129 - Analysis of Corpus Callosum and Ventricles in Brain Tissue of MK801/CDPPB Treated C57BL6/J Mice

The neurodevelopmental hypothesis depicts schizophrenia as a long-term consequence of aberrant development of the glutamate and dopamine neurotransmitter systems during the perinatal period. The drug MK-801 is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that produces schizophrenia-like symptoms in laboratory rodents when administered early in development. Our laboratory has been investigating whether CDPPB, a positive allosteric modulator of the metabotropic glutamate receptor 5 (mGluR5), would reverse the effects of MK-801. To test this, mice were first administered 0.25 mg/kg MK-801 as neonates, and later given 10.0 mg/kg CDBBD or saline during their juvenile period. Previously, our lab found that MK-801 produced a series of long-term behavioral deficits, some of which were reversed with CDPPB treatment. For the current study, brains were extracted, sectioned with a cryostat, and stained with myelin-specific Luxol-Fast Blue. Brain sections were digitized and examined microscopically. Morphometric measures such as total section volume, lateral ventricle volume and corpus callosum volume were determined with ImageJ software. The goal of the current study is to determine if a reduction of myelinated structures such as the corpus callosum and/or enlargement of the cerebral ventricles are related to the behavioral deficits observed earlier

PD-1 Co-inhibitory and OX40 Co-stimulatory Crosstalk Regulates Helper T Cell Differentiation and Anti-Plasmodium Humoral Immunity

SummaryThe differentiation and protective capacity of Plasmodium-specific T cells are regulated by both positive and negative signals during malaria, but the molecular and cellular details remain poorly defined. Here we show that malaria patients and Plasmodium-infected rodents exhibit atypical expression of the co-stimulatory receptor OX40 on CD4 T cells and that therapeutic enhancement of OX40 signaling enhances helper CD4 T cell activity, humoral immunity, and parasite clearance in rodents. However, these beneficial effects of OX40 signaling are abrogated following coordinate blockade of PD-1 co-inhibitory pathways, which are also upregulated during malaria and associated with elevated parasitemia. Co-administration of biologics blocking PD-1 and promoting OX40 signaling induces excessive interferon-gamma that directly limits helper T cell-mediated support of humoral immunity and decreases parasite control. Our results show that targeting OX40 can enhance Plasmodium control and that crosstalk between co-inhibitory and co-stimulatory pathways in pathogen-specific CD4 T cells can impact pathogen clearance

Transcriptional and Epigenetic Regulation of Effector and Memory CD8 T Cell Differentiation

Immune protection and lasting memory are accomplished through the generation of phenotypically and functionally distinct CD8 T cell subsets. Understanding how these effector and memory T cells are formed is the first step in eventually manipulating the immune system for therapeutic benefit. In this review, we will summarize the current understanding of CD8 T cell differentiation upon acute infection, with a focus on the transcriptional and epigenetic regulation of cell fate decision and memory formation. Moreover, we will highlight the importance of high throughput sequencing approaches and single cell technologies in providing insight into genome-wide investigations and the heterogeneity of individual CD8 T cells

Exenatide Sensitizes Insulin-Mediated Whole-Body Glucose Disposal and Promotes Uptake of Exogenous Glucose by the Liver

OBJECTIVE— Recent progress suggests that exenatide, a mimetic of glucagon-like peptide-1 (GLP-1), might lower glycemia independent of increased β-cell response or reduced gastrointestinal motility. We aimed to investigate whether exenatide stimulates glucose turnover directly in insulin-responsive tissues dependent or independent of insulinemia

Evaluation of an adaptive game that uses EEG measures validated during the design process as inputs to a Biocybernetic Loop

Biocybernetic adaptation is a form of physiological computing whereby real-time data streaming from the brain and body is used by a negative control loop to adapt the user interface. This article describes the development of an adaptive game system that is designed to maximize player engagement by utilizing changes in real-time electroencephalography (EEG) to adjust the level of game demand. The research consists of four main stages: (1) the development of a conceptual framework upon which to model the interaction between person and system; (2) the validation of the psychophysiological inference underpinning the loop; (3) the construction of a working prototype; and (4) an evaluation of the adaptive game. Two studies are reported. The first demonstrates the sensitivity of EEG power in the (frontal) theta and (parietal) alpha bands to changing levels of game demand. These variables were then reformulated within the working biocybernetic control loop designed to maximize player engagement. The second study evaluated the performance of an adaptive game of Tetris with respect to system behavior and user experience. Important issues for the design and evaluation of closed-loop interfaces are discussed

Inhibition of Dipeptidyl Peptidase-4 by Vildagliptin During Glucagon-Like Peptide 1 Infusion Increases Liver Glucose Uptake in the Conscious Dog

OBJECTIVE—This study investigated the acute effects of treatment with vildagliptin on dipeptidyl peptidase-4 (DPP-4) activity, glucagon-like peptide 1 (GLP-1) concentration, pancreatic hormone levels, and glucose metabolism. The primary aims were to determine the effects of DPP-4 inhibition on GLP-1 clearance and on hepatic glucose uptake

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Bristol Girls Dance Project: A cluster randomised controlled trial of an after-school dance programme to increase physical activity among 11- to 12-year-old girls

Background: Many children do not meet UK physical activity (PA) guidelines. Girls are less active than boys, and the age-related decline in activity is steeper for girls. Dance is the favourite form of PA among adolescent girls in the UK. Participation in after-school dance classes could significantly contribute to girls’ PA. Therefore, after-school dance may be effective for increasing PA levels.Objectives: To determine the effectiveness and cost effectiveness of a dance-based intervention to increase the objectively assessed mean weekday minutes of moderate- to vigorous-intensity physical activity (MVPA) of Year 7 girls (11- and 12-year olds) 1 year after baseline measurement.Design: Two-arm cluster randomised controlled trial and economic evaluation. Year 7 girls in participant schools received a ‘taster’ session and were invited to participate. Up to 33 girls per school were able to participate. Schools were randomly assigned (equal numbers) to intervention or control arms.Setting: A total of 18 mainstream secondary schools across greater Bristol.Participants: Year 7 girls in participating schools who could participate in physical education.Intervention: Nine intervention schools received an after-school dance intervention (40 × 75-minute sessions) underpinned by self-determination theory, which attempts to improve intrinsic motivation for being active, and delivered by external dance instructors. Control schools continued as normal.Main outcome measures: The main outcome was accelerometer-assessed mean minutes of MVPA at T2. Measures were assessed at baseline (T0), the end of the intervention (T1) and at T0 + 52 weeks (T2).Results: Baseline MVPA levels were high. A total of 508 girls were included in the primary analysis, which found no difference in weekday MVPA between trial arms. There was no effect on secondary accelerometer outcomes. Data were subjected to a per-protocol analysis and no effect was found. However, at T1, girls who attended dance classes had 4.61 minutes more of MVPA and 14.27 minutes more of light-intensity activity between 15.00 and 17.00 on the days on which they attended intervention sessions. The intervention was inexpensive at £73 per participant (£63 when excluding dance instructor travel) but was not cost-effective owing to the ineffectiveness of the intervention. The European Quality of Life-5 Dimensions Youth survey data were unresponsive to changes in the sample. The process evaluation reported that girls in attendance enjoyed the sessions, that exertion levels were low during sessions and that attendance was low and declined. Fidelity to the session-plan manual was low but theoretical fidelity (to self-determination theory) was good. Qualitative information provides information for improving future interventions.Conclusions: The intervention was enjoyed by participants. However, there was no difference in the MVPA levels (which were high at baseline) of girls allocated to receive dance compared with girls receiving the control. High baseline MVPA levels indicate that the study appealed to an already active cohort and, therefore, may not have targeted those most in need of an intervention. Dance is an enjoyable activity for adolescent girls and could be further trialled as a means by which to increase PA. Research might consider the impact of dividing the intervention period into smaller blocks