Biophysical Characterization of the Par-4 Tumor Suppressor: Evidence of Structure Outside the Coiled Coil Domain and Interactions with Platinum Chemotherapeutics

Prostate apoptosis response-4 (Par-4) is an apoptosis-inducing tumor suppressor protein. Full-length Par-4 has previously been shown to be a predominantly intrinsically disordered protein (IDP) under neutral conditions, with significant regular secondary structure evident only within the C-terminal coiled coil domain. However, IDPs can gain ordered structure through the process of induced folding, which often occurs under non-neutral conditions. Previous work has shown that the Par-4 leucine zipper, which is a subset of the C-terminal coiled coil domain, is disordered under neutral conditions, but forms a dimeric coiled coil at acidic pH. Increase in ionic strength was also shown to increase leucine zipper formation. Building on this work, we undertook to study the effects of environment on a naturally occurring Par-4 segment, the cl-Par-4 fragment. During apoptosis, intracellular full-length Par-4 is cleaved at aspartic acid 131 by caspase-3, generating a 24 kilodalton fragment (cl-Par-4). Cl-Par-4 enters the nucleus and inhibits pro-survival genes, thereby preventing cancer cell proliferation. Here, the structure of cl-Par-4 was investigated using circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), intrinsic tyrosine fluorescence, and size exclusion chromatography with multi-angle light scattering (SEC-MALS). Biophysical characterization showed that under conditions of low salt and neutral pH, cl-Par-4 forms large soluble aggregates. We have clearly identified two disparate conditions under which cl-Par-4 forms non-aggregated largely helical structures. First, with low salt and acidic pH, c l-Par-4 folds into a predominantly alpha helical and coiled coil structure. Second, at neutral pH and high ionic strength, cl-Par-4 forms highly helical tetramers. Together, these results suggest that the cellular environment influences the in vivo structure and self-association state of cl-Par-4 and that the tetramer may be the active conformation under specific intracellular conditions. A third area of research involves the chemotherapeutic drug cisplatin and its trans isomer transplatin. We have shown that both bind directly to full-length Par-4 and the caspase-cleaved fragment. It appears that this binding interaction occurs through coordination of platinum to sulfur ligands in the protein, such as methionine and/or cysteine residues. This direct binding of cisplatin and transplatin could also subsequently influence apoptotic activity and Par-4 structure

Children's Moral Reasoning about Attribution of Intentions: The Influence of Gender Stereotypes and Theory of Mind

The present study investigated how holding gender stereotypes and having a false belief theory of mind impacts children's understanding of intentionality when evaluating morally relevant stories. Children 3 - 4, 5 - 6, and 7 - 8-years-of-age (N = 127) were interviewed about the intentions of a potential transgressor in two hypothetical stories. Both stories involved a child accidentally (or on purpose) putting another child's toy into their own backpack. One of the stories utilized the taking of a toy that was gender stereotype consistent (a girl taking a doll) while the other story involved a gender stereotype inconsistent toy (a boy taking a doll or a girl taking a truck). A false belief theory of mind task as well as gender stereotype knowledge, tolerance, and flexibility tasks were administered to each participant. Results revealed that children over-attributed negative intentions and endorsed more punishment in the story with the counter-stereotypic toy than in the story with the stereotype consistent toy, indicating that stereotypes were impacting the children's decisions concerning intentionality. Additionally, across scenarios, older children as well as children able to pass the false belief theory of mind task, endorsed less punishment and indicated less negative intentions than their counterparts, demonstrating that as children get older and more cognitively advanced they are better able to see the ambiguity of a morally relevant scenario, despite gender stereotypes, in order to attribute less negative intentions. Furthermore, children who were aware of gender stereotypes and children who were tolerant of others playing with any toy regardless of the associated gender stereotype also endorsed less punishment and indicated less negative intentions than their counterparts. The present study therefore shows how children may erroneously focus on stereotypic knowledge when making attributions of intentionality. This is important as over-attributing negative intentions can lead to peer rejection and exclusion. Understanding when and how contextual variables such as gender stereotypes as well as when and how having a false belief theory of mind impacts attributions of intentions is critical to understanding the ontogeny and development of moral reasoning

Utopia on tour: exploring a generative relationship between dramaturgy, devising, touring and utopia

This practice-as-research thesis proposes a novel understanding about the relationship between utopia and theatre, by investigating it as a question of method. Via the devising and touring practices of a small ensemble, the research asks: how does, or how might utopia operate in the making of a theatre work? How might this provoke new ways of approaching the generation and composition of theatre? What does this reveal about the creation of utopia? Through an emphasis on method, the research rejects the need for theatre-makers to predetermine rational utopian content, arguing instead that idealistic and romantic desires might be harnessed and grappled with through the generative structures of making and performing, bringing once-vague ideals to greater consciousness over the course of a production. In Part One, chapters focus in turn on practices of dramaturgy, devising, and touring, developing utopian framings that both prompt a reconsideration of existing works and propose original generative methods. In doing so, it advocates for the value of the carnivalesque as a utopian dramaturgical tool; explores devising practice as an act of opening and closing spaces of contingency; and proposes several structuring principles and generative techniques that can mobilise ideals in touring theatre. In Part Two, a discussion of a practical research project – Travelling Show - explores how these different approaches can work together and thus significantly expands understandings about how utopia operates in theatre practice. The interdependence of dramaturgy, devising and touring, which constitutes Travelling Show's creative method, encounters utopia in both the structural properties of the work's dramaturgy and the openness of its devising process, while subjecting ideals to continual movement and encounter over the course of a tour. In its innovative investigation of the relationship between dramaturgy, devising, touring and utopia, the research uniquely demonstrates how utopia can be understood as at once ideal, unknown, and unfinished; operating in theatre practice as a dream of a better life that is ever-becoming

Using a Forward Chain to Teach Intruder Training to Children with Autism

Safety drills, such as tornado, fire and intruder drills are mandated in schools across the United States. These drills require prolonged compliance by students and are commonly taught using verbal instructions. However, individuals with autism spectrum disorder (ASD), may struggle with complex routines, attending to verbal stimuli, or complying for long durations. Thus, when children with ASD transition to school these drills may be difficult for them to complete and little to no research has been conducted on this topic. Thus, the current study utilized a concurrent multiple baseline design across participants to examine the use of a forward chain to teach intruder training to two children diagnosed with ASD. The results demonstrated that both participants met mastery criterion for all components of the intruder drill and the results have important implications for the school setting

Morphological and Geochemical Characteristics of Volcanic Ash: Insights into Eruption Energetics

Energetic volcanic eruptions are driven by early bubble nucleation. In some cases, during magmatic ascent, decompression rates near the vent become sufficiently high to oversaturate inter-bubble melt enough to trigger a second phase of nucleation. This process creates a bi-modal bubble size distribution: pre-eruptive (50-100 μm) and syn-eruptive (10-50 μm). A scanning electron microscope (SEM) was used to examine bubble imprints preserved in volcanic ash particles and determine an explosivity threshold, represented by the volcanic explosivity index (VEI), below which decompression rates are too slow for a second nucleation event to occur. This threshold is manifested in ash particles as a lack of syn-eruptive bubbles and was found to be between VEI 3 and 4. Furthermore, examination of ash from six eruptions (Redoubt, Spurr, Augustine, Okmok, Novarupta-Katmai, and St. Helens) indicates that eruptions with a higher VEI (e.g., Novarupta-Katmai, VEI 6) have a higher percent of observed particles displaying syn-eruptive bubbles than lower VEI eruptions (e.g., Redoubt, VEI 3). This may reflect a decompression rate gradient horizontally across the conduit during magmatic ascent. For eruptions with higher bulk decompression rates, a larger cross-sectional area of magma within the conduit was able to overcome the slowing force of shear created by this gradient, and decompress rapidly enough to nucleate syn-eruptive bubbles. Furthermore, Micro Raman data show the presence of water in ash from some eruptions (Spurr, Okmok), indicating that magmatic water is still present in some systems upon eruption, and also alluding to complex diffusion and nucleation mechanics. This study advances understanding of the relationship between eruptive products and eruption energetics; this provides a tool to better constrain eruption energetics of ancient eruptions, and thus to better characterize volcanic activity in the past in order to project it to eruption hazards in the future

Abroad View of Wellness

A presentation on a Study Abroad trip taken to Hungary

How do antidepressants affect sexual function?

Evidence-based answer: patients treated with elective serotonin reuptake inhibitors (SSRIs) and the serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine have significantly higher rates of overall sexual dysfunction--including desire, arousal, and orgasm--than patients treated with placebo (strength of recommendation [SOR]: B, randomized controlled trials [RCTs] with heterogeneous results). Patients treated with bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI), have rates of overall sexual dysfunction comparable to placebo (SOR: B, RCTs with heterogeneous results)

The Use of Technology to Support Vocabulary Development of English Language Learners

This study asks the question: how can the use of an iPad application be used to support English language learners vocabulary development? Technology can be used as an engaging, supplementary tool to foster vocabulary learning for ELLs. Research was conducted in Clark, New York (pseudonym) with a group of five ELL students and focused on vocabulary development; three students completed teacher-made worksheets and two students completed iPad activities. Three themes were found when conducting research: explicit instruction compared to the iPad, the use of visual and audio components to increase vocabulary knowledge, and differences in engagement and behavior. These findings call for teachers to create learning environments that focus on oral language skills to develop vocabulary and incorporate technological tools

Case 7 : Going Beyond Bike Racks and Pedestrian Crossovers: Achieving Health Equity in School Travel Planning

The Elgin-St. Thomas, London-Middlesex, and Oxford Active and Safe Routes to School (ASRTS) Steering Committee have established a School Travel Planning Equity Working Group. The goal of this group is to use the Government of Ontario’s Health Equity Impact Assessment tool to evaluate current inequities in school travel planning programming – a community-based approach to addressing barriers to and facilitators of walking and wheeling to and from school – by identifying relevant populations, potential impacts, and mitigation, monitoring, and dissemination strategies (Ministry of Health and Long-Term Care, 2018). The goal of the case is to provide readers with the opportunity to evaluate the inequities in current school travel planning by conducting a Health Equity Impact Assessment