The brattleboro rat displays a natural deficit in social discrimination that is restored by clozapine and a neurotensin analog.

Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long-Evans (LE) rats, in a social discrimination paradigm, which is an ethologically relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine, and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 agonist, on social discrimination in these rats. Adult rats were administered saline or one of the three doses of clozapine (0.1, 1.0, or 10 mg/kg) or PD149163 (0.1, 0.3, or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-min learning period. Animals were then housed individually for 30 min and then simultaneously exposed to the juvenile presented previously and a new juvenile for 4 min. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported

Limited Wildlife Diversity at Highway Right-of-Way Crossings

This project included estimation of animal occurrence near and using structures (e.g., culverts, street, and RR crossing structures) to cross the Interstate-80 right-of-way in the Sierra Nevada, California. A combination of track plates near over-crossings and remote cameras at under-crossings was used to index wildlife occurrence and crossings. Diversity was relatively low in the highway right-of-way and at highway under-crossings. Across six highway under-crossings, only eight of 38 possible species were observed moving through these crossings from one side of the highway right-of-way to the other. Alpha diversity at highway crossings ranged widely for wildlife near street under and over-crossings, but was not related to nearby land development. Wildlife use of existing under-crossing structures was inversely proportional to the presence of humans and frequency of human use of the same structures. This has important implications for effectiveness of existing structures and purpose-built “wildlife crossings” to provide for wildlife movement

Cell-free protein synthesis as a tool to study RXFP3- Relaxin-3 protein interactions

With the discovery of the relaxin family peptide receptors there is interest in obtaining a clearer understanding of the structure of these proteins and the molecular mechanism of receptor-ligand interaction. As G-protein coupled receptors, obtaining milligram quantities for structural investigations is hampered by the inherent instability of these integral membrane proteins. In the current context, understanding of GPCR structural biology has increased dramatically with crystal structures of several inactive and now active forms solved. In addition, the first nuclear magnetic resonance structure of a GPCR was obtained which is of crucial importance to studying these receptors in a more “biologically relevant” setting. However despite this expansion in the field, most structures have been solved on modified systems so as to increase stability and are not necessarily representative of the native receptors. In relation to the relaxin family peptide receptors, we chose to investigate relaxin-family peptide receptor-3 expressed by cellfree protein synthesis. In contrast to in-vivo expression, cell-free was capable of producing large amounts of native receptor which makes it amenable to demanding structural studies

Defects in IL-2R Signaling Contribute to Diminished Maintenance of FOXP3 Expression in CD4+CD25+ Regulatory T-Cells of Type 1 Diabetic Subjects

OBJECTIVE In humans, multiple genes in the interleukin (IL)-2/IL-2 receptor (IL-2R) pathway are associated with type 1 diabetes. However, no link between IL-2 responsiveness and CD4+CD25+FOXP3+ regulatory T-cells (Tregs) has been demonstrated in type 1 diabetic subjects despite the role of these IL-2–dependent cells in controlling autoimmunity. Here, we address whether altered IL-2 responsiveness impacts persistence of FOXP3 expression in Tregs of type 1 diabetic subjects. RESEARCH DESIGN AND METHODS Persistence of Tregs was assessed by culturing sorted CD4+CD25hi natural Tregs with IL-2 and measuring FOXP3 expression over time by flow cytometry for control and type 1 diabetic populations. The effects of IL-2 on FOXP3 induction were assessed 48 h after activation of CD4+CD25− T-cells with anti-CD3 antibody. Cytokine receptor expression and signaling upon exposure to IL-2, IL-7, and IL-15 were determined by flow cytometry and Western blot analysis. RESULTS Maintenance of FOXP3 expression in CD4+CD25+ Tregs of type 1 diabetic subjects was diminished in the presence of IL-2, but not IL-7. Impaired responsiveness was not linked to altered expression of the IL-2R complex. Instead, IL-2R signaling was reduced in Tregs and total CD4+ T-cells of type 1 diabetic subjects. In some individuals, decreased signal transducer and activator of transcription 5 phosphorylation correlated with significantly higher expression of protein tyrosine phosphatase N2, a negative regulator of IL-2R signaling. CONCLUSIONS Aberrant IL-2R signaling in CD4+ T-cells of type 1 diabetic subjects contributes to decreased persistence of FOXP3 expression that may impact establishment of tolerance. These findings suggest novel targets for treatment of type 1 diabetes within the IL-2R pathway and suggest that an altered IL-2R signaling signature may be a biomarker for type 1 diabetes

1939: Abilene Christian College Bible Lectures - Full Text

Delivered in the Auditorium of Abilene Christian College, February, 1939, Abilene, Texas Published October, 1939 PRICE, $1.00 FIRM FOUNDATION PUBLISHING HOUSE Austin, Texas