This study examined a Pseudoword Phonics Curriculum to determine if this form of instruction would increase students’ decoding skills compared to typical real-word phonics instruction. In typical phonics instruction, children learn to decode familiar words which allow them to draw on their prior knowledge of how to pronounce the word and may detract from learning decoding skills. By using pseudowords during phonics instruction, students may learn more decoding skills because they are unfamiliar with the “words” and therefore cannot draw on memory for how to pronounce the word. It was hypothesized that students who learn phonics with pseudowords will learn more decoding skills and perform higher on a real-word assessment compared to students who learn phonics with real words. Students from two kindergarten classes participated in this study. An author-created word decoding assessment was used to determine the students’ ability to decode words. The study was broken into three phases, each lasting one month. During Phase 1, both groups received phonics instruction using real words, which allowed for the exploration of baseline student growth trajectories and potential teacher effects. During Phase 2, the experimental group received pseudoword phonics instruction while the control group continued real-word phonics instruction. During Phase 3, both groups were taught with real-word phonics instruction. Students were assessed on their decoding skills before and after each phase. Results from multiple regression and multi-level model analyses revealed a greater increase in decoding skills during the second and third phases of the study for students who received the pseudoword phonics instruction compared to students who received the real-word phonics instruction. This suggests that pseudoword phonics instruction improves decoding skills quicker than real-word phonics instruction. This also suggests that teaching decoding with pseudowords for one month can continue to improve decoding skills when children return to real-word phonics instruction. Teacher feedback suggests that confidence with reading increased for students who learned with pseudowords because they were less intimidated by the approach and viewed pseudoword phonics as a game that involved reading “silly” words. Implications of these results, limitations of this study, and areas for future research are discussed.

Le processus de recombinaison V(D)J des gènes d’immunoglobulines (Ig) est caractérisé par une grande imprécision des jonctions entre les segments variables (V), de diversité (D) et de jonction (J). Deux fois sur trois, un décalage du cadre de lecture apparaît, aboutissant à une jonction non productive dite « hors phase ». Plusieurs études ont démontré que les deux allèles productifs et non-productifs sont activement transcrits. Les transcrits matures issus des allèles non-productifs sont pris en charge par un mécanisme de surveillance des ARNm appelé NMD « Nonsense-Mediated mRNA Decay ». En dégradant efficacement les ARNm d’Ig contenant des codons non-sens, ce mécanisme prévient l’apparition des Ig tronquées au cours de l’ontogénie B. Néanmoins, aucune étude n’a jusqu’ici analysé l’impact de l’épissage alternatif des transcrits d’Ig non-productifs. Ce phénomène appelé NAS « Nonsense-associated Altered Splicing » peut conduire à une production d’Ig tronquées présentant des délétions internes du domaine variable (V).Les projets développés lors de cette thèse ont montré que la présence d’un codon non-sens, au niveau de l’exon variable (VJ) des transcrits Igκ, favorise le saut d’exon et la production de chaînes légères dépourvues de domaine variable (ΔV-κLCs). De façon intéressante, ces Ig tronquées provoquent un stress cellulaire et conduisent à l’apoptose des plasmocytes (Article 1). Ces observations ont permis d’identifier un nouveau point de contrôle agissant tardivement lors de la différenciation plasmocytaire : le TIE « Truncated-Ig Exclusion » checkpoint. Ce processus de contrôle provoque l’élimination des plasmocytes qui produisent des chaînes d’Ig tronquées. Nous avons également étudié l’épissage alternatif des transcrits d’Ig non-productifs en l’absence de TIE-checkpoint (Article 2). Cette étude a révélé que l’hypertranscription des gènes d’Ig dans les plasmocytes favorise l’épissage alternatif des transcrits d’Ig non-productifs. En utilisant un modèle d’expression forcée d’Ig tronquées, nous avons mis en évidence une coopération entre les mécanismes assurant la surveillance des ARNm (NMD) et la surveillance au niveau protéique (UPR : « Unfolded Protein Response », autophagie) (Article 3). Sur la base de ces résultats, nous avons mis au point une nouvelle approche thérapeutique qui consiste à forcer la production d’Ig tronquées en utilisant des oligonucléotides anti-sens (AON) capables de provoquer l’élimination de l’exon variable lors de l’épissage. Cette invention pourrait ouvrir des perspectives thérapeutiques pertinentes dans le traitement du Myélome Multiple et d’autres pathologies touchant les plasmocytes. / The recombination process V(D)J of immunoglobulin (Ig) genes is characterized by random junctions between the variable (V), diversity (D) and joining (J) segments. A frameshift mutation appears in two-third of cases, generating a non-productive or « out of frame » junction. Several studies have shown that both productive and non-productive alleles are actively transcribed. The mature transcripts from nonproductive alleles are usually considered sterile and innocuous as a result of an mRNA surveillance mechanism called NMD « Nonsense-Mediated mRNA Decay ». By degrading aberrant mRNA, this mechanism prevents the appearance of truncated Ig during B cell ontogeny. However, less is known about the impact of alternative splicing on non-productive Ig transcripts. This mechanism, called NAS « Nonsense-associated Altered Splicing » can lead to the production of truncated Ig with internal deletions of variable domain (V). During my thesis, we have shown that the presence of a stop codon, within the variable exon (VJ) of Igκ transcripts, promotes exon skipping and synthesis of V domain-less κ light chains (ΔV-κLCs). Interestingly, such truncated Ig causes cellular stress and leads to plasma cells apoptosis (Article 1). These findings have identified a new checkpoint acting late during plasma cell differentiation: TIE « Truncated-Ig Exclusion » checkpoint. This process ensures counter-selection of plasma cells producing truncated-Ig. We also studied the alternative splicing of non-productive Ig transcripts in the absence of TIE-checkpoint (Article 2). We found that hypertranscription of Ig genes in plasma cells promote alternative splicing of non-productive Ig transcripts. Using a model forcing the expression of truncated Ig, we identified a cooperative action between mRNA surveillance mechanisms (NMD) and those of protein surveillance (UPR « Unfolded Protein Response », autophagy) (Article 3). Based on these results, we have developed a new therapeutic approach by increasing the production of truncated Ig using antisense oligonucleotides (AON) that leads to the elimination of the variable exon during splicing. This invention could open new avenues for the treatment of Multiple Myeloma patients and other pathologies affecting plasma cells.

Les mutations non sens introduisent un codon stop prématuré dans une phase ouverte de lecture. Ce type de mutation est retrouvé chez environ 11% des patients atteints de maladies génétiques et dans de nombreux cancers. En effet, entre 5 et 40% des mutations affectant des gènes suppresseurs de tumeurs sont des mutations non sens. La conséquence de la présence d’une mutation non sens dans un gène est la dégradation rapide de l’ARN messager correspondant, par l’activation d’un mécanisme de surveillance des ARN appelé NMD (pour nonsense-mediated mRNA decay) conduisant à une absence d’expression du gène mutant. Dans le cas des cancers, l’absence d’expression d’un gène suppresseur de tumeurs tel que TP53, perturbe un ensemble de processus biologiques dont l’apoptose, facilitant ainsi la progression tumorale.En utilisant un système de criblage moyen débit permettant d’identifier des molécules capables de ré-exprimer des gènes porteurs d’une mutation non sens en inhibant le NMD et/ou en activant la translecture, plusieurs molécules ont été identifiées. La translecture est un mécanisme naturel conduisant à l’incorporation d’un acide aminé à la position du codon stop prématuré au cours de la traduction. Parmi les molécules identifiées, je me suis intéressée à un extrait végétal nommé H7 et au composé CNSM1 (pour corrector of nonsense mutation 1) qui permettent une ré-expression très efficace du gène TP53 lorsqu’il est porteur d’une mutation non sens. J’ai caractérisé ces composés en montrant notamment la ré-expression du gène TP53 porteur d’une mutation non sens dans différentes lignées cellulaires issues de différents cancers. J’ai montré également la très faible toxicité de ces molécules, validant leur potentielle utilisation en clinique. Mon étude a aussi permis de montrer que la protéine p53 synthétisée est fonctionnelle puisqu'elle est capable d’induire l’activation transcriptionnelle d’un de ses gènes cibles, le gène TP21.En permettant la ré-expression du gène suppresseur de tumeur mutant, des molécules comme CNSM1 ou H7 restaurent la capacité des cellules à entrer en apoptose et pourraient aussi réduire certaines résistances à la chimiothérapie.De plus, par une approche d’édition du génome, j’ai confirmé le lien existant entre le blocage du cytosquelette et l’inhibition du NMD. J’ai aussi identifié deux protéines impliquées dans le réarrangement du cytosquelette qui pourraient être ciblées pour inhiber le NMD en thérapie et ré-exprimer une protéine tronquée fonctionnelle. L’utilisation de H7 ou de CNMS1 pourrait ainsi être couplée à une inhibition du NMD pour optimiser la correction des mutations non sens. Ces molécules correctrices de mutations non sens représentent de nouvelles approches thérapeutiques ciblées du cancer et des maladies rares liées aux mutations non sens. / Nonsense mutations generate premature termination codons (PTC) within an open reading frame. This type of mutation is found in about 11% of patients with genetic disorders. Concerning cancer, 5 to 40% of mutations affecting tumor-suppressing genes are nonsense mutations. The presence of a PTC in a gene leads to rapid degradation of its mRNA mediated by the RNA surveillance mechanism named NMD (Nonsense-mediated mRNA decay) preventing the synthesis of truncated proteins. In cancer, the absence of expression of tumor suppressing genes such as TP53 interferes with many biological pathways including apoptosis enabling tumor progression.A screening system that allows identifying molecules capable of re-expressing genes harboring nonsense mutations by inhibiting the NMD system and/or by activating readthrough has been developed in the lab. Readthrough is a natural mechanism, which occurs during translation, leading to the incorporation of an amino acid at the PTC position. Among the molecules that have been identified thanks to the screen, a natural extract named H7 and a compound named CNSM1 efficiently rescues the expression of the nonsense-mutated TP53 gene carrying a PTC.CNSM1 and H7 induces the expression of full-length proteins from PTC-containing genes indicating that these compounds are capable of activating readthrough. I validated the screen results on several cancer cell lines harboring an endogenous nonsense mutation in TP53 gene and showed that the function of p53 was restored in the presence of CNSM1 or H7. I also investigated the cellular toxicity related with the use of CMNS1 on cultured cells and the in vivo effect of H7 in a mouse model harboring a nonsense mutation in dystrophin gene. My results demonstrate that these compounds have a mild cellular toxicity. In addition, using a genome editing approach I confirmed the relationship between the cytoskeletal blockage and the NMD inhibition. I identified two proteins that are implicated in the cytoskeletal rearrangement, which might be targeted to induce NMD inhibition and then the expression of truncated but functional protein from the mutated mRNA. H7 or CNMS1 might be coupled to an NMD inhibition strategy to improve the nonsense mutation correction. Knowing CNSM1 and H7 are so far the most efficient molecule capable of rescuing the expression of PTC-containing genes, these compounds represents a realistic hope for a new-targeted therapy for pathologies associated with nonsense mutations.

The diploma thesis describes Polish and Czech nonsense in children's literature. The main goal is to define nonsense literature, its development from a historical and formative point of view, considering contemporary events. The first part of the thesis focuses on the theoretical definition of the term nonsense and its historical aspect, especially on the two key representatives of English nonsense Edward Lear and Lewis Carroll. The next part deals with the development of Polish nonsense in children's literature. Two main authors, Julian Tuwim and Jan Brzechwa, who are considered as the creators of the new poetic school, took part in the formation of nonsense in Poland. Absurd humour and the world of children readers became the main inspirations for their work. This poetics was followed by other representatives of the Polish nonsense, including Ludwik Jerzy Kern, Wanda Chotomska and others. The work also focuses on the development of Czech nonsense for children, its main personalities and major works, which are based on nonsense, absurdity and word play. The diploma describes nonsense work for children of Josef Kainar, Jiří Kolář, Miloš Macourek, Pavel Šrut and other writers of literature. The last part of the thesis deals with specific nonsense literature for children of Polish and Czech authors....

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The purpose of this quantitative study was to examine the effects, if any, of a supplemental phonics curriculum, Saxon Phonics, on the reading achievement of first-grade students in one mountain-west, semirural, school district. The design was casual-comparative and ex post facto, and answered the questions: (1) Do students taught using a traditional basal program and students taught using both the traditional basal program and a supplemental phonics program (control vs. treatment) differ on selected end-of-year reading achievement scores (i.e., portions of the DIBELS Next assessment—nonsense word fluency [NWF], oral reading fluency [ORF], and accuracy [ACC])? (2) do any possible interactions among selected variables (i.e., instructional program, gender, and beginning-of-year reading level) exist related to performance differences on end-of-year reading achievement scores among students receiving reading instruction with or without a supplemental phonics program? The independent variables were the instructional program Saxon Phonics, a traditional/basal reading curriculum and the reading levels of low, medium, and high. The dependent variables were oral reading fluency, accuracy and nonsense word fluency, measured by the DIBELS Next assessment. The 2014-2015 and 2015-2016 DIBELS Next data were collected from the school district database upon approval from the Institutional Review Board in January of 2017. A mixed effects model was utilized to explore the relationship between use of the selected supplemental phonics curriculum and selected reading achievement scores of first-grade students. Results revealed that there was no significant difference between the control and treatment groups, though there was a statistically significant improvement of low readers in the treatment group over the control group.

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The life of RNA polymerase II (RNAPII) transcripts is shaped by the dynamic formation of mutually exclusive ribonucleoprotein complexes (RNPs) that direct transcript biogenesis and turnover. A key regulator of RNA metabolism in the nucleus is the scaffold protein ARS2 (arsenic resistance protein 2), that binds to the cap binding complex (CBC) and regulates processing, degradation, and export of RNAPII transcripts. We report here that alternative splicing of ARS2’s intron 5, generates cytoplasmic isoforms that lack 270 amino acids from the N-terminal of the protein and are functionally distinct from nuclear ARS2. ARS2 isoforms distinctive roles are evidenced under physiological conditions and stress. Under physiological conditions, ARS2 isoforms differentially regulate transcript degradation through nonsense mediated decay (NMD). Switching of ARS2 isoforms within the CBC in the cytoplasm has dramatic functional consequences, changing ARS2 from a NMD inhibitor to a NMD promoter that enhances the binding of UPF1 to CBP80 and ERF1, favouring SURF complex formation, SMG7 recruitment and transcript degradation. ARS2 isoform exchange is also relevant during arsenic stress. Cytoplasmic ARS2 is specifically induced during arsenic exposure. It is crucial for arsenic sensitivity, and promotes a global response to arsenic in a CBC independent manner. We propose that ARS2 isoform switching promotes the proper recruitment of RNP complexes during NMD and the cellular response to arsenic stress. The existence of non-redundant ARS2 isoforms is relevant for cell homeostasis, stress response and cancer treatment. / Graduate / 2023-04-14