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SMAC mimetic compounds (SMCs) are small molecule antagonists of the Inhibitor of Apoptosis (IAP) family of proteins. Binding of SMCs to the IAPs results in the sensitization of cancer cells to apoptosis in the presence of death ligands, such as tumour necrosis factor alpha (TNFα). I hypothesize that type I interferon (IFN) stimulation in cancer cells and in immune cells leads to the production of TNFα, which can then synergize with SMCs to kill cancer cells. The combined treatment of SMC and IFNα induces tumour regression in mice, and this effect is completely abrogated upon treatment with TNFα-neutralizing antibody. The synergistic effects are mediated by tumour cells and by contribution of immune cells, particularly macrophages and dendritic cells, as the systemic depletion of phagocytic innate immune cells results in an increase in tumour volume following combination treatment. The characterization of immune cell contribution will aid in the translation of the SMC combination therapy into clinical applications for the treatment of cancer.

Mimetics in Japanese comprise both onomatopoeic expressions (phonomimes) and other ideophones (phenomimes; psychomimes), which do not imitate acoustic phenomena. They can appear in various syntactic positions and adopt the syntactic functions of nouns in a referential phrase, predicates, attributes in a noun phrase and adverbs, with the latter being the most common usage. Since the stem of mimetic expressions such as SUTON ("thump"), KIRARI ("flash"), KYAAA ("Aaaah!") or GAN-GAN ("pounding") cannot be altered and common suffixes such as /N/, /RI/ and /Q/ (glottal stop) cannot be inflected, the syntactic function of mimetics in Japanese is determined by their position in the sentence and the particles (postpositions) used to indicate their function within a larger constituent. In colloquial speech, these particles may also be omitted, which sometimes results in the syntactic position being the only indicator of the syntactic function. However, when contrasting the grammatical usage of mimetics in data sources from various speech registers, it becomes apparent that not all mimetics are used with all particles and in all syntactic positions. Moreover, some mimetics may be combined with certain particles in idiomatic contexts, but would be used differently in spontaneous speech. For this reason, it is not surprising that opinions vary greatly when it comes to determining the distribution of individual mimetics, and mimetics as a class. This often results in L2 learners of Japanese being confused by contradictory statements in dictionaries and textbooks, which may not necessarily reflect the actual usage of mimetics in spoken Japanese and thus constitute an obstacle to effective language learning. The focus of this thesis is a description of the variable use of selected mimetics in attributive contexts, to shed light on the factors underlying the variation, and to establish whether a language change has been taking place in recent years. Empirical data collected from dictionaries, corpora, surveys and interviews shows that sociolinguistic factors such as gender, age and media exposure may influence the grammatical preferences of native speakers and their perception of mimetics. For this reason, both linguistic and extra-linguistic factors have to be taken into account in order to establish a grammatical framework for mimetics in Japanese.

Recent research on Japanese mimetics examines which part of speech the mimetic occurs as. An individual mimetic can appear as a noun, an adjective, an adverb, or a verb (Tsujimura & Deguchi 2007, 340). It is assumed by many scholars that mimetic words essentially function as adverbs (Inose 2007, 98). Few data-based studies exist that quantify the relative frequency of mimetic words in different word categories. Akita (2009) and Caldwell (2009a) have performed small scale or preliminary studies of this aspect of Japanese mimetics. The use of mimetics in other grammatical function categories has been attributed to the polysemous nature of Japanese mimetics (Key 1997). The common explanation is that the flexibility of mimetics is probably due to their iconicity (Sugiyama 2005, 307; Akita 2009; among others). Yet the definition of "iconicity" is often incomplete or cursory in nature. Newmeyer, Nuckolls, Kohn, and Key all accept or suggest the philosophies of C.S. Peirce as a possible explanation or source for understanding the iconicity of mimetic words. The purpose of this thesis is twofold: first, examine the prominent semantic theories regarding Japanese mimetics and show how the philosophies of Peirce can add clarity; second, examine overall occurrence of 1700+ mimetics per parts of speech using the data from the Kotonoha (http://www.kotonoha.gr.jp) and JpWaC (http://corpus.leeds.ac.uk/) Corpora. Peirce identified three distinct icon types: icons of abstract quality (1-1-1), icons of physical instantiation (1-1-2), and icons of abstract relation (1-1-3). These three types correspond to three distinct types of mimetic word: phonomimes (abstract sound qualities), typically predicate modifiers, phenomimes (physical actions), more often nouns or noun modifiers, and psychomimes, (relational), more often verbs or parts of verbs. Corpus data validates the observation that mimetics are usually functioning as predicate modifiers, but also supports Akita's hypothesis that psychomimes are incorporated into verbs more readily than other mimetics, which in turn is explained by the Peircean analysis.

The Inhibitor of Apoptosis (IAP) proteins are a highly conserved group of anti-apoptotic proteins that regulate various pathways, particularly those that affect proliferation and cell death. Smac mimetics compounds (SMCs) are IAP antagonists that induce the degradation of two IAPs, cellular IAP 1 (cIAP1) and cellular IAP 2 (cIAP2). cIAP1 and cIAP2 are negative regulators of the alternative NF-κB pathway, which is critical to the regulation, activation, proliferation, and survival of immune cells. Consequently, SMCs can affect immunological responses by providing co-stimulatory signals for antigen-presenting cells or promoting proliferation and activation of T cells. Due to their potent immunomodulatory properties, SMCs are an ideal candidate for new vaccine adjuvants. I sought to demonstrate the potential of SMCs as a vaccine adjuvant by evaluating SMCs effects on dendritic cells (DCs). I demonstrated that SMC treatment of bone marrow derived dendritic cells (BMDCs) induces degradation of both cIAP1 and cIAP2 and leads to activation of the alternative NF-κB signalling pathway. Furthermore, SMC treatment led to upregulation of proteins associated with DC maturation, as well as secretion of pro-inflammatory cytokines. Despite the activating effects elicited by SMCs in vitro, the use of SMCs as an adjuvant for peptide vaccination failed to prevent tumour growth. Further work to determine the best use of SMCs as adjuvants in vivo needs to be done to explore the potential of this class of drugs. Thus, these findings will guide the use of SMCs in adjuvant vaccine therapies for robust protective immunity.

The relationship between ideophones and gestures has only recently been studied and is not yet completely understood. The topic has been specifically addressed by Kita (1993), Klassen (1998), Dingemanse (2013), Mihas (2013), and Reiter (2013). Yet there has been little focus on onomatopoeic ideophones. Onomatopoeic ideophones have been set aside as different by many previous researchers (Klassen, 1998, pp. 28-31; Kilian-Hatz, 2001, pp. 161-163; Dingemanse, 2011, pp. 131, 165-167; Mihas, 2012, pp. 327-329; Reiter, 2013, pp. 9-10, 308). Being stigmatized as simple, they have been labeled as "sound mimicking words" (McGregor, 2002, p. 341), "non-linguistic sounds" (Güldemann, 2008, p. 283), or "imitative sounds" (Hinton et al., 1994, §2.1). This thesis specifically addresses the relationship between onomatopoeic ideophones and gestures in Pastaza Quichua (PQ). My data acquired from primary and secondary sources, consists of 69 interactions, comprising eight hours of video recordings collected in Tena, Ecuador. These recordings include traditional narratives, personal experience tellings, elicited descriptions of nature, short didactic explanations, and folksongs. My methodology consists of close examination, classification, and tagging of 435 ideophones in the PQ data for sensory class and gestural accompaniment, using McNeill's (1992) typology. This thesis demonstrates that onomatopoeic ideophones do not have the same relationship with gestures that synesthetic ideophones do. Synesthetic ideophones are consistently accompanied by gestures (94.4% of the time) while onomatopoeic ideophones are much less likely to be accompanied by gestures (27.0% of the time). The lack of gestures occurring with onomatopoeic ideophones is striking given that PQ speakers seem to be constantly gesturing during speech. The PQ data supports previous observations that most gestures accompanying ideophones are iconic (Kunene, 1965; Dingemanse, 2013; Reiter, 2013; Mihas, 2013; Kita, 1993). The data also supports McNeill's (2007, p. 11) statement that gestures are used to make an image more real and that repetition can lead to fading gestures. However, it challenges his prediction that a minimal departure from context is the cause of a conspicuous lack of gesture. Sensory type, that is whether an ideophone is onomatopoeic or not, seems to be the most important factor in predicting gestural behavior. This paper also contributes to a better understanding of the relationship between ideophones and gestures and, ultimately, between language and gesture.

Small molecular Inhibitor of Apoptosis (IAP) antagonists, known as Smac mimetic compounds (SMCs), are a novel class of anti-cancer drugs currently undergoing clinical trials. SMCs were designed to mimic the function of the pro-apoptotic protein, Smac, which directly depletes cells of cIAP1 and cIAP2, and consequently renders tumour cells sensitive to death in the presence of proinflammatory ligands such as TNFα. The Korneluk lab recently reported that SMCs synergize with the attenuated oncolytic virus Vesicular stomatitis virus (VSVΔ51) by eliciting an enhanced immune response in mice, such that the combined therapy is vastly superior to stand-alone therapies. To improve on this SMC-mediated synergistic response, I generated variants of TNFα-armed VSVΔ51. Due to high ectopic expression of TNFα in infected cells, a five times lower viral dose of TNFα-armed VSVΔ51 combined with SMC treatment was sufficient to improve the survival rate as compared to SMC and VSVΔ51 co-therapy. This improved synergistic response is attributed to a bystander effect whereby the spread of TNFα from infected cells leads to the death of neighbouring, uninfected cells in the presence of a SMC. In addition, the double treatment induced vasculature collapse in solid tumours, revealing another mechanism by which cytokine-armed VSVΔ51 in combination with a SMC can induce cancer cell death. This approach demonstrates great potential for engineered oncolytic virus and SMCs as a new combination immunotherapy for cancer treatment.

L'autophagie est un processus d'auto-digestion durant lequel les cellule dégradent leurs propres composants afin de maintenir l’homéostasie en conditions basales. L'autophagie est donc nécessaire à l’échelle de la cellule et de l’organisme car elle joue un rôle dans l’élimination des organites endommagés et des agrégats de protéines potentiellement nocifs et a la capacité de mobiliser les métabolites essentiels des réserves énergétiques en conditions de stressLa détérioration des fonctions cellulaires et au niveau de l’organisme liée à l'âge est associée à une dérégulation des voies de détection des nutriments ainsi qu’à une autophagie déficiente. La réactivation du flux autophagique peut prévenir ou améliorer ces dysfonctionnements métaboliques liés à l'âge. Les composés non toxiques capables de réduire les taux globaux d'acétylation des protéines et d'induire l'autophagie ont été classés dans la catégorie des agents mimétiques de restriction calorique (CRMs, de l’anglais « caloric restriction mimetic »). Nous montrons ici que l'aspirine et son métabolite actif, le salicylate, induisent une autophagie en raison de leur capacité à inhiber l'activité acétyltransférase de EP300. Alors que le salicylate stimule le flux autophagique dans les cellules « Wild Type », il ne permet pas d’augmenter le niveau d'autophagie dans les cellules déficientes en EP300, ni dans les cellules dans lesquelles EP300 endogène a été remplacé par les mutants EP300 résistants au salicylate. En conséquence, l'activité pro-autophagique de l'aspirine et du salicylate sur le nématode Caenorhabditis elegans est perdue lorsque l'expression de l'orthologue EP300 cpb-1 est réduite. Ces résultats permettent de conclure que l'aspirine est un CRM dont le mécanisme est conservé au cours de l’évolution. / Autophagy is a self-digestion process in which cell degrades its own components in order to maintain homeostasis in basal conditions; autophagy is required for the maintenance of cellular and organismal fitness due to its role in eliminating damaged organelles and potentially harmful protein aggregates, as well as its unique capacity to mobilize essential metabolites from complex energy stores in conditions of stress.The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21133号 / 農博第2259号 / 新制||農||1057(附属図書館) / 学位論文||H30||N5107(農学部図書室) / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 保川 清, 教授 金本 龍平, 准教授 井上 和生 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM