Otoacoustic emissions (OAEs) have been under investigation since their discovery 30 years ago (Kemp, 1978). Otoacoustic emissions are quiet sounds generated within the cochlea that can be detected with a sensitive microphone placed within the ear canal. They are used clinically as a hearing screening tool but have the potential for diagnostic and monitoring purposes. For this dissertation, high-resolution instrumentation was developed for improving the acquisition of OAEs. It was shown that a high bit-depth device is required in order to simultaneously characterize the ear canal and the cochlear responses. This led to a reduction in the stimulus artifact that revealed early latency, high-frequency otoacoustic emissions. Next, a swept-tone technique originally developed for use in acoustical systems was formally developed for use in the human ear. The swept-tone technique allows for the simultaneous acquisition of a system's impulse response and its distortion components. The swept-tone was first used in this study to characterize the ear canal transfer properties. From that transfer function, a compensation routine was developed which equalized the magnitude and phase distortions of the ear canal. As a result, an improved acoustical click could be presented to the ear, which allowed for further reduction of the stimulus artifact, revealing early latency emissions. Spectral flatness and effective duration measurements of the compensated click showed an improvement over traditional click stimuli. Furthermore, wavelet analysis and time-frequency latency computations showed that higher frequency otoacoustic emissions were recoverable when using a compensated click stimulus. The swept-tone technique was then utilized for the direct acquisition of otoacoustic emissions. The swept-tone response was compressed to an impulse response and compared to a standard click response. It was found that several similarities exist between the two response types. The divergences, primarily in the low-frequencies, have implications in the generation mechanisms involved in a click-evoked otoacoustic emission. The swept-tone response provided some clinical benefits, namely in an improved signal-to-noise ratio, and in the removal of obstructive synchronized spontaneous OAEs when compared to a standard click response. Current methods are restricted by noise contamination, and the use of a swept-tone technique can reduce the acquisition time by up to a factor of four, compared to standard click methods. These implications and future potential studies are discussed.

Due to most studies on vibration of pre-loaded rectangular plate being subject to uniform loading, this thesis will investigate vibration of plate under preloading with sine functional distributions. The approach behind this study is using first-order shear deformation plate theory and finite element method to analyze vibration frequency. Study results show that, when a plate¡¦s boundary condition is CCCC, SSSS, CFCF, or SFSF with sine functional pre-loading, its vibration frequency will increase to an extent with little difference when the number of modes increases. Vibration frequency will increase shortly then decrease when increasing the number of sine waves. Vibration frequency will also increase when increasing stress parameters. However, obvious frequency changes are observed only at lower modes with SFSF boundary condition.

Univ., Diss./06--Köln, 2005.

Zugl.: Frankfurt (Main), Univ., Diss., 2008

No description available.

Η διακριτοποίηση των μερικών διαφορικών εξισώσεων (ΜΔΕ) αποτελεί κεντρικό βήμα στην αριθμητική τους επίλυση, και ως εκ τούτου είναι ένα από τα βασικά θέματα στα σύγχρονα μαθηματικά. Η μετάβαση από τη συνεχή ΜΔΕ στο αντίστοιχο διακριτό σύστημα μπορεί να γίνει με διάφορες αριθμητικές μεθόδους, ωστόσο δεν είναι όλες οι μέθοδοι εξίσου κατάλληλες και οφείλουμε πάντα να αναζητήσουμε την αρμόζουσα διακριτοποίηση για το εκάστοτε πρόβλημα. Στο 1ο κεφάλαιο γίνεται φανερό, μέσω του απλού παραδείγματος της λογιστικής εξίσωσης, πως μια αφελής διακριτοποίηση δύναται να αλλάξει δραματικά τη φύση του προβλήματος και των λύσεών του. Ιδιαίτερη προσοχή απαιτεί η διατήρηση (πριν και μετά τη διακριτοποίηση) των συμμετριών και των αναλλοίωτων μεγεθών του προβλήματος. Στην παρούσα διπλωματική εργασία μελετάμε την περίπτωση της εξίσωσης sine-Gordon, εστιάζοντας στις σολιτονικές της λύσεις. Στο 2ο κεφάλαιο παρουσιάζεται αναλυτικά η εξίσωση αυτή. Στο 3ο κεφάλαιο μέσω δύο διαφορετικών μεθόδων διακριτοποίησης, δείχνουμε τί ακριβώς πρέπει να προσέξει κανείς έτσι ώστε να δέχεται και το διακριτό σύστημα σολιτονικές λύσεις. Ως γνωστόν οι σολιτονικές λύσεις οφείλουν να πληρούν την ιδιότητα να παραμένουν αναλλοίωτες, διατηρώντας την ταχύτητα και το πλάτος τους πριν και μετά την αλληλεπίδρασή τους. Στο 4ο κεφάλαιο παρουσιάζονται συνοπτικά τα συμπεράσματα της παρούσας εργασίας ενώ συγκρίνουμε και τις δύο μεθόδους αριθμητικής επίλυσης που αναφέραμε. / The discretization of partial differential equations (PDEs) is a key step in their numerical solution, and therefore is one of the main issues in modern mathematics. The transition from continuous PDEs to their discrete counterparts can be done by various numerical methods, though not all methods are equally suitable; for this reason one should be careful to use an appropriate discretization method for each specific problem. In the first chapter it becomes clear, through the simple example of the logistic equation, that a naive discretization may dramatically change the nature of the problem and its solutions. Particular attention needs to be paid to the preservation (before and after the discretization) of the symmetries and invariant quantities of the problem. In the present work we study the case of the famous sine-Gordon equation, focusing on its soliton solutions. The second chapter presents a step-by-step derivation of the aforementioned equation. In the third chapter we show, by means of two different discretization schemes, which conditions must be met in order to guarantee that also the discrete system will admit soliton solutions. As is well known, soliton solutions are required to remain unchanged when they interact with each other, maintaining their speed and amplitude before and after the interaction. In the fourth chapter we summarize the conclusions of this work and draw a comparison between the two numerical schemes we have studied.

SIRT1, appartenant à la famille des sirtuines, est une déacétylase NAD-dépendante, jouant un rôle essentiel dans le contrôle de l’expression génique. En plus de modifier les histones, SIRT1 peut affecter l’activité de certains facteurs de transcription et leurs gènes cibles. Une question fondamentale est de comprendre le mécanisme moléculaire par lequel SIRT1 contrôle l'expression des gènes impliqués dans la prolifération cellulaire et le métabolisme énergétique. Pour identifier les partenaires protéiques de SIRT1, nous avons utilisé la méthode de purification TAP-TAG à partir d'une fraction nucléaire soluble et d'une fraction ancrée à la chromatine de cellules Mef exprimant stablement une copie ectopique de SIRT1 (e-SIRT1). Nous avons ainsi pu identifier un complexe SIRT1 associé à la fois au facteur de prolifération cellulaire Ki67, et à la sous-unité TFIIIC, nécessaire à l'assemblage du complexe de pré-initiation de l'ARN Polymérase III. En délétant sirt1, et en inhibant spécifiquement l'expression de Ki67, nous avons montré que la machinerie de transcription de l'ARN Polymérase III et la prolifération cellulaire étaient fortement affectées. L'ensemble de mes résultats démontre très clairement que SIRT1, Ki67, et TFIIIC sont au sein d'un même complexe protéique, SIRT1 et Ki67 agissant de manière coordonnée pour réguler le niveau d'expression des SINEs et des LINEs, transcrits issus de la machinerie de transcription de l'ARN Polymérase III. / SIRT1, member of the sirtuins family, is an NAD-dependent deacetylase, playing an essential role in controlling gene expression. In addition to modifying histones, SIRT1 can affect the activity of several transcription factors and their target genes. A fundamental question is to understand the molecular mechanisms by which SIRT1 controls the expression of genesinvolved in cell proliferation and energy metabolism. To identify protein partners of SIRT1, we used the method of TAP-TAG purification from a soluble nuclear fraction and a chromatin anchored fraction of Mef cells stably expressing ectopic copy of SIRT1 (SIRT1-e). We were able to identify a SIRT1 complex associated with both cell proliferation factor Ki67, and TFIIIC,subunit required for assembly of the RNA polymerase III pre-initiation complex. By deleting Sirt1, and by specifically inhibiting Ki67 expression, we showed that the RNA Polymerase III transcription machinery and cell proliferation were strongly affected. All of my results clearly shows that SIRT1, Ki67, and TFIIIC are within a same protein complex, SIRT1 and Ki67, acting in coordination to regulate the expression level of SINES and LINES, transcribed from RNA polymerase III transcription machinery.

The aim of this master s dissertation is to identify the social representations constructed around the institution SINE in Santa Maria, having as the main source reports from social actors who frequent this place in search for jobs. It basically intends to understand how the social imaginary takes this institution as one of the main interlocutors with labor world in Santa Maria and as an agency that manages and performs actions of market insertion. Then, this study aims to learn how actors experience this relationship and the meaning they attribute to their actions, having as reference political and institutional practices mirrored by SINE. It intends to rescue the several meanings that people excluded from formal market place have about labor world and the relation with their biographies and their different insertions in the social contexts they are. From this universe of meanings it infers that people establish action plans in their daily routine in relation to labor world and their insertions in it. It highlights that this first view of people about labor world and the place and role of SINE in this context is important because it is a diagnosis not only of the restrict labor world but also of the political world as well as of the status and classes structures in which they are inserted. The contents are linked: basic reasons, such as economic survival with visions about the functioning of the political world. SINE itself constitutes an entity which conserves in its nature and routine these two dimensions to be an organism of (economical) labor managing while it maintains deep connections to the world of politics. The conclusions of the study come from qualitative analysis of semi-structured interviews applied in November, 2009. / A presente dissertação de mestrado tem como finalidade identificar as representações sociais construídas acerca da instituição SINE em Santa Maria utilizando como principal fonte interpretativa os relatos dos atores sociais que circulam neste local à procura de trabalho. Aspira-se, fundamentalmente, entender como o imaginário social apropria-se desta instituição enquanto um dos principais interlocutores com o mundo do trabalho em Santa Maria e enquanto agência que administra e executa ações de inserção no mercado. Com isso, o estudo procura aprender a forma como os atores vivem essa relação e o sentido que atribuem as suas ações tendo como referência as políticas e práticas institucionais espelhadas pelo SINE. Pretende-se recuperar os universos de significados dos indivíduos excluídos do mercado de trabalho formal sobre o mundo do trabalho e da relação que se verifica com suas biografias e suas inserções mais diversas nos contextos sociais em que estão inseridos. Deste universo de significados capturado depreende-se que os indivíduos estabelecem planos de ação no cotidiano relativamente ao mundo do trabalho e de suas inserções nele. Enfatiza-se que esta primeira leitura dos indivíduos sobre o mundo do trabalho e do lugar e função do SINE nessa conjuntura é importante porque se trata de um diagnóstico não somente do mundo estrito do trabalho, como do mundo da política e da estrutura de status e de classes em que estão inseridos. Os conteúdos interligam-se: motivos básicos, como os da sobrevivência econômica, com visões sobre o funcionamento do mundo político. A própria instituição SINE constitui-se em uma entidade que conserva na sua natureza e rotinas estas duas dimensões, a de ser um organismo de gestão de mão de obra (econômico), ao tempo em que mantém profunda conexão com o mundo da política. As conclusões do estudo emanam da análise qualitativa das entrevistas semi-estruturadas aplicadas no mês de novembro de 2009.

Retrotransposons comprise a large portion of mammalian genomes. They contribute to structural changes and more importantly to gene regulation. The expansion and diversification of gene families have been implicated as sources of evolutionary novelties. Given the roles retrotransposons play in genomes, their contribution to the evolution of gene families warrants further exploration. In this study, we found a significant association between two major retrotransposon classes, LINEs and LTRs, and lineage-specific gene family expansions in both the human and mouse genomes. The distribution and diversity differ between LINEs and LTRs, suggesting that each has a distinct involvement in gene family expansion. LTRs are associated with open chromatin sites surrounding the gene families, supporting their involvement in gene regulation, whereas LINEs may play a structural role promoting gene duplication. Our findings also suggest that gene family expansions, especially in the mouse genome, undergo two phases. The first phase is characterized by elevated deposition of LTRs and their utilization in reshaping gene regulatory networks. The second phase is characterized by rapid gene family expansion due to continuous accumulation of LINEs and it appears that, in some instances at least, this could become a runaway process. We provide an example in which this has happened and we present a simulation supporting the possibility of the runaway process. Altogether we provide evidence of the contribution of retrotransposons to the expansion and evolution of gene families. Our findings emphasize the putative importance of these elements in diversification and adaptation in the human and mouse lineages.

Influenza A virus (IAV) is a global health threat, causing seasonal epidemics and potential pandemics leading to morbidity, death and economic losses. Currently, there are two main classes of licensed antivirals against IAV available in the US and Europe; adamantanes and neuraminidase inhibitors, both of which are hindered by the generation of resistant virus variants. The viral polymerase has a high error rate leading to mutations that allow the virus to overcome selection pressures directed at its own genome from conventional antivirals. The prospect of inhibiting host proteins that the virus exploits to facilitate its replication is of increasing interest as an antiviral strategy as the emergence of resistance has been predicted to be slower when targeting a host cellular factor. IAV utilizes the host nuclear export protein CRM1 to transport viral ribonucleoproteins (vRNPs) from the nucleus to the cytoplasm of an infected cell, a critical late stage of the influenza lifecycle. Leptomycin B (LMB), a Streptomyces metabolite, has been previously shown to target this pathway, resulting in reduced viral propagation; however, LMB's potent cytotoxicity has limited its use as a therapeutic agent. This thesis examined two novel selective inhibitors of nuclear export (SINE), KPT-335 and KPT-185, with less cytotoxicity. In vitro, KPT-335 inhibited replication of human and animal IAV strains in a dose-dependent manner with minimal cytotoxicity. To assess the resistance potential of KPT-335, IAV viruses were serially passaged in the presence of a sub-optimal concentration of the compound and assayed for the development of resistance. Resistance to KPT-335 became evident at 8-10 rounds of passage. Sequencing analysis of independently derived resistant virus clones identified 4 single amino acid changes on a surface exposed patch of the viral nucleoprotein (NP). Introduction of these amino acid changes, into otherwise wild type viruses by reverse genetics, confirmed that changes Q311R and N309T conferred a drug-resistant phenotype. However, these substitutions came at a fitness cost to virus replication. The molecular basis for resistance was unclear but Q311R and N309T NP-mutant viruses produced increased levels of M1 during infection as well as producing virus particles with increased M1:NP ratios. Furthermore, the KPT-335-resistance mutations were surprisingly similar to NP sequence polymorphisms previously associated with susceptibility to the innate defence protein MxA. Consistent with this, viruses harbouring the Q311R mutation displayed increased susceptibility to MxA inhibition compared to wild-type virus. Altogether this study confirms that SINEs have the potential to be successful therapeutic agents against IAV replication and that although resistance could be generated, it may be difficult for the virus to overcome both drug selection pressures and the human innate immune response restrictions by escape mutations.