Turing's menagerie:Talking lions, virtual bats, electric sheep and analogical peacocks: Common ground and common interest are necessary components of engagement

This theoretical paper attempts to define some of the key components and challenges required to create embodied conversational agents that can be genuinely interesting conversational partners. Wittgenstein's argument concerning talking lions emphasizes the importance of having a shared common ground as a basis for conversational interactions. Virtual bats suggests that-for some people at least-it is important that there be a feeling of authenticity concerning a subjectively experiencing entity that can convey what it is like to be that entity. Electric sheep reminds us of the importance of empathy in human conversational interaction and that we should provide a full communicative repertoire of both verbal and non-verbal components if we are to create genuinely engaging interactions. Also we may be making the task more difficult rather than easy if we leave out non-verbal aspects of communication. Finally, analogical peacocks highlights the importance of between minds alignment and establishes a longer term goal of being interesting, creative, and humorous if an embodied conversational agent is to be truly an engaging conversational partner. Some potential directions and solutions to addressing these issues are suggested.

Ravel’s Gaspard de la Nuit: Extra-musical subtext, and its role within interpretive performance

Few works within the realm of the piano repertoire have amassed a reputation as formidable as Gaspard de la Nuit. These three pieces, each unique in character and pianistic requirements, arguably represent a pinnacle of early 20th-century French piano music. This paper seeks to illuminate points for consideration for the pianist who wishes to embark upon studying the work for performance, and for the musicologist.

I shall first consider the three character poems of Aloysius Bertrand that inspired the suite, as an understanding of these Diabolic creations is essential to understanding the piece analytically and programmatically. I shall then explore the subtitle of Bertrand’s Gaspard de la Nuit: ‘Fantaisies À La Manière De Rembrandt Et De Callot’, as an acknowledgement of these artists helps us better to engage with Bertrand’s poetry, and provides us with a direct link to the visual stimuli for Ravel’s compositions.

Finally, using Ondine as a case study, I shall explore how the composer unifies his inspirations to paint a musical portrait of both the character and the content of Bertrand’s poem. I shall focus on three particular aspects of Ravel’s style: the refined textures that create washes of watery colour, subtle rhythmic variations that imply the ‘deep, rolling currents of the sleeping lake’, and the simple melodic lines sung by the water nymph in the manner of a French air. Each element plays its part in the thematic development that illustrates Ondine’s seductive powers.

An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors.

Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation.

Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM).

Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene).

Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

Molecular characterization of immunoglobulin gene rearrangements in diffuse large B-cell lymphoma: antigen-driven origin and IGHV4-34 as a particular subgroup of the non-GCB subtype.

The pathogenesis of diffuse large B-cell lymphoma (DLBCL) remains partially unknown. The analysis of the B-cell receptor of the malignant cells could contribute to a better understanding of the DLBCL biology. We studied the molecular features of the immunoglobulin heavy chain (IGH) rearrangements in 165 patients diagnosed with DLBCL not otherwise specified. Clonal IGH rearrangements were amplified according to the BIOMED-2 protocol and PCR products were sequenced directly. We also analyzed the criteria for stereotyped patterns in all complete IGHV-IGHD-IGHJ (V-D-J) sequences. Complete V-D-J rearrangements were identified in 130 of 165 patients. Most cases (89%) were highly mutated, but 12 sequences were truly unmutated or minimally mutated. Three genes, IGHV4-34, IGHV3-23, and IGHV4-39, accounted for one third of the whole cohort, including an overrepresentation of IGHV4-34 (15.5% overall). Interestingly, all IGHV4-34 rearrangements and all unmutated sequences belonged to the nongerminal center B-cell-like (non-GCB) subtype. Overall, we found three cases following the current criteria for stereotyped heavy chain VH CDR3 sequences, two of them belonging to subsets previously described in CLL. IGHV gene repertoire is remarkably biased, implying an antigen-driven origin in DLBCL. The particular features in the sequence of the immunoglobulins suggest the existence of particular subgroups within the non-GCB subtype.

Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma.

The ability to rearrange the germ-line DNA to generate antibody diversity is an essential prerequisite for the production of a functional repertoire. While this is essential to prevent infections, it also represents the "Achilles heel" of the B-cell lineage, occasionally leading to malignant transformation of these cells by translocation of protooncogenes into the immunoglobulin (Ig) loci. However, in evolutionary terms this is a small price to pay for a functional immune system. The study of the configuration and rearrangements of the Ig gene loci has contributed extensively to our understanding of the natural history of development of myeloma. In addition to this, the analysis of Ig gene rearrangements in B-cell neoplasms provides information about the clonal origin of the disease, prognosis, as well as providing a clinical useful tool for clonality detection and minimal residual disease monitoring. Herein, we review the data currently available on both Ig gene rearrangements and protein patterns seen in myeloma with the aim of illustrating how this knowledge has contributed to our understanding of the pathobiology of myeloma.

Molecular characteristics and gene segment usage in IGH gene rearrangements in multiple myeloma.

BACKGROUND AND OBJECTIVES: Analysis of IgH rearrangements in B-cell malignancies has provided clinical researchers with a wide range of information during the last few years. However, only a few studies have contributed to the characterization of these features in multiple myeloma (MM), and they have been focused on the analysis of the expressed IgH allele only. Comparison between the expressed and the non-functional IgH alleles allows further characterizion of the selection processes to which pre-myeloma cells are submitted. DESIGN AND METHODS: We analyzed a cohort of 84 untreated MM patients in order to characterize their functional VDJH and non-functional DJH rearrangements. The pattern of mutations and gene segment usage for both types of rearrangements was analyzed by polymerase chain reaction and sequencing. RESULTS: VH3 and VH1 family members were over- and under-represented, respectively. VH3-30 and VH3-15 segments were the most frequently used, whereas VH4-34 was found only in non-functional or heavily mutated VDJH rearrangements. DH2 and DH3 family members were over-represented in both VDJH and DJH repertoires, while the DH1 family was under-represented only in the productive VDJH rearrangements. Finally, DH3-22 and DH2-21 gene segments were found to be over-represented in the functional repertoire while segments commonly used by less mature B-cell malignancies, such as DH6-19 or DH3-3, were under-represented. INTERPRETATION AND CONCLUSIONS: Data reported here help to identify the clonogenic MM cell as a post-germinal center B cell that has undergone selection processes during the germinal center reaction.

Cell cycle-coupled expansion of AR activity promotes cancer progression

The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

To breathe or fight? Siamese fighting fish differ when facing a real opponent or mirror image

Displays are a feature of animal contest behaviour and have been interpreted as a means of gathering information on opponent fighting ability, as well as signalling aggressive motivation. In fish, contest displays often include frontal and lateral elements, which in the latter involves contestants showing their flanks to an opponent. Previous work in a range of fish species has demonstrated population-level lateralization of these displays, preferentially showing one side to their opponent. Mirrors are commonly used in place of a real opponent to study aggression in fish, yet they may disrupt the normal pattern of display behaviour. Here, using Siamese fighting fish, Betta splendens, we compare the aggressive behaviour of males to a mirror image and real opponent behind a transparent barrier. As this species is a facultative air-breather, we also quantify surface breathing, providing insights into underlying fight motivation. Consistent with previous work, we found evidence of population-level lateralization, with a bias to present the left side and use the left eye when facing a real opponent. Contrary to expectations, there were no differences in the aggressive displays to a mirror and real opponent, with positive correlations between the behaviour in the two scenarios. However, there were important differences in surface breathing, which was more frequent and of longer duration in the mirror treatment. The reasons for these differences are discussed in relation to the repertoire of contest behaviour and motivation when facing a real opponent.

Étude de la reconstitution de l’immunité spécifique au cytomégalovirus et au virus de la varicelle suite à la transplantation de sang de cordon ombilical

La transplantation de sang de cordon ombilical (TSCO) constitue un traitement de choix pour une multitude de pathologies hématologiques malignes et non malignes chez l’enfant et dans certains cas l’adulte. La TSCO est associée à certaines complications, dont une reconstitution immunitaire plus lente et une incidence élevée d’infections opportunistes, notamment celles reliées au cytomégalovirus (CMV) et au virus varicella-zoster (VZV). Dans le cadre de ce travail, nous nous sommes intéressés dans un premier temps à la caractérisation de la reconstitution immunitaire spécifique au CMV et au VZV. Nos résultats ont démontré que la reconstitution de l’immunité cellulaire ne requiert ni un statut séropositif pré-transplantation ni le développement de la maladie. De plus, des reconstitutions spontanées ont été détectées chez certains patients séronégatifs vis-à-vis du CMV ou du VZV. Outre le fait qu’elle se manifeste surtout à partir de 6 mois post-transplantation, ladite reconstitution mérite le qualificatif de « protectrice » en termes de réactivations virales et du développement de signes cliniques lorsqu’une fréquence de 150 cellules produisant l’IFN-γ/million est dépassée. Toutefois, moins de 5% des patients développent une réponse T anti-VZV et anti-CMV au cours 100 premiers jours suivant la TSCO. Il est donc possible que les lymphocytes CD8+ T provenant du SCO, comparativement à leurs homologues provenant de la moelle osseuse (MO), présentent un défaut de fonctionnalité, communément appelé « épuisement clonal ». La caractérisation du répertoire de récepteurs inhibiteurs exprimés par les cellules T CD8+ suivant la TSCO ou la transplantation de moelle osseuse (TMO) a révélé une augmentation significative de la fréquence des cellules exprimant PD-1 tôt suivant la transplantation. Cette population, caractérisée majoritairement par un phénotype effecteur-mémoire (EM), démontre une perte significative de la capacité proliférative et exprime moins d'IFN-γ, d'IL-2, de TNF-α et de CD107a. Une meilleure caractérisation de la reconstitution immunitaire après TSCO permettrait, d'une part de sélectionner des biomarqueurs en vue d’une meilleure gestion des patients à risques de développer des infections virales et/ou de rechuter, et d'autre part d'améliorer leur pronostic.

An investigation of Hebbian phase sequences as assembly graphs

Hebb proposed that synapses between neurons that fire synchronously are strengthened, forming cell assemblies and phase sequences. The former, on a shorter scale, are ensembles of synchronized cells that function transiently as a closed processing system; the latter, on a larger scale, correspond to the sequential activation of cell assemblies able to represent percepts and behaviors. Nowadays, the recording of large neuronal populations allows for the detection of multiple cell assemblies. Within Hebb's theory, the next logical step is the analysis of phase sequences. Here we detected phase sequences as consecutive assembly activation patterns, and then analyzed their graph attributes in relation to behavior. We investigated action potentials recorded from the adult rat hippocampus and neocortex before, during and after novel object exploration (experimental periods). Within assembly graphs, each assembly corresponded to a node, and each edge corresponded to the temporal sequence of consecutive node activations. The sum of all assembly activations was proportional to firing rates, but the activity of individual assemblies was not. Assembly repertoire was stable across experimental periods, suggesting that novel experience does not create new assemblies in the adult rat. Assembly graph attributes, on the other hand, varied significantly across behavioral states and experimental periods, and were separable enough to correctly classify experimental periods (Naïve Bayes classifier; maximum AUROCs ranging from 0.55 to 0.99) and behavioral states (waking, slow wave sleep, and rapid eye movement sleep; maximum AUROCs ranging from 0.64 to 0.98). Our findings agree with Hebb's view that assemblies correspond to primitive building blocks of representation, nearly unchanged in the adult, while phase sequences are labile across behavioral states and change after novel experience. The results are compatible with a role for phase sequences in behavior and cognition.

Un répertoire de musique brésilienne adapté à l’enseignement collectif du trombone

Cette thèse, complémentaire à deux récitals donnés dans le cadre de la réalisation d’un doctorat en études pédagogiques et pratiques musicales instrumentales, a comme fil conducteur l’enseignement collectif du trombone au Brésil et examine le trombone sous trois angles : historique, pédagogique et dans une perspective d’interprétation musicale. Bien que le sujet ne soit pas nouveau, le projet présente une réflexion, sur le trombone et son enseignement, encore inexplorée en raison principalement du répertoire sélectionné pour la présente étude. En effet, à notre connaissance, le répertoire populaire brésilien n’a jusqu’à maintenant pas fait l’objet d’arrangements musicaux écrits, en vue d’une exploitation non seulement en contexte de représentation publique, mais aussi avec des visées pédagogiques. Les morceaux choisis ont été retenus en raison de leur contenu, qui présente un vocabulaire musical lié à la culture régionale de quatre des cinq régions géographiques du Brésil. Dans le processus de réalisation du projet, les morceaux choisis ont fait l’objet d’arrangements dans la perspective qu’ils servent comme outil pédagogique pour la formation en trombone, en contexte de musique brésilienne. Les arrangements ont été conçus pour des ensembles réduits, où le trombone tient fréquemment le rôle de soliste. Ainsi, au-delà des concepts et techniques issus de la formation traditionnelle reçue, l’interprétation des arrangements a été une occasion pour le doctorant et soliste de présenter, à travers l’improvisation dans le langage de la musique populaire brésilienne, les résultats de processus développés au cours des deux dernières années. Les partitions sont annexées au texte de la thèse, afin d’illustrer certains propos et avec l’objectif de soutenir les recherches futures dans ce domaine. La thèse est divisée en quatre chapitres lesquels, bien que présentés séparément, possèdent entre eux d’étroites relations. Le premier chapitre donne un aperçu général de l’histoire de l’instrument, à travers les cinq siècles de son existence. Le deuxième chapitre s’articule autour de l’histoire de la musique brésilienne et de la présence du trombone au Brésil. Le troisième chapitre présente d’abord un aperçu de l’enseignement artistique et musical au Brésil au 20e et 21e siècle, poursuit en abordant la situation de l’enseignement du trombone au Brésil et aboutit à une proposition favorisant l’apprentissage du trombone en contexte d’enseignement musical collectif. Finalement, le quatrième chapitre fait un retour sur l’expérience musicale vécue dans le premier volet du projet, celui se rapportant à la pratique musicale instrumentale, établit des liens et trace des pistes dans une perspective d’enseignement et d’apprentissage du trombone.

It's Not Rocket Library Science: Design Epistemology and American Librarianship

Thesis (Ph.D.)--University of Washington, 2016-06

Saraswati Sings: The Slide-Guitar in India

Thesis (Ph.D.)--University of Washington, 2016-08

Modern Horn Playing in Beethoven: An Exploration of Period Appropriate Techniques for the Orchestral Music of Beethoven for the Modern Horn Player

Thesis (D.M.A.)--University of Washington, 2016-06