Panel II

Each in its Ordered Place : The Spatiality of Suffering in Faulkner\u27s The Sound and the Fury / Eric Matthew Bledsoe, Florida State University Women in Motion: Escaping Yoknapatawpha / Lori Watkins Fulton, William Carey University Jamestown and Jimson Weed : Autochthnous Territory in The Sound and the Fury / Kita Douglas, University of Victori

Effects of the Selective GSK3B Inhibitor, Tideglusib, on Ethanol Consumption, Anxiety-like Behavior, Taste Preference, and Downstream Proteins

Background: We have shown modulations in glycogen synthase kinase 3 beta (GSK3B) abundance or activity regulate ethanol consumption, suggesting potential as a therapeutic target for alcohol use disorder (AUD). Here we report the GSK3B inhibitor tideglusib’s actions on ethanol consumption, basal behaviors, and modulation of GSK3B targets. Methods: C57BL/6J males and females received i.g. 200mg/kg tideglusib, except drinking-in-the-dark (males;100mg/kg i.p.). Drinking-in-the-dark (DID): Mice given 20% ethanol 4-hours, 4-days/week x 3 weeks and then i.p. tideglusib or vehicle x 4 days in a Latin Square design with ethanol consumption measured daily. Light/Dark Box: Mice gavaged with tideglusib or vehicle and i.p. injected with 1.8g/kg ethanol or saline then tested for 10-min. Taste Preference: Mice received tideglusib x 6 days and then tested daily for saccharin or quinine taste preference. Western Blots: Mice received tideglusib or vehicle i.g. 3x/week for 2-weeks and mPFC assayed for phosphorylated and total GSK3B, Dynamin1, and PSD-95. Results: Tideglusib decreased ethanol DID consumption, transiently increased locomotion, and had no effect on anxiety-like behaviors or taste preference. Only total Dynamin1 showed tideglusib-induced modulation where females had increased Dynamin1 and decreased pDynamin1/total Dynamin1. Conclusion: Tideglusib is a promising AUD therapeutic, rapidly decreasing ethanol consumption in a binge-drinking model. Tideglusib is likely not reducing consumption by altering taste or anxiety-like behaviors. Dynamin1 is integral in activity-dependent bulk endocytosis and requires GSK3B-induced rephosphorylation. Tideglusib increased Dynamin1 levels likely represent a compensatory response to decreased GSK3B activity, providing insight to tideglusib’s mechanism in ethanol behaviors. Funded by NIAAA grant R01AA027581.https://scholarscompass.vcu.edu/gradposters/1177/thumbnail.jp

Algorithms for HVAC Acoustic

The research in this project was derived from RP-556. The purpose of the research was to develop a set of algorithms and related computer programs in the area of HVAC acoustics that are useful and reliable. All algorithms were to be based on currently verifiable published and unpublished test results. The objectives of this project were to: (1) develop algorithms in English, along with discussions related to the development of the algorithms, references, and other appropriated data; (2) develop computer programs associated with each algorithm programmed in Basic; and (3) produce a final report in a form that could be readily published by ASHRAE. This book, published in 1991, was the final result of that research. However, it is now out of print as the sponsoring technical committee considered it to be out of date. ASHRAE has made this scanned copy available believing that it does contain sound algorithms to be used to predict acoustical performance of fans, ductwork, walls, ceilings, etc. Algorithms written in Basic with support documentation included

Ligand binding domain interface: A tipping point for pharmacological agents binding with GluN1/2A subunit containing NMDA receptors.

N-methyl D-aspartate (NMDA) receptors play a crucial role in normal brain function, pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDA receptor contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that evolve from six different genes including four GluN2 (A-D) and two GluN3 (A-B) subunits. Since NMDA receptors confer varied physiological properties and spatiotemporal distributions in the brain, pharmacological agents that target NMDA receptors with specific GluN2 subunits have significant potential for therapeutic applications. In the present work, by using electrophysiology techniques, we have studied the role of ligand binding domain (LBD) interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, channel blockers and an allosteric modulator. Remarkably, point mutations at the distal end (site-II&III) of GluN1 LBD interface increased memantine potency up to sevenfold when co-expressed with wild type GluN2A receptors but exhibit no effect on Mg activity. Conversely, mutations at the proximal end (site-I) of the LBD interface did not affect the memantine but altered Zn and Mg potency towards opposite directions. These results indicate that GluN1/2A LBD interface interactions play a key role in determining channel function. Further, subtle changes in LBD interaction can be readily translated to the downstream extracellular vestibule of channel pore to adopt a conformation that may affect memantine, Zn and Mg binding. Further studies on NMDA receptor LBD to transmembrane domain signal propagation mechanisms will help develop GluN2 subunit selective biomolecules that can be used for the treatment of neurological and psychiatric disorders

The effect of child fostering on feeding practices and access to health services in rural Sierra Leone

In Sierra Leone, where infant and child mortality rates are quite high, a large proportion of small children from 1 to 5 yr are fostered: living away from their mothers. This paper examines the relationships between fosterage and child feeding practices and children's access to Western medical care. Ethnographic data from field studies in Sierra Leone are combined with quantitative data from Serabu Hospital, which show that fostered children are underrepresented in hospital admissions and that young fosters present more problems of malnutrition. (Fostered girls appear to be at more risk in both these categories than boys.) Unlike young fosters, however, older ones do not appear to be at more risk than children with mothers. We draw connections between these results and patterns of intrahousehold discrimination in food allocation and access to medical treatment for young fostered children: especially those sent to elderly rural caretakers. Finally, we examine the implications of the findings for applied issues, arguing that fostered children may slip through the cracks of maternal-child health care programs.

Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity.

N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A-D) and two GluN3 (A-B) subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD) and ligand binding domain (LBD), transmembrane domain (TMD) and an intracellular C-terminal domain (CTD). Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate) potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A) than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics

Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D) and two GluN3 (A–B) subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD) and ligand binding domain (LBD), transmembrane domain (TMD) and an intracellular C-terminal domain (CTD). Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate) potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A) than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics

Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D) and two GluN3 (A–B) subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD) and ligand binding domain (LBD), transmembrane domain (TMD) and an intracellular C-terminal domain (CTD). Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate) potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A) than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics