Development and Characterization of Synthetic Glucopyranosyl Lipid Adjuvant System as a Vaccine Adjuvant

Innate immune responses to vaccine adjuvants based on lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, are driven by Toll-like receptor (TLR) 4 and adaptor proteins including MyD88 and TRIF, leading to the production of inflammatory cytokines, type I interferons, and chemokines. We report here on the characterization of a synthetic hexaacylated lipid A derivative, denoted as glucopyranosyl lipid adjuvant (GLA). We assessed the effects of GLA on murine and human dendritic cells (DC) by combining microarray, mRNA and protein multiplex assays and flow cytometry analyses. We demonstrate that GLA has multifunctional immunomodulatory activity similar to naturally-derived monophosphory lipid A (MPL) on murine DC, including the production of inflammatory cytokines, chemokines, DC maturation and antigen-presenting functions. In contrast, hexaacylated GLA was overall more potent on a molar basis than heterogeneous MPL when tested on human DC and peripheral blood mononuclear cells (PBMC). When administered in vivo, GLA enhanced the immunogenicity of co-administered recombinant antigens, producing strong cell-mediated immunity and a qualitative TH1 response. We conclude that the GLA adjuvant stimulates and directs innate and adaptive immune responses by inducing DC maturation and the concomitant release of pro-inflammatory cytokines and chemokines associated with immune cell trafficking, activities which have important implications for the development of future vaccine adjuvants

Is There Evidence that Runners can Benefit from Wearing Compression Clothing?

Background: Runners at various levels of performance and specializing in different events (from 800 m to marathons) wear compression socks, sleeves, shorts, and/or tights in attempt to improve their performance and facilitate recovery. Recently, a number of publications reporting contradictory results with regard to the influence of compression garments in this context have appeared. Objectives: To assess original research on the effects of compression clothing (socks, calf sleeves, shorts, and tights) on running performance and recovery. Method: A computerized research of the electronic databases PubMed, MEDLINE, SPORTDiscus, and Web of Science was performed in September of 2015, and the relevant articles published in peer-reviewed journals were thus identified rated using the Physiotherapy Evidence Database (PEDro) Scale. Studies examining effects on physiological, psychological, and/or biomechanical parameters during or after running were included, and means and measures of variability for the outcome employed to calculate Hedges’g effect size and associated 95 % confidence intervals for comparison of experimental (compression) and control (non-compression) trials. Results: Compression garments exerted no statistically significant mean effects on running performance (times for a (half) marathon, 15-km trail running, 5- and 10-km runs, and 400-m sprint), maximal and submaximal oxygen uptake, blood lactate concentrations, blood gas kinetics, cardiac parameters (including heart rate, cardiac output, cardiac index, and stroke volume), body and perceived temperature, or the performance of strength-related tasks after running. Small positive effect sizes were calculated for the time to exhaustion (in incremental or step tests), running economy (including biomechanical variables), clearance of blood lactate, perceived exertion, maximal voluntary isometric contraction and peak leg muscle power immediately after running, and markers of muscle damage and inflammation. The body core temperature was moderately affected by compression, while the effect size values for post-exercise leg soreness and the delay in onset of muscle fatigue indicated large positive effects. Conclusion: Our present findings suggest that by wearing compression clothing, runners may improve variables related to endurance performance (i.e., time to exhaustion) slightly, due to improvements in running economy, biomechanical variables, perception, and muscle temperature. They should also benefit from reduced muscle pain, damage, and inflammation.First Online: 22 April 2016</p

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

Elucidating how the brain's serotonergic network mediates diverse behavioral actions over both relatively short (minutes–hours) and long period of time (days–weeks) remains a major challenge for neuroscience. Our relative ignorance is largely due to the lack of technologies with robustness, reversibility, and spatio-temporal control. Recently, we have demonstrated that our chemogenetic approach (eg, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) provides a reliable and robust tool for controlling genetically defined neural populations. Here we show how short- and long-term activation of dorsal raphe nucleus (DRN) serotonergic neurons induces robust behavioral responses. We found that both short- and long-term activation of DRN serotonergic neurons induce antidepressant-like behavioral responses. However, only short-term activation induces anxiogenic-like behaviors. In parallel, these behavioral phenotypes were associated with a metabolic map of whole brain network activity via a recently developed non-invasive imaging technology DREAMM (DREADD Associated Metabolic Mapping). Our findings reveal a previously unappreciated brain network elicited by selective activation of DRN serotonin neurons and illuminate potential therapeutic and adverse effects of drugs targeting DRN neurons