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IUPUI Research Day 2012
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Item HE AMOT FAMILY OF PROTEINS BINDS AND ACTIVATES NEDD4 FAMILY LIGASES TO PROMOTE THE UBIQUITINATION OF LATS AND YAP(Office of the Vice Chancellor for Research, 2012-04-13) Adler, Jacob J.; Heller, Brigitte L.; Tuchek, Chad A.; Ingham, Robert J.; Wells, Clark D.Amot adaptor proteins bind and integrate signaling that controls cell po-larity and growth. All three Amot family members (Amot, AmotL1 and AmotL2) directly bind YAP; a transcriptional co-activator that controls the expression of genes involved in organ homeostasis and cell growth. Preven-tion of nuclear accumulation of YAP by either sequestration or degradation in the cytosol abolishes its transcriptional functions and is a major mechanism for growth arrest in response to cellular differentiation. This is mainly thought to be regulated by phosphorylation of YAP by the Hippo kinases LATS1/2. Recently, binding by the Amot proteins was also found to inhibit YAP by sequestering it in the cytosol through both LATS dependent and in-dependent mechanisms. This study identifies a novel mechanism whereby Amot proteins control YAP activation in a Hippo independent mechanism by coupling it to ubiquitination by Nedd4 family ligases. Amot proteins mediate the coupling of Nedd4 ligases with YAP by simultaneously binding both pro-teins via multiple PY motifs that are recognized by WW domains in both YAP and Nedd4. Binding of Nedd4 by Amot is also shown to relieve the auto-inhibition of its ligase activity. This may be a direct consequence of binding Amot or from being re-targeted in cells by Amot proteins to endosomes. Im-portantly, Amot induced ubiquitination of YAP by Nedd4 proteins is shown to enhance the residence of YAP in the nucleus and in YAP activated transcrip-tion. Taken together our data suggest that Amot couples Nedd4 family ubiq-uitin ligases with the transcriptional co-activator YAP to drive the ubiquitination and activation of YAP.Item THE USE OF A MULTI-OBJECTIVE GENETIC ALGORITHM FOR CALIBRATION OF WATER QUALITY NUMERICAL MODEL OF EAGLE CREEK RESERVOIR, IN(Office of the Vice Chancellor for Research, 2012-04-13) Agee, Elizabeth A.; Babbar-Sebens, MeghnaWater quality models used for water resource management require large amounts of input parameters, whose values may or may not be readily available. The calibration of these models involves the adjustment of several input parameters. The credibility of calibrated models is judged based on their agreement with actual data. However, calibration of water quality numerical models can be an exceptionally computationally challenging process. In this research, the Environmental Fluid Dynamic Code’s (EFDC) HEM3D water quality model was developed for the Eagle Creek Reservoir in order to model three algal groups (cyanobacteria, diatoms, and greens) as well as reservoir nutrient dynamics. A multi-objective genetic algorithm was then used for calibration by adjusting predetermined input parameters within a certain range and based on the model’s agreement with observed data in the reservoir. The genetic algorithm was parallelized to work across a network of machines and on multiple threads. This presentation will demonstrate the advantages of using such a parallelized genetic algorithm for efficiently calibrating computationally expensive numerical models.Item Acute d-Amphetamine alters the temporal patterning of intermittent synchronized oscillations in hippocampal and prefrontal circuits of the rat(Office of the Vice Chancellor for Research, 2012-04-13) Ahn, S.; Lapish, C.C.; RUBCHINSKY, L.L.D-Amphetamine (d-AMPH) increases the bioavailability of numerous catecholamines, including dopamine, throughout the brain and modulates neural firing in cortical and subcortical regions. While a complex array of d-AMPH-mediated effects on firing have been reported, less is known regarding how d-AMPH affects the oscillatory properties of cortical circuits. In the current study, we simultaneously recorded local field potentials from electrode arrays implanted in the medial prefrontal cortex (PFC) and hippocampus (HC) of awake freely moving rats treated with saline, 1.0 mg/kg, or 3.3 mg/kg d-AMPH. The fine temporal structure of synchrony in delta, theta, beta, and gamma bands between these brain regions was examined to characterize how phase synchronization was altered by each dose of d-AMPH relative to saline. Differences were observed in the average level of phase-locking and in the variation of temporal patterns of synchrony on short (sub-second) time scales (including the distribution of durations of desynchronization events. In general, treatment with d-AMPH evoked higher levels of phase-locking. While this imperfect phase-locking can be potentially attained with both large number of short desynchronization episodes and small number of long desynchronization episodes, the data are marked by the dominance of short desynchronization episodes. These results suggest that within the HC and PFC, d-AMPH acts to increase synchronized oscillatory activity. The dominance of short desynchronization episodes suggests that the synchrony can be easily destabilized, yet it can be quickly re-established. The ease with which neural circuits can transition between synchronized and desynchronized dynamics may reflect altered information transfer regimes in these circuits and contribute to the spectrum of effects on cognition frequently observed with d-AMPH.Item POSTNATAL BRAIN DYSMORPHOLOGY INDUCED BY PRENATAL ALCOHOL EXPOSURE: A PRECLINICAL MRI STUDY(Office of the Vice Chancellor for Research, 2012-04-13) Ai, H.; Liang, Y.; Anthony, B.; Wetherill, L.; Ward, R.; Zhou, F.C.; CIFASD ConsortiumBrain dysmorphology is one of the most critical features of Fetal Alcohol Spectrum Disorders (FASD). This study was designed to use high resolution preclinical MRI system to compare the brain structures between alcohol exposed C57BL/6 mice with control. The objective is to examine how alcohol affects a dose- and timing-dependent brain dysmorphology during development comparable to that of human FASD. Three treated groups, ALC (pre- and pregnancy alcohol with 4.2 % (v/v) alcohol liquid), PF (pre alcohol and a calorically matched liquid pregnancy diet), and CHOW (ad lib chow/water), were examined. Mouse heads were imaged using 9.4T preclinical MRI system with 3D gradient echo (GRE) sequence to acquire volumetric images with voxel size as low as 40 microns. Whole brain, olfactory bulbs, cortex, hypothalamus, and cerebellum were segmented and the volumes were calculated. Data was examined by ANOVA followed with paired comparison between treatment groups to test the effect of prenatal alcohol exposure. ALC group had shown consistently smaller mean volumes of difference brain regions than the other two groups. Volume of total brain, olfactory bulbs and cerebellum were observed to be significantly different for ALC compared to PF pups. This indicated that prenatal alcohol exposure caused retarded fetal brain development. Comparing PF with CHOW pups, only cerebellum volume was observed to be significantly different. For cortex volume, no significant difference was shown for any pairwise comparison. These results suggest that alcohol effect contribute to brain dysmorphology, and match with our previous craniofacial dysmorphology study. This could be important to assist in the understanding of clinical variants of human FASD patients in brain dysmorphology.Item URINE THC METABOLITE LEVELS CORRELATE WITH STRIATAL D2/D3 RECEPTOR AVAILABILITY(Office of the Vice Chancellor for Research, 2012-04-13) Albrecht, Daniel S.; Skosnik, Patrick D.; Vollmer, Jennifer M.; Brumbaugh, Margaret S.; Perry, Kevin M.; Zheng, Qi-Huang; Federici, Lauren A.; Patton, Elizabeth A.; Herring, Christine M.; Yoder, Karmen K.Rationale: Although the incidence of cannabis abuse/dependence in Americans is rising, the neurobiology of cannabis addiction is not well understood. Previous PET and SPECT studies have demonstrated deficits in striatal D2/D3 receptor availability in several substance-dependent populations. However, this has not been studied in chronic cannabis users. Objective: The purpose of this study was to compare striatal D2/D3 receptor availability between currently-using chronic cannabis users and healthy controls. Methods: Eighteen right-handed males, 18-34 years of age, were studied. Ten subjects were chronic cannabis users; eight were demographically matched controls. Subjects underwent a [11C]raclopride (RAC) PET scan. On the scan day, urine samples were obtained from cannabis users for quantification of urine Δ-9-tetrahydrocannabinol (THC; the active compound in cannabis smoke) and THC metabolites (11-nor-Δ-9-THC-9-carboxylic acid and 11-hydroxy-THC). Striatal RAC binding potential (BPND) was used as an index of D2/D3 receptor availability; this parameter was estimated at each image voxel for every subject. SPM5 software was used to test for differences in BPND between groups and, in cannabis subjects, for associations between BPND and markers of cannabis use. Results: There were no differences in D2/D3 receptor availability between cannabis users and controls. Smokers of either cannabis and/or tobacco had 10.2% lower BPND values than nonsmokers in the bilateral putamen (“any-smokers”: 2.66 ± 0.2; nonsmokers: 2.97 ± 0.2). In cannabis users, RAC BPND values were negatively associated with both urine levels of cannabis metabolites and self-report of recent cannabis consumption. Conclusions: There is an inverse relationship between chronic cannabis use and striatal RAC BPND. This may be caused by inhibition of monoamine oxidase (MAO) by the pyrolyzation of cannabis, which could lead to increased endogenous dopamine levels (and hence, lower BPND in heavier users). Additional studies are needed to identify the neurochemical consequences of chronic cannabis use on the dopamine system.Item THE EFFECT OF NANO-FILLED RESIN COATING ON FLUORIDE RELEASE IN A NEW CONVENTIONAL GLASS IONOMER CEMENT(Office of the Vice Chancellor for Research, 2012-04-13) Al Dehailan, Laila; Eckert, George; Platt, JeffreyThe objective of this study was to evaluate fluoride release amounts and patterns from high strength tooth filling material (EQUIA™) which is a con-ventional Glass Ionomer Cement, and investigate whether the application of nano-filled resin-based coating with different thicknesses has any effect on fluoride release from this new material. A total of 120 disc shaped specimens (10 x 2 mm) of EQUIA™ were fabricated according to manufacturer’s in-structions. Samples were subsequently divided into three groups: no resin coating; coated with nano-filled resin-based coat; coated with nano-filled resin-based coat then subjected to abrasion using a mechanical tooth brush-ing machine. Each specimen was soaked individually into a polyethylene container with 20 ml of distilled water and stored at 37ºC. Samples from each group were soaked for four time points; 1 day, 7 days, 14 days and 21 days. Fluoride content was then measured using a fluoride-specific ion elec-trode (Model 9609BNWP, Orion Research, Boston MA, USA). The effects of time and coating on fluoride release were analyzed using two-way analysis of variance (ANOVA), with multiple comparisons performed using the Sidak method at an overall 5% significance level. The distribution of the fluoride release measurements was examined and a natural logarithm transformation of the data was necessary to satisfy the ANOVA assumptions. The time-by-coating interaction was significant (p<0.0001). We can conclude that fluo-ride level significantly increased with time for non-coated and coated then abraded samples only. Application of resin coat significantly reduced fluoride release. Also, subjecting coated samples to tooth brush abrasion increased the fluoride release when compared to coated specimens but was still signifi-cantly less than uncoated samples.Item EVALUATION OF MICROTENSILE BOND STRENGTH AND MICROLEAKAGE OF A ONE-STEP SELF-ETCH ADHESIVE(Office of the Vice Chancellor for Research, 2012-04-13) AlZain, Afnan; Eckert, George; Platt, JeffreyNew dental glue (G-aenial Bond-GB) was developed to increase the strength of bonding the white tooth filling to the tooth. An extra roughening step of the tooth surface using a specific acid should help the flow of the glue to the tooth and increases the strength of the bond between the tooth and the filling. Therefore, this study was done to evaluate how strong the bond is between the filling and the tooth using GB, and how much GB leaks and compare both tests with two other glue products and, with and without adding an extra roughening step. For the bond strength test, human molars teeth were divided into 5 groups, each containing 15 teeth. In 3 groups, each glue type was applied on tooth dentin according to company's instructions. In the last 2 groups an extra roughening step using a specific acid was added before applying the glue. The samples were stored in fake saliva where four samples were soaked for 48h and four samples were placed in a machine (thermocycling) that resembles drinking hot and cold beverages where samples are exposed to hot and cold water for 40 days and then the strength of the bond was tested (α=0.05). The broken edges were examined using a light microscope. For the leak test, human molars were divided randomly into the same 5 groups as bond strength test but each containing 11 teeth. A cavity was pre-pared and filled on the check and tongue sides of the tooth. Teeth were then also subjected to thermocylcling and stored for four weeks, soaked in dye for 24 hours and sectioned. The dye penetration was evaluated using light mi-croscopy (α=0.05). Bond strength of GB was significantly higher when an acid roughening step was added. No significant difference in leak of GB was observed.Item “Don’t Jobs Change?” Substitution of Professionals by Support Staff in Public Libraries, 1997-2007(Office of the Vice Chancellor for Research, 2012-04-13) Applegate, Rachel A.Among MLS-level librarians, there is substantial anecdotal prevalence of the idea that administrators of public libraries seek to reduce costs by replacing MLS librarians with support staff. The migration of tasks such as copy and original cataloging and reference services to support staff has been well-documented. This study used national data from the Public Libraries Survey, from 1997 and 2007, to test this substitution hypothesis. Data indicates that for this time period, the utilization of MLS librarians as a percent of total library staffs did not diminish overall. Relative to population served, libraries did not reduce MLS positions but did increase support staffing. This has implications for understanding the 2008-2013 period of reduced public resources, and for the staffing of public libraries in the longer term.Item HOW MALTOSE BINDING PROTEINS RECOGNIZE SUBSTRATES: INSIGHTS FROM COMPUTER SIMULATIONS(Office of the Vice Chancellor for Research, 2012-04-13) Audu, Cornelius; Zhou, Yan; Pu, JingzhiAs a periplasmic component of the Maltose transporter system, the Maltose binding protein (MBP) is known to be able to capture the substrate with high affinity and load it to the entrance of the transmembrane portion of the transporter to initiate the ATP facilitated substrate transportation. Such substrate recognition and binding events trigger a large conformational change in MBP, as suggested from several X-ray crystal structures that capture MBP in an “open” or a “closed” state. To characterize the dynamical natures of these conformational states, we performed Molecular Dynamics (MD) simulations of MBP under three conditions: (1) a closed structure with ligand, (2) a closed structure without ligand, and (3) an open structure without ligand. Based on these equilibrium simulations and additional transition pathway simulations using Targeted Molecular Dynamics (TMD), possible reaction coordinates to describe the conformational change of MBP will be identified. Finally, free energy profiles of the conformational transition will be obtained by umbrella sampling simulations and the molecular recognition mechanism of MBP will be discussed.Item Convergent Functional Genomics of Schizophrenia: From Comprehensive Understanding to Genetic Risk Prediction(Office of the Vice Chancellor for Research, 2012-04-13) Ayalew, M.; Le-Niculescu, H.; Levey, D.F.; Jain, N.; Changala, B.; Patel, S.D.; Winiger, E.; Breier, A.; Shekhar, A.; Amdur, R.; Koller, D.; Nurnberger, J.I.; Corvin, A.; Geyer, M.; Tsuang, M.T.; Salomon, D.; Schork, N.; Fanous, A.H.; O’ Donovan, M.C.; Niculescu, A.B.We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study (GWAS) data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein coupled receptor signaling and cAMP- mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data is consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European-American (EA) and one African-American (AA), increasing overlap, reproducibility and consistency of findings from SNPs to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Lastly, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics, and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.