Molecular mechanism of insulin-enhancing and -mimetic action of Vanadium compounds

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

β-Strand mimetic foldamers rigidified through dipolar repulsion

Many therapeutically relevant protein-protein interactions contain hot-spot regions on secondary structural elements, which contribute disproportionately to binding enthalpy. Mimicry of such α-helical regions has met with considerable success, however the analogous approach for the β-strand has received less attention. Presented herein is a foldamer for strand mimicry in which dipolar repulsion is a central determinant of conformation. Computation as well as solution- and solid-phase data are consistent with an ensemble weighted almost exclusively in favor of the desired conformation.

An anti-TNF--α antibody mimetic to treat ocular inflammation

Infliximab is an antibody that neutralizes TNF-α and is used principally by systemic administration to treat many inflammatory disorders. We prepared the antibody mimetic Fab-PEG-Fab (FpFinfliximab) for direct intravitreal injection to assess whether such formulations have biological activity and potential utility for ocular use. FpFinfliximab was designed to address side effects caused by antibody degradation and the presence of the Fc region. Surface plasmon resonance analysis indicated that infliximab and FpFinfliximab maintained binding affinity for both human and murine recombinant TNF-α. No Fc mediated RPE cellular uptake was observed for FpFinfliximab. Both Infliximab and FpFinfliximab suppressed ocular inflammation by reducing the number of CD45+ infiltrate cells in the EAU mice model after a single intravitreal injection at the onset of peak disease. These results offer an opportunity to develop and formulate for ocular use, FpF molecules designed for single and potentially multiple targets using bi-specific FpFs.

Use of GLP-1 mimetic in type 2 diabetes mellitus: is it the end of fragility fractures?

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A PHENOMENOLOGY OF MIMETIC LEARNING AND MULTIMODAL COGNITION: INTEGRATING EXPERIENTIAL KNOWLEDGE INTO PROGRAMS IN RHETORIC, COMPOSITION, AND TECHNICAL COMMUNICATION

My dissertation emphasizes a cognitive account of multimodality that explicitly integrates experiential knowledge work into the rhetorical pedagogy that informs so many composition and technical communication programs. In these disciplines, multimodality is widely conceived in terms of what Gunther Kress calls “socialsemiotic” modes of communication shaped primarily by culture. In the cognitive and neurolinguistic theories of Vittorio Gallese and George Lakoff, however, multimodality is described as a key characteristic of our bodies’ sensory-motor systems which link perception to action and action to meaning, grounding all communicative acts in knowledge shaped through body-engaged experience. I argue that this “situated” account of cognition – which closely approximates Maurice Merleau-Ponty’s phenomenology of perception, a major framework for my study – has pedagogical precedence in the mimetic pedagogy that informed ancient Sophistic rhetorical training, and I reveal that training’s multimodal dimensions through a phenomenological exegesis of the concept mimesis. Plato’s denigration of the mimetic tradition and his elevation of conceptual contemplation through reason, out of which developed the classic Cartesian separation of mind from body, resulted in a general degradation of experiential knowledge in Western education. But with the recent introduction into college classrooms of digital technologies and multimedia communication tools, renewed emphasis is being placed on the “hands-on” nature of inventive and productive praxis, necessitating a revision of methods of instruction and assessment that have traditionally privileged the acquisition of conceptual over experiential knowledge. The model of multimodality I construct from Merleau-Ponty’s phenomenology, ancient Sophistic rhetorical pedagogy, and current neuroscientific accounts of situated cognition insists on recognizing the significant role knowledges we acquire experientially play in our reading and writing, speaking and listening, discerning and designing practices.

Varieties of Asian capitalism : toward an institutional theory of Asian enterprise

In this paper we respond to calls for an institution-based perspective on strategy. With its emphasis upon mimetic, coercive, and normative isomorphism, institutional theory has earned a deterministic reputation and seems an unlikely foundation on which to construct a theory of strategy. However, a second movement in institutional theory is emerging that gives greater emphasis to creativity and agency. We develop this approach by highlighting co-evolutionary processes that are shaping the varieties of capitalism (VoC) in Asia. To do so, we examine the extent to which the VoC model can be fruitfully applied in the Asian context. In the spirit of the second movement of institutional theory, we describe three processes in which firm strategy collectively and intentionally feeds back to shape institutions: (1) filling institutional voids, (2) retarding institutional innovation, and (3) deploying institutional escape. We outline the key contributions contained in the articles of this Special Issue and discuss a research agenda generated by the VoC perspective.

Social change grant-making : a failure of innovation?

Focusing primarily on Anglophone countries, this article begins by looking at the changing environment of foundations, the pressures on foundations and some responses to those pressures. It then focuses on the potential of a structural change approach - often known as 'social change' or 'social justice' grant-making - as a solution to some of the modern dilemmas of foundations, and considers why this approach has, with some exceptions, gained relatively little support. This raises the wider issues of why and how resource-independent, endowed foundations change when conventional explanations of organisational change do not easily apply. Researching a 'lack' is clearly difficult; this article adopts an analytic perspective, examining the characteristics of the structural change approach as a mimetic model, and draws on the work of Rogers (2003) on the characteristics required for the successful diffusion of innovations. It suggests that the structural change approach suffers from some fundamental weaknesses as a mimetic model, failing to meet some key characteristics for the diffusion of innovations. In conclusion, the article looks at conditions under which these weaknesses may be overcome.

Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides

Tissue damage resulting from the extracellular production of HOCl (hypochlorous acid) by the MPO (myeloperoxidase)-hydrogen peroxide-chloride system of activated phagocytes is implicated as a key event in the progression of a number of human inflammatory diseases. Consequently, there is considerable interest in the development of therapeutically useful MPO inhibitors. Nitroxides are well established antioxidant compounds of low toxicity that can attenuate oxidative damage in animal models of inflammatory disease. They are believed to exert protective effects principally by acting as superoxide dismutase mimetics or radical scavengers. However, we show here that nitroxides can also potently inhibit MPO-mediated HOCl production, with the nitroxide 4-aminoTEMPO inhibiting HOCl production by MPO and by neutrophils with IC50 values of approx. 1 and 6 μM respectively. Structure–activity relationships were determined for a range of aliphatic and aromatic nitroxides, and inhibition of oxidative damage to two biologically-important protein targets (albumin and perlecan) are demonstrated. Inhibition was shown to involve one-electron oxidation of the nitroxides by the compound I form of MPO and accumulation of compound II. Haem destruction was also observed with some nitroxides. Inhibition of neutrophil HOCl production by nitroxides was antagonized by neutrophil-derived superoxide, with this attributed to superoxide-mediated reduction of compound II. This effect was marginal with 4-aminoTEMPO, probably due to the efficient superoxide dismutase-mimetic activity of this nitroxide. Overall, these data indicate that nitroxides have considerable promise as therapeutic agents for the inhibition of MPO-mediated damage in inflammatory diseases.

Protrusion I

Protrusion I is a self-portrait bust, rendered with a high degree of naturalism. The work depicts a male subject with a bulbous white form projecting from it nasal and oral orifices. The work forms part of the artist’s ongoing self-portraiture project, in which the tensions between objectivity and subjectivity that pervade the self-portrait as a genre are cross referenced with the notions of materiality and interiority integral to the language of sculpture. The iconography of the work parodies the connection between amorphous form and artistic subjectivity in the history of sculpture. The dough-like forms that emerge from the figure thus refer to a sense of ‘inner life’ while also operating as more analytical projections of the cavities of the bust – areas of the where the mimetic program are necessarily suspended. The result is a figure that appears to be in a state of resigned suffocation. The work was selected for the 2005 National Sculpture Prize and Exhibition at the National Gallery of Australia in Canberra. The work was later included in the group show Crash (and other earthy pleasures) at the Lawrence Wilson Art Gallery at the University of Western Australia in Perth.

Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells

Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.

p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

On secrets, lies, and fiction : girls learning the art of survival

This chapter’s interest in fiction’s relationship to truth, lies, and secrecy is not so much a matter of how closely fiction resembles or mirrors the world (its mimetic quality), or what we can learn from fiction (its epistemological value). Rather, the concern is both literary and philosophical: a literary concern that takes into account how texts that thematise secrecy work to withhold and to disclose their secrets as part of the process of narrating and sequencing; and a philosophical concern that considers how survival is contingent on secrets and other forms of concealment such as lies, deception, and half-truths. The texts selected for examination are: Secrets (2002), Skim (2008), and Persepolis: The Story of a Childhood (2003). These texts draw attention to the ways in which the lies and secrets of the female protagonists are part of the intricate mechanism of survival, and demonstrate the ways in which fiction relies upon concealment and revelation as forms of truth-telling.

ICT driven pedagogies and its impact on learning outcomes in high school mathematics

ICT (Information and Communication Technology) creates numerous opportunities for teachers to re-think their pedagogies. In subjects like mathematics which draws upon abstract concepts, ICT creates such an opportunity. Instead of a mimetic pedagogical approach, suitably designed activities with ICT can enable learners to engage more proactively with their learning. In this quasi-experimental designed study, ICT was used in teaching mathematics to a group of first year high school students (N=25) in Australia. The control group was taught predominantly through traditional pedagogies (N=22). Most of the variables that had previously impacted on the design of such studies were suitably controlled in this yearlong investigation. Quantitative and qualitative results showed that students who were taught by ICT driven pedagogies benefitted from the experience. Pre and post-test means showed that there was a difference between the treatment and control groups. Of greater significance was that the students (in the treatment group) believed that the technology enabled them to engage more with their learning.