For people with hearing impairments, attending to a single speaker in a multi-talker background can be very difficult and something which the current hearing aids can barely help with. Recent studies have shown that the audio stream a human focuses on can be found among the surrounding audio streams, using EEG and linear models. With this rises the possibility of using EEG to unconsciously control future hearing aids such that the attuned sounds get enhanced, while the rest are damped. For such hearing aids to be useful for every day usage it better be using something other than a motion sensitive, precisely placed EEG cap. This could possibly be archived by placing the electrodes together with the hearing aid in the ear. One of the leading hearing aid manufacturer Oticon and its research lab Erikholm Research Center have recorded an EEG data set of people listening to sentences and in which electrodes were placed in and closely around the ears. We have analyzed the data set by applying a range of signal processing approaches, mainly in the context of audio estimation from EEG. Two different types of linear sparse models based on L1-regularized least squares are formulated and evaluated, providing automatic dimensionality reduction in that they significantly reduce the number of channels needed. The first model is based on linear combinations of spectrograms and the second is based on linear temporal filtering. We have investigated the usefulness of the in-ear electrodes and found some positive indications. All models explored consider the in-ear electrodes to be the most important, or among the more important, of the 128 electrodes in the EEG cap.This could be a positive indication of the future possibility of using only electrodes in the ears for future hearing aids.

Willin is a novel member of the Four-point-one Ezrin Radixin Moesin (FERM) protein superfamily, containing an N-terminal FERM domain most like the Ezrin-Radixin-Moesin (ERM) family but also the closely related protein Merlin. Willin was initially discovered as a yeast two-hybrid binding partner of neurofascin155, and this interaction has now been confirmed by both co-localisation studies and the use of two different biochemical methods. Like neurofascin155, Willin also localises to detergent resistant membranes, and like the ERM family, it is able to bind to phospholipids. The expression of Willin appears to be toxic as the production of cell-lines stably expressing Willin proved to be not possible and this appears to be because it induces apoptosis in cultured cells. This is a proliferation control function consistent with the suggestion that Willin is the human homologue of the Drosophila tumour suppressor ‘Expanded’. Three antibodies to Willin were also characterised and a novel splice variant, Willin2, subcloned into a GFP-tagged plasmid for comparison with the original form.

L1 attrition - which in the context of this study is defined as the decline of any native language skill (or portion thereof) in a healthy bilingual speaker (Ecke, 2004) - has been studied extensively for several decades. However, only few studies have examined the native speech of immigrants who use their L1 for professional purposes, such as language instructors (Isurin, 2007; Major, 1992; Porte, 1999, 2003). Furthermore, no research has been conducted comparing the L1 speech of such individuals with that of individuals who do not use their L1 for professional purposes. This study analyzed and compared L1 speech samples from two populations of German immigrants in the U.S., German Instructors and Other Professionals, and from a monolingual control group in Germany. It was hypothesized that German instructors may be less vulnerable to L1 attrition due to more frequent L1 use, a higher motivation to maintain the L1, and greater identification with the native language and culture. Data elicited through verbal fluency tasks, a film retelling task, a semi-structured interview, and a sociolinguistic questionnaire revealed significant differences between the control group and the two bilingual groups which point to L1 attrition (primarily as an access problem) in the bilingual speakers. The data also revealed significant differences between the German Instructors and the Other Professionals, suggesting that the severity of L1 attrition is not the same for all populations. In addition, a comparison of the two bilingual groups with regard to sociolinguistic variables, and correlations between linguistic measures and sociolinguistic variables also yielded interesting findings which have implications for L1 attrition research as well as L1 maintenance.

This thesis examines the L2 acquisition and L1 attrition of aspectual properties in Spanish. Specifically, it investigates preterite versus imperfect distinctions and the ongoing value of the Spanish present tense among English-speaking L2 learners and long-term Spanish immigrants. In contrast to previous research which explains L2 learners’ difficulties as a result of either maturational constraints or morphosyntactic development, this study provides a supplementary explanation focusing on L1 transfer of the semantic patterns of tense morphemes. The study proceeds by comparing data from L2 learners with that of long-term Spanish immigrants. Unlike what is argued for L2 acquisition difficulties, the difficulties immigrants may have with tense and aspect cannot stem solely from impairment reasons. These immigrants acquired the L2 as adults. Therefore, to the extent that L2 learners share similar patterns of errors with adult immigrants, L2 speakers’ difficulties cannot be unequivocally linked to causes related to impairment. Instead, following a selectional approach to aspectual variation (De Swart, 1998), it is argued that transfer of the selectional patterns of tense morphemes offers a more encompassing explanation of the difficulties L2 speakers face with tense and aspect. Data collection involved two truth-value judgment tasks, two acceptability judgment tasks and two elicited production tasks. Twenty long-term immigrants, twenty English-speaking L2 learners of Spanish, and twenty native speakers of Spanish serving as control participants took part in the study. Results show incorrect activation of aspectual patterns by both experimental groups and similar patterns of difficulties in some of the conditions under investigation. I conclude that transfer from the other language offers a more adequate explanation of the difficulties L2 learners face

The neural cell adhesion molecule L1 is a member of the immunoglobulin superfamily and it mediates many adhesive interactions during brain development. Mutations in the L1 gene are associated with a spectrum of X-linked neurological disorders known as CRASH or L1 syndrome. The objective of this thesis was to use the zebrafish model to investigate the molecular mechanisms of L1 functions and the pathological effects of its mutations. Zebrafish has two L1 homologs, L1.1 and L1.2. Inhibition of L1.1 expression by antisense morpholino oligonucleotides resulted in phenotypes that showed resemblances to L1 patients. However, knockdown of L1.2 expression did not result in notable neural defects. Furthermore, analysis of the expression pattern of L1.1 has led to the discovery of a novel soluble L1.1 isoform, L1.1s. L1.1s is an alternatively spliced form of L1.1, consisting of the first four Ig-like domains and thus a soluble secreted protein. L1.1 morphants exhibited disorganized brain structures with many having an enlarged fourth/hindbrain ventricle. Further characterization revealed aberrations in ventricular polarity, cell patterning and proliferation and helped differentiate the functions of L1.1 and L1.1s. While L1.1 plays a pivotal role in axonal outgrowth and guidance, L1.1s is crucial to brain ventricle formation. Significantly, L1.1s mRNA rescued many anomalies in the morphant brain, but not the trunk phenotypes. Receptor analysis confirmed that L1.1 undergoes heterophilic interactions with neuropilin-1a (Nrp1a). Peptide inhibition studies demonstrated further the involvement of L1.1s in neuroepithelial cell migration during ventricle formation. In the spinal cord, spinal primary motoneurons expressed exclusively the full-length L1.1, and abnormalities in axonal projections of morphants could be rescued only by L1.1 mRNA. Further studies showed that a novel interaction between the Ig3 domain of L1.1 and Unplugged, the zebrafish muscle specific kinase (MuSK), is crucial to motor axonal growth. Together, these results demonstrate that the different parts of L1.1 contribute to the diverse functions of L1.1 in neural development.

Syftet med studien är att undersöka hur mycket talutrymme elever med annat modersmål än svenska får och tar i klassrummet, i jämförelse med elever med svenska som modersmål. Särskild vikt läggs vid utrymmet för utforskande tal och mediering. Studien utgår från det sociokulturella perspektivet enligt vilket allt lärande sker i en social kontext. Det empiriska underlaget bygger på strukturerade observationer i sammanlagt sex klasser i år 1-2, med kompletterande anteckningar. Observationerna genomfördes under 100 minuter per klass. Resultatet presenteras i kvantitativ form. Resultatet visade att L1-talarna var de som tog och fick mest talutrymme även om skillnaden var marginell. Däremot fick L2-talarna något fler direkta frågor än L1-talarna. Mediering användes i samtliga klasser, men inte i den grad som var befogat. Utforskande tal användes aldrig under de sammanlagt 600 minuter som observerades. Detta resultat visar att lektionsstrukturen behöver ses över så att den bättre uppmuntrar och kräver att eleverna ska prata. Att använda sig av fler direkta, öppna frågor kan även fördela talutrymmet bättre mellan eleverna. Man kan även använda sig av så kallade minilektioner där talet står i fokus. Genom att vara mer flexibel med möbleringen i klassrummet kan man skapa fler möjligheter till interaktion eleverna emellan.

A good distance metric can improve the accuracy of a nearest neighbour classifier. Xing et al. (2002) proposed distance metric learning to find a linear transformation of the data so that observations of different classes are better separated. For high-dimensional problems where many un-informative variables are present, it is attractive to select a sparse distance metric, both to increase predictive accuracy but also to aid interpretation of the result. In this thesis, we investigate three different types of sparsity assumption for distance metric learning and show that sparse recovery is possible under each type of sparsity assumption with an appropriate choice of L1-type penalty. We show that a lasso penalty promotes learning a transformation matrix having lots of zero entries, a group lasso penalty recovers a transformation matrix having zero rows/columns and a trace norm penalty allows us to learn a low rank transformation matrix. The regularization allows us to consider a large number of covariates and we apply the technique to an expanded set of basis called rule ensemble to allow for a more flexible fit. Finally, we illustrate an application of the metric learning problem via a document retrieval example and discuss how similarity-based information can be applied to learn a classifier.

Un des mécanismes d’évasion des cellules tumorales au système immunitaire fait intervenir la famille des molécules de type B7. Ces molécules de costimulation ont aussi un rôle dans les mécanismes de tolérance immunitaire. La molécule B7-H1 (PD-L1 ou CD274) inhibe directement les lymphocytes T cytotoxiques (CTL) et est fortement exprimée à la surface de nombreux types de cellules tumorales. Les mécanismes de régulation de son expression ne sont pas bien connus. Il existe une augmentation d’expression de cette molécule après stimulation par l’IFNγ et récemment les ligands des Toll-Like-Receptor (TLR) 2, 4 et 9 ont été impliqués dans sa régulation au niveau du myélome multiple. L’implication possible des TLR dans l’expression de B7-H1 suggère un rôle possible de pathogènes dans l’échappement des tumeurs au système immunitaireIl n’existe aucune donnée dans la littérature sur l’expression des TLR au niveau des cellules blastiques de patients atteints de leucémies aigues myéloblastique (LAM). Nous avons dans un premier temps étudié l’expression des TLR dans les LAM et l’inductibilité de l’expression de la molécule B7-H1 par les ligands des TLR en cytométrie en flux. Nos résultats montrent que les TLR sont exprimés dans les LAM, avec une grande variabilité suivant les patients. On observe une augmentation significative de l’expression de B7-H1 après stimulation par le LPS (ligand TLR4) alors qu’elle n’est pas significative pour les autres ligands (PGN et ODN). Comme dans les tumeurs solides et le myélome multiple, l’expression de B7-H1 est augmentée par l’IFN γ. Des tests de lyse CTL sont en cours afin de confirmer le rôle fonctionnel de cette expression de B7-H1 via les TLR dans les LAM.Une autre partie de l’étude a été réalisée sur deux lignées murines leucémiques : DA1-3B et WEHI-3B, afin de disposer de modèles expérimentaux d’expression de B7-H1. On retrouve sur ces deux modèles l’augmentation d’expression de B7-H1 après stimulation par l’IFN γ et les ligands des TLR. L’utilisation de différents inhibiteurs chimiques des voies de signalisation suggère le rôle des voies MEK/ERK et de la voie JAK/STAT dans l’expression de cette molécule. La voie PI3kinase/Akt semble au contraire jouer un rôle inhibiteur. Le travail se poursuit avec la transfection de transdominants négatifs des différentes voies et de mutants constitutivement actifs. L’objectif à terme est de tester des stratégies d’immunothérapies des LAM par blocage pharmacologique de l’expression de B7-H1. / B7-H1 (PD-L1) is a B7-related protein that inhibits T-cell responses. B7-H1 participates in the immunoescape of cancer cells and is also involved in the long-term persistence of leukemic cells in a mouse model. B7-H1 can be constitutively expressed by cancer cells but is also induced by various stimuli. We therefore examined the constitutive and inducible expression of B7-H1 and the consequences of expression in human acute myeloid leukemia (AML). We analyzed B7-H1 expression in a cohort of 79 patients with AML. Blast cells were also studied after incubation with interferon-gamma or TLR ligands. Functionality was evaluated by cytotoxic T-cell activity against blast cells. Expression of B7-H1 at diagnosis was high in 18% of patients. Expression of toll-like receptors (TLR) 2, 4, and 9 was detected in one-third of AML samples. Expression of TLR2 and TLR4 ligands or IFN- induced by B7-H1 was found to protect AML cells from CTL-mediated lysis. Spontaneous B7-H1 expression was also found to be enhanced at relapse in some patients. MEK inhibitors including UO126 and AZD6244 reduced B7-H1 expression and restored CTL-mediated lysis of blast cells. In AML, B7-H1 expression by blasts represents a possible immune escape mechanism. The inducibility of B7-H1 expression by IFN- or TLR ligands suggests that various stimuli, either produced during the immune response against leukemia cells or released by infectious microorganisms, could protect leukemic cells from T-cells. The efficacy of MEK inhibitors against B7-H1-mediated inhibition of CTLs suggests a possible cancer immunotherapy strategy using targeted drugs.

Les verbes de position suédois encodent la localisation statique (stå « être debout », ligga « être couché », sitta « être assis ») et dynamique (ställa « mettre debout », lägga « coucher », sätta « asseoir ») d'un objet concret ou d'une personne. Selon nos données, élicitées à partir de stimuli présentés à 98 participants, la fréquence élevée de l'emploi de ces verbes en assure une acquisition précoce par les enfants apprenant le suédois en tant que langue maternelle et par les francophones adultes apprenant le suédois en tant que langue étrangère. Or, leur complexité sémantique rend difficile leur utilisation dans la mesure où les choix d'un verbe ne correspondent pas toujours à ceux de la langue cible. En effet, les difficultés perdurent même à un haut niveau de compétence (enfants de 10 ans, apprenants L2 avancé). Un ordre d'acquisition se discerne d'une part selon le type de verbe (les verbes statiques sont appris avant les dynamiques), d'autre part selon les paramètres sémantiques (l'HORIZONTALITÉ et la VERTICALITÉ sont appris avant la BASE et le CONTACT/INCLUSION), et enfin selon le sens prototypique (acquis avant les sens élargis). Plusieurs stratégies sont utilisées par les apprenants pour résoudre ces problèmes : l'usage d'un verbe statique pour encoder une situation dynamique ; l'usage généralisé de l'un des verbes (généralement celui encodant l'HORIZONTALITÉ) ; l'usage collocationnel d'un verbe avec une Figure ; l'usage d'une ellipse verbale ou d'un verbe positionnellement neutre (ex. la copule). L'acquisition par les apprenants L2 de l'organisation discursive de la langue cible semble se faire en dernier lieu, due à la différence typologique des deux langues. / The Swedish posture verbs encode static (stå « stand », ligga « lie », sitta « sit ») and dynamic (ställa « stand », lägga « lay », sätta « set ») location of a person or a concrete object. The elaborated stimuli elicited data from 98 participants. Our data shows that the usage frequency of these verbs guarantees an early acquisition by children learning Swedish as their first language and by adult French-speaking learners of Swedish as a second language. However, their semantic complexity constitutes an obstacle for arriving at idiomatic language use with regard to choosing the correct verb. These difficulties exist even at high levels of competence (children of 10 years and advanced L2 learners respectively). An acquisition order can be distinguished regarding the verb type (static verbs are acquired before the dynamic ones), the semantic parameters (HORIZONTALITY and VERTICALITY are acquired before BASE and CONTACT/CONTAINMENT) and the prototypical meaning (acquired before the extended meanings). Several strategies are used by the learners to solve these problems: the use of a static verb to encode a dynamic situation; the generalized use of one of the verbs (generally the one encoding HORIZONTALITY); a collocational use of a verb and a Figure; the use of a verbal ellipsis or a positionally neutral verb, like the copula. The Swedish discourse organization seems to be acquired late by the L2 learners, due to the typological differences between the two languages.

付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム / 京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第22400号 / 薬科博第122号 / 新制||薬科||13(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 掛谷 秀昭, 教授 二木 史朗, 教授 土居 雅夫 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM