OR05-3 Mir-21 Contributes to Cytokine-Induced Beta Cell Dysfunction via Inhibition of mRNAs Regulating Beta Cell Identity

A hallmark of diabetes is the loss of physical or functional β cell mass. Alterations in β cell microRNA (miRNA) profiles have been described in diabetes. MiRNAs have also been shown to serve as important regulators of β cell development and function, implicating them in β cell dysfunction during diabetes development. Our lab has previously demonstrated that β cell microRNA 21 (miR-21) is increased in models of diabetes. However, a comprehensive analysis of the β cell effects of miR-21 remain poorly defined, and the effects of miR-21 on in vivo glucose homeostasis have never been explored. To this end, we performed a comprehensive in silico analysis of bioinformatics databases to identify potential β cell targets of miR-21, which yielded multiple targets in the Transforming Growth Factor Beta 2 (Tgfb2) and Fibroblast Growth Factor Receptor 3 (Fgfr3) pathways associated with regulation of differentiation. We hypothesize that β cell miR-21 plays a critical role in inhibiting β cell function and inducing loss of β cell identity. To validate targets in vitro, we developed a model whereby miR-21 is upregulated using a dose dependent lentiviral Tetracycline-on system in INS1 cells. Overexpression of miR-21 led to a reduction in expression levels of several members of the Tgfb2 and Fgfr3 pathways as well as multiple transcription factors associated with β cell function and identity, and an increase in aldehyde dehydrogenase transcripts, consistent with β cell dedifferentiation. To verify direct interactions between miR-21 and candidate target mRNAs, a biotin pulldown experiment was performed using a 3’ biotinylated mature miR-21 construct and a 3’ biotinylated cel-miR-67 control construct. Several mRNAs associated with β cell identity were enriched in the pulldown, indicating a direct interaction with miR-21. Lineage tracing was performed within an in vivo zebrafish model of β cell specific oxidative stress in which β cells expressed a nuclear GFP signal. Whole body knock down of miR-21 by morpholino microinjection showed a protective effect in stressed β cells and rescued against a dedifferentiated phenotype. To test the effect of miR-21 on glucose tolerance in vivo, inducible β cell specific knockout (βmiR-21KO) and overexpression (βmiR-21) mice were generated by crossing Ins1tm1(CreERT2)Thor mice with miR-21 floxed mice and miR-21-CAG-Z-EGFP mice, respectively. When compared to littermate controls, intraperitoneal glucose tolerance tests (IPGTT) exhibited hyperglycemia in βmiR-21 mice and euglycemia in βmiR-21KO mice. Metabolic studies, including glucose stimulated insulin secretion (GSIS) and insulin tolerance tests (ITT) are ongoing in our mouse models. Our results implicate miR-21 as a regulator of β cell dedifferentiation during diabetes development

Predicting Treatment Success in Child and Parent Therapy Among Families in Poverty

Behavior problems are prevalent in young children and those living in poverty are at increased risk for stable, high-intensity behavioral problems. Research has demonstrated that participation in child and parent therapy (CPT) programs significantly reduces problematic child behaviors while increasing positive behaviors. However, CPT programs, particularly those implemented with low-income populations, frequently report high rates of attrition (over 50%). Parental attributional style has shown some promise as a contributing factor to treatment attendance and termination in previous research. The authors examined if parental attributional style could predict treatment success in a CPT program, specifically targeting low-income urban children with behavior problems. A hierarchical logistic regression was used with a sample of 425 families to assess if parent- and child-referent attributions variables predicted treatment success over and above demographic variables and symptom severity. Parent-referent attributions, child-referent attributions, and child symptom severity were found to be significant predictors of treatment success. Results indicated that caregivers who viewed themselves as a contributing factor for their child\u27s behavior problems were significantly more likely to demonstrate treatment success. Alternatively, caregivers who viewed their child as more responsible for their own behavior problems were less likely to demonstrate treatment success. Additionally, more severe behavior problems were also predictive of treatment success. Clinical and research implications of these results are discussed

Bramble and Knife

This thesis is a collection of poems that center on the themes of extinction, family, the female body, and the presence of the animal. During my time in the Upper Peninsula, I found a connection with the natural world around me, and this led to my fascination with animals and extinction, both of which manifested in my poetry. As I struggled with the residual effects of toxic relationships, as well as the bleak romantic landscape of the UP, I saw my own body reflected in the bodies of animals. I specifically noticed this reflection while studying the art of taxidermy; I saw my own struggle with my body in the preservation of the animal body. During my summers at NMU, I was also funded through grants to travel through Scandinavia, as well as various parts of the Midwest, and these travels developed into poems in this manuscript as well, often poems about family and familial history and the slow forgetting of that history. In this thesis, I interrogate what Adrienne Rich calls “a fascination and a terror” in the manifestation of men in women’s writing. I also see this fascination and terror in the animal body, as well as in the themes of extinction, both natural and familial. The collecting of these memories and these words is an anxiety, a terrible and beautiful thing. Throughout these pages, these themes dwell between the poetic lyricism, and the raw feeling in these pieces. These poems are brambles. These poems are knives

Galaxy pairs in the Sloan Digital Sky Survey - XII: The fuelling mechanism of low excitation radio-loud AGN

We investigate whether the fuelling of low excitation radio galaxies (LERGs) is linked to major galaxy interactions. Our study utilizes a sample of 10,800 spectroscopic galaxy pairs and 97 post-mergers selected from the Sloan Digital Sky Survey with matches to multi-wavelength datasets. The LERG fraction amongst interacting galaxies is a factor of 3.5 higher than that of a control sample matched in local galaxy density, redshift and stellar mass. However, the LERG excess in pairs does not depend on projected separation and remains elevated out to at least 500 kpc, suggesting that major mergers are not their main fuelling channel. In order to identify the primary fuelling mechanism of LERGs, we compile samples of control galaxies that are matched in various host galaxy and environmental properties. The LERG excess is reduced, but not completely removed, when halo mass or D4000 are included in the matching parameters. However, when BOTH M_halo and D4000 are matched, there is no LERG excess and the 1.4 GHz luminosities (which trace jet mechanical power) are consistent between the pairs and control. In contrast, the excess of optical and mid-IR selected AGN in galaxy pairs is unchanged when the additional matching parameters are implemented. Our results suggest that whilst major interactions may trigger optically and mid-IR selected AGN, the gas which fuels the LERGs has two secular origins: one associated with the large scale environment, such as accretion from the surrounding medium or minor mergers, plus an internal stellar mechanism, such as winds from evolved stars.Comment: Accepted for publication in MNRAS Letters; 5 page

Tidal Disruption Event Host Galaxies in the Context of the Local Galaxy Population

We study the properties of tidal disruption event (TDE) host galaxies in the context of a catalog of ~500,000 galaxies from the Sloan Digital Sky Survey. We explore whether selection effects can account for the overrepresentation of TDEs in E+A/post-starburst galaxies by creating matched galaxy samples. Accounting for possible selection effects due to black hole (BH) mass, redshift completeness, strong AGN presence, bulge colors, and surface brightness can reduce the apparent overrepresentation of TDEs in E+A host galaxies by a factor of ~4 (from ~$\times$100-190 to ~$\times$25-48), but cannot fully explain the preference. We find that TDE host galaxies have atypical photometric properties compared to similar, "typical" galaxies. In particular, TDE host galaxies tend to live in or near the "green valley" between star-forming and passive galaxies, and have bluer bulge colors ($\Delta (g-r) \approx 0.3$ mag), lower half-light surface brightnesses (by ~1 mag/arcsec$^2$), higher Sersic indices ($\Delta n_{\rm g} \approx 3$), and higher bulge-to-total-light ratios ($\Delta B/T \approx 0.5$) than galaxies with matched BH masses. We find that TDE host galaxies appear more centrally concentrated and that all have high galaxy Sersic indices and $B/T$ fractions---on average in the top 10% of galaxies of the same BH mass---suggesting a higher nuclear stellar density. We identify a region in Sersic index and BH mass parameter space that contains ~2% of our reference catalog galaxies but $\ge\!60\%$ of TDE host galaxies. The unique photometric properties of TDE host galaxies may be useful for selecting candidate TDEs for spectroscopic follow-up observations in large transient surveys.Comment: 26 pages, 11 figures, 5 tables. Published in Ap

Enabling prosperity: success factors in Indigenous economic development

Public discussion about ‘closing the gap’ between Indigenous and non-Indigenous Australians tends to focus on measures such as life expectancy, child mortality, early childhood education, literacy and numeracy, and employment.  These are, rightly, essential markers of health and well-being for all people, and for decades they have provided evidence that Australia’s health and social systems have not met the needs of Indigenous Australians. However, there is another story, one that focuses on the measures of success, as evident in the many thriving Indigenous businesses and corporations around the country.  Across Australia, there is a growing story of economic security and success, in which Indigenous Australians are creating enterprises combining sound business principles with strong cultural and social foundations for the benefit of individuals, families and communities. Urbis was commissioned by Westpac to undertake research into Indigenous business development, to provide an evidence base to support the work of the Empowered Communities group. The report, Enabling Prosperity: Success Factors in Indigenous Economic Development, suggests that these factors are much the same as for any other businesses: human capital, access to capital and markets, infrastructure, location and an authorising environment created through government policy and regulation. In practice, businesses succeed because of more than one factor, and multiple factors can strengthen the capacity of a business to grow and develop.  For instance, access to capital often relies on the development of successful partnerships, while ownership of land and resources requires human capital to realise its potential. Indigenous culture can be both a support and a resource. Individual attitude and vision are also essential ingredients in business success, while government plays an important role in ensuring the regulatory environment enables rather than hinders business efforts. Much can be learned by examining successful Indigenous businesses both in Australia and internationally. Businesses are the key driver for wealth creation, helping to provide job opportunities and improve social and economic conditions. Fostering business success, therefore, has the potential to increase employment, improve living standards, and contribute to stable and nurturing communities. Current government policy frameworks, such as the Indigenous Economic Development Strategy, are largely focused on increasing education and training and generating opportunities for private sector employment and enterprise.  This is important. Just as important is the contribution that successful community or non-profit enterprises can make in providing employment, generating business investment for growth, building partnerships and demonstrating positive role models. The Empowered Communities group is such a national initiative. Formed in 2013, the group brings together Indigenous leaders from eight communities across Australia and seeks to strengthen Indigenous individuals and communities through a range of activities (see https://empoweredcomms.wordpress.com for more information). Strategies that strengthen both individual and community business initiatives will help to ensure that more Indigenous Australians have the opportunity to live successful and productive lives.  Everyone has a contribution to make in this regard. Governments can create an enabling regulatory environment. Banks can enable access to capital. Local chambers of commerce can foster business development through support and networks for new entrepreneurs. Communities and individuals can purchase goods and services from Indigenous businesses. Building a strong and vibrant Indigenous business and social enterprise sector can then contribute to improving many of the health and social indicators, such as improving nutrition and healthy lifestyle choices, and increasing employment and education.  Efforts to improve Indigenous outcomes really are everyone’s business

Space-Filling Designs for Multi-Layer Nested Factors

This articles considers computer experiments where levels for continuous factors are selected in sequential order with the level selected for one factor directly a ecting the range of possible levels for the nested factor, and so on for a nite number of factors. In addition, we assume the nested relationships between the factors have no closed form solution. In this paper, we propose an approach for constructing a multi-layer nested factor design, or multi-NFD for short. This space- lling design approach takes advan- tage of the maximin criterion and can be analyzed using a standard Gaussian process model. While the multi-NFD approach can be adapted for future computer experi- ments involving factor relationships of this type, we present results from a particular aerospace computer simulation study

Galaxy pairs in the Sloan Digital Sky Survey - IX: Merger-induced AGN activity as traced by the Wide-field Infrared Survey Explorer

Interactions between galaxies are predicted to cause gas inflows that can potentially trigger nuclear activity. Since the inflowing material can obscure the central regions of interacting galaxies, a potential limitation of previous optical studies is that obscured Active Galactic Nuclei (AGNs) can be missed at various stages along the merger sequence. We present the first large mid-infrared study of AGNs in mergers and galaxy pairs, in order to quantify the incidence of obscured AGNs triggered by interactions. The sample consists of galaxy pairs and post-mergers drawn from the Sloan Digital Sky Survey that are matched to detections by the Wide Field Infrared Sky Explorer (WISE). We find that the fraction of AGN in the pairs, relative to a mass-, redshift- and environment-matched control sample, increases as a function of decreasing projected separation. This enhancement is most dramatic in the post-merger sample, where we find a factor of 10-20 excess in the AGN fraction compared with the control. Although this trend is in qualitative agreement with results based on optical AGN selection, the mid-infrared selected AGN excess increases much more dramatically in the post-mergers than is seen for optical AGN. Our results suggest that energetically dominant optically obscured AGNs become more prevalent in the most advanced mergers, consistent with theoretical predictions.Comment: 8 pages, 7 figures accepted to MNRAS (with minor revisions

Intracellular energy variability modulates cellular decision-making capacity

Cells are able to generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. The biologically and medically vital process of a cell assuming a functionally important fate from a range of phenotypic possibilities can be thought of as a cell decision. To make these decisions, a cell relies on energy dependent pathways of signalling and expression. However, energy availability is often overlooked as a modulator of cellular decision-making. As cells can vary dramatically in energy availability, this limits our knowledge of how this key biological axis affects cell behaviour. Here, we consider the energy dependence of a highly generalisable decision-making regulatory network, and show that energy variability changes the sets of decisions a cell can make and the ease with which they can be made. Increasing intracellular energy levels can increase the number of stable phenotypes it can generate, corresponding to increased decision-making capacity. For this decision-making architecture, a cell with intracellular energy below a threshold is limited to a singular phenotype, potentially forcing the adoption of a specific cell fate. We suggest that common energetic differences between cells may explain some of the observed variability in cellular decision-making, and demonstrate the importance of considering energy levels in several diverse biological decision-making phenomena