This study aims to investigate the developmental ability of beginning and advance L1 English learners of Arabic to pronounce standard Arabic geminate consonants when enrolled in a full time L2 program. The results showed that English learners produced shorter closure duration when pronouncing geminates. In particular, the beginners lengthened singletons more than the advanced learners did, while both groups of learners shortened geminates much more so than native speakers of Arabic. The advanced L1 English learners of Arabic produced longer geminate duration than beginners. The ultimate result was a smaller ratio between singleton and geminate consonants in comparison to native speakers of Arabic.

The present study observed the use of educational code-switching to the L1 (Arabic) among six Arabic EFL teachers at Majmaah University, in Saudi Arabia. It used an a priori set of purposes based on Creswell (2003) and derived categories to examine the linguistic, social, and class management purposes behind code-switching. The instrument consisted of two parts: a demographic questionnaire and an audio recorder used in conjunction with a classroom observation sheet. Although some studies have suggested that educational code-switching to the L1 in EFL classrooms is an unconscious act (e.g., Moghadam, Abdul Samad, & Shahraki, 2012), the present study's results concluded the reverse: that the use of educational code-switching could be interpreted as an intentional practice among teachers in EFL classrooms. The results provided a more in-depth understanding of the use of educational code-switching to the L1 (Arabic). They agreed with previous studies that have found such code-switching to be very common among EFL teachers. Although participants displayed different linguistic, social, and class management purposes, analysis of the data revealed that certain purposes were more common than others, with linguistic purposes being far more common than social, class management, or other purposes. The most common linguistic purpose was to explain new words, and for class management was to clarify activities/exercises. Only two purposes, to engage in small talk with students and to connect between sentences, could not be categorized into one of the three main types.

L1 syndrome is an X-linked recessive disorder, characterised by congenital hydrocephalus, adducted thumbs, spastic paraplegia, agenesis of the corpus callosum and mental retardation. The disease is caused by mutations in the L1CAM gene, encoding a protein predominantly expressed in the nervous system. This protein has been implicated in a variety of processes including neuronal migration, neurite outgrowth and fasciculation, myelination, and long-term memory formation. L1 syndrome was suspected at genetic counselling of a family with a boy suffering from congenital hydrocephalus and mental retardation. Complete sequencing of L1CAM, performed by an external laboratory, revealed a novel mutation in the family, including a boy, affected with L1 syndrome, his sister, his mother and his maternal grandmother. To verify this mutation and to be able to detect mutations in the L1CAM gene locally in the future, a method for mutational analysis of this gene was set up using PCR optimisation and cycle sequencing. Sequencing of L1CAM was then performed on DNA samples from the four family members and the mutation was verified. A point mutation (c.3458-1G>C) in the 5’ splice site of exon 26 was detected in all of them. This new, not previously described, mutation is supposed to cause a deletion of the 26th exon and a frameshift in the part of the protein encoded by exons 27 and 28. This means that almost the entire cytoplasmic domain of the protein would have a loss of function, explaining the symptoms affecting the boy.

Made available in DSpace on 2014-06-12T18:04:40Z (GMT). No. of bitstreams: 2 arquivo6203_1.pdf: 1326366 bytes, checksum: 5cd77ce2de56aff15acaf6fb51f8cd1f (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2007 / Os papilomavírus constituem um grupo de pequenos vírus de DNA de dupla fita caracterizados por induzirem a formação de lesões que são em geral benignas, podendo regredir naturalmente ou se transformar em tumores malignos. Dentre eles se encontra o papilomavírus bovino (BPV). Até o momento são bem caracterizados seis diferentes tipos de BPV (BPV de 1-6) e recentemente outros dois novos tipos (BPVs 7 e 8) foram descritos. Na região Nordeste do Brasil, em especial no Estado de Pernambuco (região da Zona da Mata), a incidência de papilomatose bovina é muito alta provocando grandes perdas econômicas para os criadores. No momento não há tratamento com eficácia comprovada. A proteção contra infecção é conferida por anticorpos neutralizantes direcionados proteína estrutural L1. Estes anticorpos podem ser eficientemente induzidos por imunização com virus-like particles (VLP), que se formam espontaneamente após a expressão de L1 em vetores recombinantes. A levedura metilotrófica Pichia pastoris emergiu como um sistema heterólogo, eficiente e de baixo custo para a produção de proteínas. Neste trabalho foi avaliada a produção da proteína L1 de BPV-4 por células de P. pastoris. O gene L1 foi amplificado e clonado no vetor de expressão pPICZA (Invitrogen). As células de P. pastoris foram transformadas com pPICZAL1B4. Os transformantes de P. pastoris obtidos foram analisados para expressão do gene L1 por RT-PCR e Dot blot. Os transformantes analisados mostraram transcrição do gene L1 e conseqüente produção da proteína

Abstract The partitive (one of the fifteen Finnish cases and a typical case characterizing Finnic languages) developed from the Uralic separative locative into a grammatical case. In modern Finnish, it is one of the object, existential subject and predicative cases, representing that side of the case alternations that expresses unboundedness and negative polarity. Probably because the three case alternations differ in certain respects and clear-cut grammar rules cannot always be formulated, the use of the partitive remains a constant struggle for learners of Finnish. This study investigates the use of partitive objects, subjects and predicatives in Estonian, German and Dutch learners of Finnish as a foreign language. By comparing groups of learners from L1 backgrounds closely related and non-related to the target language (TL), it is aimed to explore the role of presence versus lack of relevant prior linguistic knowledge. The use of the partitive is namely largely similar in the closely related Estonian language. However, the purpose of the study is not only to gain valuable insights into the phenomena of L1 influence and intralingual influence but also to identify (common and L1 background-specific) stumbling blocks in the use of the partitive case, and to draw pedagogical implications based upon the findings. Research materials were selected from the Estonian, German and Dutch subcorpora of the International Corpus of Learner Finnish (ICLFI), aligned to the CEFR proficiency levels, and analyzed based on combined error-frequency analyses, involving partitive over- and underuse errors and partitive-requiring contexts (PRCs). As will be shown, the study reveals conspicuous differences between the learner corpora. In general, the Estonian learner corpus not only shows significantly fewer partitive errors than the other corpora, but also some specific error patterns attributable to subtle L1-L2 differences and, unlike the remaining corpora, a lack of overgeneralization of L2 grammar rules. The findings do not only indicate that -and how- prior linguistic knowledge matters, but also suggest that stumbling blocks could potentially be turned into stepping stones by emphasizing L1-L2 differences in the case of Estonian learners of Finnish, and by highlighting similarities and differences from within the TL in cases of learners from non-related L1 backgrounds. / Tiivistelmä Itämerensuomalaisille kielille tyypillinen partitiivi on aikaa myöten kehittynyt separatiivi-nimisestä uralilaisen kantakielen paikallissijasta syntaktisia funktioita ilmaisevaksi sijamuodoksi. Nykysuomessa partitiivi on yksi objektin, eksistentiaali-subjektin ja predikaativin sijoista, jolla ilmaistaan rajaamattomuutta ja kielteisyyttä. Partitiivin käyttö aiheuttaa suomen kielen oppijoille usein ongelmia, luultavasti koska objektin, subjektin ja predikatiivin sijanvalinnassa on vaihtelua ja ratkaisevien kieliopillisten sääntöjen muodostus on toisinaan erittäin vaikeaa. Tässä tutkimuksessa tarkastelen virolaisten, saksalaisten ja hollantilaisten suomea vieraana kielenä opiskelevien partitiiviobjektin, -subjektin ja -predikatiivin käyttöä lähde- ja kohdekielen samanlaisuuden ja erilaisuuden näkökulmasta. Lähde- ja kohdekielen roolin selvittämisen lisäksi tutkimuksen tavoitteina on identifioida partitiivin (yleiset ja lähdekielikohtaiset) ongelmakohdat ja yhdistää tutkimustulokset vieraan kielen oppimiseen ja -opetukseen. Tutkimusaineistoina on virolaisten, saksalaisten ja hollantilaisten opiskelijoiden kirjoittamia tekstejä, jotka on poimittu Kansainvälisestä oppijansuomen korpuksesta (ICLFI) ja arvioitu Eurooppalaisen viitekehyksen (CEFR) kielitaitotasojen mukaan. Virhe- ja frekvenssianalyyseissä aineistoista analysoidaan muun muassa partitiivin yli- ja alikäyttövirheet ja partitiivin vaatimat kontekstit. Tutkimuksesta käy ilmi, että virolaisten oppijoiden ja ei-sukukieliä puhuvien oppijoiden tuotoksissa on silmiinpistäviä eroja. Virolaisten aineistosta löytyy yleisesti tilastollisesti vähemmän partitiivivirheitä kuin kahdesta muusta osakorpuksesta ja lisäksi myös virhekategorioita ja -rakenteita, jotka johtunevat lähdekielen vaikutuksesta. Tämän lisäksi saksalaisten ja hollantilaisten tuotoksissa on selvästi enemmän kohdekielen sääntöjen yliyleistämistä kuin virolaisten osakorpuksessa. Tutkimustulokset siis osoittavat, että lähdekieli vaikuttaa kohdekielen oppimiseen, ja sen, miten se vaikuttaa. Lisäksi tutkimustulosten avulla on mahdollista kehittää sellaisia opetuksen apuvälineitä, joilla voidaan selventää virolaisille suomenoppijoille L1:n ja L2:n partitiivin käytön eroja ja yhtäläisyyksiä ja tehostaa oppimista; ei-sukukielisten oppijoiden opetuksessa ovat puolestaan kohdekielen ja sijanvaihteluiden sisäiset tunnusmerkit tärkeitä.

Peripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate similar to 30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4(+)/CD8(+) cells, we hypothesized that Program Death Ligand-1 (PDL1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3K alpha (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells. Expression of PD-L1 relative to PD-1 is high in PTCL biopsies (similar to 9-fold higher) and cell lines. Combination of alisertib with pan-PI3K inhibition or VCR significantly reduced PD-L1, NF-kappa B expression and inhibited phosphorylation of AKT, ERK1/2 and AK with enhanced apoptosis. In a SCID PTCL xenograft mouse model, alisertib displayed high synergism with MLN1117. In a syngeneic PTCL mouse xenograft model alisertib demonstrated tumor growth inhibition (TGI) similar to 30%, whilst anti-PD-L1 therapy alone was ineffective. Alisertib + anti-PD-L1 resulted in TGI > 90% indicative of a synthetic lethal interaction. PF-04691502 + alisertib + anti-PD-L1 + VCR resulted in TGI 100%. Overall, mice tolerated the treatments well. Co-targeting AK, PI3K and PD-L1 is a rational and novel therapeutic strategy for PTCL.

Apolipoprotéines L est une famille nouvellement caractérisée en humain sans une fonction patho- physiologique définitive. Ces protéines sont classiquement considérées être impliquées dans le transport et métabolisme des lipides, principalement due à l'association de son premier membre de la famille sécrétée l’apolipoprotéine L1 aux particules des lipoprotéines de haute densité. Néanmoins, le reste des membres sont des protéines intracellulaires (absence de domaine de peptide signal). Apolipoprotéine L1 a été initialement identifiée comme l'élément clé du facteur trypanolytique dans le sérum humain. L'exploration de la séquence des différents apolipoprotéines L a révélé un domaine distinct «B cell lymphoma-2 homology domain 3» ayant des similitudes structurelles et fonctionnelles avec le domaine B cell lymphoma-2 homology domain 3 des protéines de la famille B cell lymphoma-2. Ainsi la découverte de ce domaine peut contribuer à la compréhension de la fonction et rôle des apoLs dans différents mécanismes et processus tels que la mort cellulaire programmée, la prolifération cellulaire, le métabolisme cellulaire .Notre étude visait à caractériser les fonctions de patho- physiologique du premier membre de la famille «apolipoprotéine L1 ». L’expression de l’apolipoprotéine L1 ARNm, à partir de 48 carcinomes papillaires de la thyroïde, a été évaluée par des études à haut débit et normalisée à un pool de tissus normal de la thyroïde. Une confirmation de PCR en temps réel valide ainsi la surexpression d’apoL1 dans 91,67 % des cas testés. Le niveau élevé de l’apolipoprotéine L1 ARNm est en corrélation avec une expression protéique élevée dans les échantillons histologiques (70%), et détermine que les cellules folliculaires de la thyroïde dans la zone de la tumeur sont les cellules principales responsables de l’expression spécifique de l’apolipoprotéine L1. Nous avons étudié l'expression apolipoprotéine L1 dans le modèle de cancer pour approfondir notre compréhension des relations reliant cette expression distincte dans le cancer papillaire de la thyroïde et son rôle et fonction concernant le métabolisme du cancer (de reprogrammation métabolique :effet Warburg).7En outre, la localisation de l’apolipoprotéine L1 dans la mitochondrie des cellules cancéreuses de la thyroïde ainsi que dans la mitochondrie de levure, a été le point de départ de la recherche dans ce nouveau modèle, il nous a permis de révéler et d'introduire de nouvelles hypothèses pour expliquer l'effet inhibiteur de l’apolipoprotéine L1 en fonction des conditions métabolique variantes et l’effet pléotropiques de l’apolipoprotéine L1 sur la levure (dommages des mitochondries et vacuoles). Dans ce manuscrit, nous avons décrit nos efforts à mettre en évidence la spécificité d'expression de l’apolipoprotéine L1 dans le cancer papillaire thyroïdien notamment au niveau de la transcription ainsi que la localisation mitochondriale et l'interférence probable avec les voies métaboliques. / Option Biologie moléculaire du Doctorat en Sciences / info:eu-repo/semantics/nonPublished

The overarching goal of the dissertation is to illustrate the relevance of learner corpus research to the field of second language acquisition (SLA). The possibility that learner corpora can be useful in mainstream SLA research has a significant implication given that they have not been systematically explored in relation to SLA theories. The thesis contributes to building a methodological framework to utilize learner corpora beneficially to SLA and argues that learner corpus research contributes to other disciplines. This is achieved by a series of case studies that quantitatively analyze individual variation and the role of native language (L1) in second language (L2) development of English grammatical morphemes and explain the findings with existing SLA theories. The dissertation investigates the L2 development of morphemes based on two largescale learner corpora. It first reviews the literature and points out that the L2 acquisition order of English grammatical morphemes that has been believed universal in SLA research may, in fact, vary across the learners with different L1 backgrounds and that individual differences in morpheme studies have been relatively neglected in previous literature. The present research, thus, provides empirical evidence testing the universality of the order and the extent of individual differences. In the first study, the thesis investigates L1 influence on the L2 acquisition order of six English grammatical morphemes across seven L1 groups and five proficiency levels. Data drawn from approximately 12,000 essays from the Cambridge Learner Corpus establish clear L1 influence on this issue. The study also reveals that learners without the equivalent morpheme in L1 tend to achieve an accuracy level of below 90% with respect to the morpheme even at the highest proficiency level, and that morphemes requiring learners to learn to pay attention to the relevant distinctions in their acquisition show a stronger effect of L1 than those which only require new form-meaning mappings. The findings are interpreted under the framework of thinking-for-speaking proposed by Dan Slobin. Following the first study, the dissertation exploits EF-Cambridge Open Language Database (EFCamDat) and analyzes the developmental patterns of morphemes, L1 influence on the patterns, and the extent to which individual variation is observed in the development. Based on approximately 140,000 essays written by 46,700 learners of 10 L1 groups across a wide range of proficiency levels, the study found that (i) certain developmental patterns of accuracy are observed irrespective of target morphemes, (ii) inverted U-shaped development is rare irrespective of morphemes, (iii) proficiency influences the within-learner developmental patterns of morphemes, (iv) the developmental patterns at least slightly vary depending on morphemes, and (v) significant individual variation is observed in absolute accuracy, the accuracy difference between morphemes, and the rate of development. The findings are interpreted with dynamic systems theory (DST), a theory of development that has recently been applied to SLA research. The thesis further examines whether any systematic relationship is observed between the developmental patterns of morphemes. Although DST expects that their development is interlinked, the study did not find any strong relationships between the developmental patterns. However, it revealed a weak supportive relationship in the developmental pattern between articles and plural -s. That is, within individual learners, when the accuracy of articles increases, the accuracy of plural -s tends to increase as well, and vice versa.

The main objective of this dissertation is to investigate the effects of acquiring a second language (L2) at later periods of language development and native-like homonym processing in the first language (L1) from the perspective of Event-Related brain Potentials (ERP) using a cross-modal lexical decision task. To date, there is a lack of neurophysiological investigations into the effect that acquiring an L2 can have on processing strategies in the L1, and whether or not there is a precise age at which L2 exposure no longer affects native-like language processing. As such, my goal is to pinpoint this sensitive period specifically for homonym processing. To achieve this, I will present and discuss the results of two studies. The first study employs behavioural response measures using a cross-modal lexical decision task where participants simultaneously heard a sentence and made a decision to a visually-presented pseudoword or real word. The second study employs ERP measures using a novel ERP paradigm which investigates not only the main objective of this dissertation, but the second objective as well. This second objective is for this dissertation to become the first to evaluate the outcome of combining the cross-modal lexical decision task with ERPs. The behavioural and neurophysiological results for the monolingual group support the Reordered Access Model (Duffy, Morris, & Rayner, 1988) while the results for the bilingual groups do not. The results of the current studies indicate that those bilinguals who acquired French as an L2 rather than as a second native L1 show increasing divergence from monolingual native speakers in L1 homonym processing, with later acquirers exhibiting an exponentially marked divergence. This was found even though the task was carried out in English, the L1 (or one of the L1s) of all participants. The diverging performances of the bilinguals from the monolinguals were apparent in behavioural responses as well as in the amplitude, scalp distribution, and latency of ERP components, These differences were unique to each group, which supports the hypothesis that the acquisition of an L2 influences processing in the L1 (Dussias & Sagarra, 2007). Specifically, the early and late bilingual groups exhibited a marked divergence from the monolingual group as they revealed syntactic priming effects (p<.001) as well as lexical frequency effects (p<.001). They also revealed the greatest P600-like effect as they processed target words which were inappropriately- related to the priming homonyms (such as skin in Richard had a shed in the back of the garden). This suggests a heightened sensitivity to surface cues due to the L2 influencing homonym processing in the L1 (Cook, 2003; Dussias & Sagarra, 2007). Comparatively, the monolingual group revealed equal N400-like effects for lexical ambiguities overall compared to the unrelated conditions, and a context-by-frequency-interaction slowing their processing of the target word that is appropriately-related to the subordinate reading of the priming homonym, suggesting that they are not as sensitive to these same surface cues. Importantly, these results confirm that using ERPs along with a cross-modal lexical decision task is a promising paradigm to further study language processing.

This paper compares English as a second language (ESL) and foreign language (FL) teachers' and students' perspectives regarding target language (TL) and first language (L1) use in the respective classrooms. Teachers and students were given questionnaires asking their opinions of a rule that restricts students' L1 use. Questionnaires were administered to 46 ESL students, 43 FL students, 14 ESL teachers, and 15 FL teachers in Texas secondary public schools. Results were analyzed using SPSS and R. Results demonstrated an almost statistical difference between perspectives of ESL and FL students regarding TL and L1 use, while teacher results demonstrated no statistical difference between the groups. Students had a more positive perspective of the rule than teachers.