRK2s in ABA signaling network. Lysine acetylation (LysAc) also emerges as one of the important posttranslational modifications for protein regulation in plants. Eleven lysine acetylated proteins with altered acetylation in response to ABA were identified in Arabidopsis using proteomic approach. The increased LysAc of Rubisco and the decreased Rubisco activity by ABA treatment indicates the acetylation of Rubisco caused by ABA resulted in the inhibition of Rubisco activity. ABA has also been shown to exist and function in both lower animals and mammalians. The medical application of ABA has become a new area of investigation. To explore the role of protein phosphorylation in ABA-mediated function in mammalians, phosphoproteomic study was conducted in mouse 3T3-L1 cells. Ten phosphoproteins with significant changes in serine/threonine phosphorylation in response to ABA were identified. These results suggest these phosphoproteins are involved in ABA signaling network in mouse cells. The significance of the function of SFRS1, ANXA1 and Galectin-3 on human diseases indicated that ABA could be a potential treatment for some human diseases, such as cancer.

This thesis aims to simultaneously minimize function error and model complexity for data fusion via the Choquet integral (CI). The CI is a generator function, i.e., it is parametric and yields a wealth of aggregation operators based on the specifics of the underlying fuzzy measure. It is often the case that we desire to learn a fusion from data and the goal is to have the smallest possible sum of squared error between the trained model and a set of labels. However, we also desire to learn as “simple’’ of solutions as possible. Herein, L1-norm regularization of a lexicographically encoded capacity vector relative to the CI is explored. The impact of regularization is explored in terms of what capacities and aggregation operators it induces under different common and extreme scenarios. Synthetic experiments are provided in order to illustrate the propositions and concepts put forth.