Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391

Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc − Activity in the Medial Prefrontal Cortex

Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc −, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Objectives: Our goal was to determine whether increased system xc − activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating. Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc −, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3–3 mg/kg, sc). N-Acetylcysteine (10–100 μM) and the system xc − inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc − activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc − activity. Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10–100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc −. Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc − independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine

3D geometric modelling of discontinuous fibre composites using a force-directed algorithm

A geometrical modelling scheme is presented to produce representative architectures for discontinuous fibre composites, enabling downstream modelling of mechanical properties. The model generates realistic random fibre architectures containing high filament count bundles (>3k) and high (~50%) fibre volume fractions. Fibre bundles are modelled as thin shells using a multi-dimension modelling strategy, in which fibre bundles are distributed and compacted to simulate pressure being applied from a matched mould tool. FE simulations are performed to benchmark the in-plane mechanical properties obtained from the numerical model against experimental data, with a detailed study presented to evaluate the tensile properties at various fibre volume fractions and specimen thicknesses. Tensile modulus predictions are in close agreement (less than 5% error) with experimental data at volume fractions below 45%. Ultimate tensile strength predictions are within 4.2% of the experimental data at volume fractions between 40%-55%. This is a significant improvement over existing 2D modelling approaches, as the current model offers increased levels of fidelity, capturing dominant failure mechanisms and the influence of out-of-plane fibres

Nanoinformatics: developing new computing applications for nanomedicine

Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended ?nanotype? to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others

Elevated Paracellular Glucose Flux across Cystic Fibrosis Airway Epithelial Monolayers Is an Important Factor for Pseudomonas aeruginosa Growth.

People with cystic fibrosis (CF) who develop related diabetes (CFRD) have accelerated pulmonary decline, increased infection with antibiotic-resistant Pseudomonas aeruginosa and increased pulmonary exacerbations. We have previously shown that glucose concentrations are elevated in airway surface liquid (ASL) of people with CF, particularly in those with CFRD. We therefore explored the hypotheses that glucose homeostasis is altered in CF airway epithelia and that elevation of glucose flux into ASL drives increased bacterial growth, with an effect over and above other cystic fibrosis transmembrane conductance regulator (CFTR)-related ASL abnormalities. The aim of this study was to compare the mechanisms governing airway glucose homeostasis in CF and non-CF primary human bronchial epithelial (HBE) monolayers, under normal conditions and in the presence of Ps. aeruginosa filtrate. HBE-bacterial co-cultures were performed in the presence of 5 mM or 15 mM basolateral glucose to investigate how changes in blood glucose, such as those seen in CFRD, affects luminal Ps. aeruginosa growth. Calu-3 cell monolayers were used to evaluate the potential importance of glucose on Ps. aeruginosa growth, in comparison to other hallmarks of the CF ASL, namely mucus hyperviscosity and impaired CFTR-dependent fluid secretions. We show that elevation of basolateral glucose promotes the apical growth of Ps. aeruginosa on CF airway epithelial monolayers more than non-CF monolayers. Ps. aeruginosa secretions elicited more glucose flux across CF airway epithelial monolayers compared to non-CF monolayers which we propose increases glucose availability in ASL for bacterial growth. In addition, elevating basolateral glucose increased Ps. aeruginosa growth over and above any CFTR-dependent effects and the presence or absence of mucus in Calu-3 airway epithelia-bacteria co-cultures. Together these studies highlight the importance of glucose as an additional factor in promoting Ps. aeruginosa growth and respiratory infection in CF disease

Mathematical modelling of antimicrobial resistance in agricultural waste highlights importance of gene transfer rate

Antimicrobial resistance is of global concern. Most antimicrobial use is in agriculture; manures and slurry are especially important because they contain a mix of bacteria, including potential pathogens, antimicrobial resistance genes and antimicrobials. In many countries, manures and slurry are stored, especially over winter, before spreading onto fields as organic fertilizer. Thus these are a potential location for gene exchange and selection for resistance. We develop and analyze a mathematical model to quantify the spread of antimicrobial resistance in stored agricultural waste. We use parameters from a slurry tank on a UK dairy farm as an exemplar. We show that the spread of resistance depends in a subtle way on the rates of gene transfer and antibiotic inflow. If the gene transfer rate is high, then its reduction controls resistance, while cutting antibiotic inflow has little impact. If the gene transfer rate is low, then reducing antibiotic inflow controls resistance. Reducing length of storage can also control spread of resistance. Bacterial growth rate, fitness costs of carrying antimicrobial resistance and proportion of resistant bacteria in animal faeces have little impact on spread of resistance. Therefore effective treatment strategies depend critically on knowledge of gene transfer rates

Parkour as a donor sport for athletic development in youth team sports: insights through an ecological dynamics lens

Analyses of talent development in sport have identified that skill can be enhanced through early and continued involvement in donor sports which share affordances (opportunities for action) with a performer's main target sport. Aligning key ideas of the Athletic Skills Model and ecological dynamics theory, we propose how the sport of parkour could provide a representative and adaptive platform for developing athletic skill (e.g. coordination, timing, balance, agility, spatial awareness and muscular strength). We discuss how youth sport development programmes could be (re) designed to include parkour-style activities, in order to develop general athletic skills in affordance-rich environments. It is proposed that team sports development programmes could particularly benefit from parkour-style training since it is exploratory and adaptive nature shapes utilisation of affordances for innovative and autonomous performance by athletes. Early introduction to varied, relevant activities for development of athleticism and skill, in a diversified training programme, would provide impetus for a fundamental shift away from the early specialisation approach favoured by traditional theories of skill acquisition and expertise in sport

(E)-2-(4-Arylbut-1-en-3-yn-1-yl)chromones as synthons for the synthesis of xanthone-1,2,3-triazole dyads

Xanthone-1,2,3-triazole dyads have been synthesized by two different approaches, both starting from novel (E)-2-(4-arylbut-1-en-3-yn-1-yl)chromones, prepared through a base-catalyzed aldol reaction of 2-methylchromone and arylpropargyl aldehydes. In the first method, the xanthone moiety is built by Diels-Alder reaction of the referred unsaturated chromones with N-methylmaleimide under microwave irradiation, followed by oxidation of the obtained adducts with DDQ, whereas the 1,2,3-triazole ring results from the cycloaddition reaction of the acetylene moiety with sodium azide. The second strategy first involves the cycloaddition reaction with sodium azide to provide the 1,2,3-triazole ring, followed by methylation of the triazole NH group prior to Diels-Alder reaction with N-methylmaleimide. The last step in this synthesis of novel xanthone-1,2,3-triazole dyads entails oxidation of the cycloadducts with DDQ

Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

Normative data on regional sweat-sodium concentrations of professional male team-sport athletes

Background: The purpose of this paper was to report normative data on regional sweat sweat-sodium concentrations of various professional male team-sport athletes, and to compare sweat-sodium concentrations among sports. Data to this effect would inform our understanding of athlete sodium requirements, thus allowing for the individualisation of sodium replacement strategies. Accordingly, data from 696 athletes (Soccer, n = 270; Rugby, n = 181; Baseball, n = 133; American Football, n = 60; Basketball, n = 52) were compiled for a retrospective analysis. Regional sweat-sodium concentrations were collected using the pilocarpine iontophoresis method, and compared to self-reported measures collected via questionnaire. Results: Sweat-sodium concentrations were significantly higher (p < 0.05) in American football (50.4 ± 15.3 mmol·L-1), baseball (54.0 ± 14.0 mmol·L-1), and basketball (48.3 ± 14.0 mmol·L-1) than either soccer (43.2 ± 12.0 mmol·L-1) or rugby (44.0 ± 12.1 mmol·L-1), but with no differences among the N.American or British sports. There were strong positive correlations between sweat-sodium concentrations and self-reported sodium losses in American football (rs = 0.962, p < 0.001), basketball (rs = 0.953, p < 0.001), rugby (rs = 0.813, p < 0.001), and soccer (rs = 0.748, p < 0.001). Conclusions: The normative data provided on sweat-sodium concentrations might assist sports science/medicine practitioners in generating bespoke hydration and electrolyte-replacement strategies to meet the sodium demands of professional team-sport athletes. Moreover, these novel data suggest that self-reported measures of sodium loss might serve as an effective surrogate in the absence of direct measures; i.e., those which are more expensive or non-readily available