Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose

Background Diabetes is a risk factor for respiratory infection, and hyperglycaemia is associated with increased glucose in airway surface liquid and risk of Staphylococcus aureus infection. Objectives To investigate whether elevation of basolateral/blood glucose concentration promotes airway Staphylococcus aureus growth and whether pretreatment with the antidiabetic drug metformin affects this relationship. Methods Human airway epithelial cells grown at air–liquid interface (±18 h pre-treatment, 30 μM–1 mM metformin) were inoculated with 5×105 colony-forming units (CFU)/cm2 S aureus 8325-4 or JE2 or Pseudomonas aeruginosa PA01 on the apical surface and incubated for 7 h. Wild-type C57BL/6 or db/db (leptin receptor-deficient) mice, 6–10 weeks old, were treated with intraperitoneal phosphate-buffered saline or 40 mg/kg metformin for 2 days before intranasal inoculation with 1×107 CFU S aureus. Mice were culled 24 h after infection and bronchoalveolar lavage fluid collected. Results Apical S aureus growth increased with basolateral glucose concentration in an in vitro airway epithelia–bacteria co-culture model. S aureus reduced transepithelial electrical resistance (RT) and increased paracellular glucose flux. Metformin inhibited the glucose-induced growth of S aureus, increased RT and decreased glucose flux. Diabetic (db/db) mice infected with S aureus exhibited a higher bacterial load in their airways than control mice after 2 days and metformin treatment reversed this effect. Metformin did not decrease blood glucose but reduced paracellular flux across ex vivo murine tracheas. Conclusions Hyperglycaemia promotes respiratory S aureus infection, and metformin modifies glucose flux across the airway epithelium to limit hyperglycaemia-induced bacterial growth. Metformin might, therefore, be of additional benefit in the prevention and treatment of respiratory infection

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

A novel fluorescent sensor protein for detecting changes in airway surface liquid glucose concentration.

Both lung disease and elevation of blood glucose are associated with increased glucose concentration (from 0.4 to ~4.0 mM) in the airway surface liquid (ASL). This perturbation of ASL glucose makes the airway more susceptible to infection by respiratory pathogens. ASL is minute (~1 μl/cm(2)) and the measurement of glucose concentration in the small volume ASL is extremely difficult. Therefore, we sought to develop a fluorescent biosensor with sufficient sensitivity to determine glucose concentrations in ASL in situ. We coupled a range of environmentally sensitive fluorophores to mutated forms of a glucose/galactose-binding protein (GBP) including H152C and H152C/A213R and determined their equilibrium binding properties. Of these, GBP H152C/A213R-BADAN (Kd 0.86 ± 0.01 mM, Fmax/F0 3.6) was optimal for glucose sensing and in ASL increased fluorescence when basolateral glucose concentration was raised from 1 to 20 mM. Moreover, interpolation of the data showed that the glucose concentration in ASL was increased, with results similar to that using glucose oxidase analysis. The fluorescence of GBP H152C/A213R-BADAN in native ASL from human airway epithelial cultures in situ was significantly increased over time when basolateral glucose was increased from 5 to 20 mM. Overall our data indicate that this GBP is a useful tool to monitor glucose homoeostasis in the lung

Observational constraints on the progenitor metallicities of core-collapse supernovae

We present constraints on the progenitor metallicities of core-collapse supernovae. To date, nearly all metallicity constraints have been inferred from indirect methods such as metallicity gradients in host galaxies, luminosities of host galaxies, or derived global galaxy metallicities. Here, progenitor metallicities are derived from optical spectra taken at the sites of nearby supernovae, from the ratio of strong emission lines found in their host HII regions.We present results from the spectra of 74 host HII regions and discuss the implications that these have on the nature of core-collapse supernova progenitors. Overall, while we find that the mean metallicity of type Ibc environments is higher than that of type II events, this difference is smaller than observed in previous studies. There is only a 0.06 dex difference in the mean metallicity values, at a statistical significance of ~1.5 sigma, while using a KS-test we find that the two metallicity distributions are marginally consistent with being drawn from the same parent population (probability >10%). This argues that progenitor metallicity is not a dominant parameter in deciding supernovae type, with progenitor mass and/or binarity playing a much more significant role.Comment: ACCEPTED for publication in MNRA

Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid.

Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5-20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of D-glucose was lower than D-fructose. However, uptake of D-glucose was higher than D-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection

Gemini GMOS--IFU spectroscopy of the compact HII galaxies Tol 0104-388 and Tol 2146-391: The dependence on the properties of the interstellar medium

Using GMOS--IFU spectroscopic observations of the compact HII/BCD galaxies Tol 0104-388 and Tol 2146-391, we study the spatial distribution of emission lines, equivalent width EW(Hb), extinction c(Hb), ionization ratios ([OIII]5007/Hb, [SII]6717,6731/Ha and [NII]6584/Ha), kinematics, and the chemical pattern (O/H, N/H and N/O) of the warm interstellar medium in these galaxies. We also investigate a possible dependence of these properties on the I(HeII4686)/I(Hb) ratio and find no significant correlation between these variables. In fact, the oxygen abundances appear to be uniform in the regions where the HeII4686 emission line was measured. It can be interpreted in the sense that these correlations are related to global properties of the galaxies and not with small patches of the interstellar medium. Although a possible weak N/H gradient is observed in Tol 2146-391, the available data suggest that the metals from previous star-formation events are well mixed and homogeneously distributed through the optical extent of these galaxies. The spatial constancy of the N/O ratio might be attributed to efficient transport and mixing of metals by starburst-driven super-shells, powered by a plethora of unresolved star cluster in the inner part of the galaxies. This scenario agrees with the idea that most of the observed HeII4686 emission line, in our sample of galaxies, is produced by radiative shocks.Comment: 16 pages, 18 figures, 5 tables, accepted for publication in MNRA

The H alpha Galaxy Survey V. The star formation history of late-type galaxies

This study of 117 low-redshift Im and Sm galaxies investigates the star formation rates of late-type galaxies, to determine whether they are quasi-continuous or dominated by bursts with quiescent interludes. We analyse the distribution of star formation timescales (stellar masses/star formation rates) for the entire sample, and of gas depletion timescales for those galaxies with gas mass measurements. We find that, on average, the late-type galaxies studied could have produced their total stellar masses by an extrapolation of their current star formation activity over a period of just under a Hubble time. This is not the case for a comparison sample of earlier-type galaxies, even those with disk-dominated morphologies and similar total stellar masses to the late-type galaxies. The earlier-type galaxies are on average forming their stars more slowly at present than the average rate over their past histories. No totally quiescent Im or Sm galaxies are found, and although some evidence of intrinsic variation in the star formation rate with time is found, this is typically less than a factor of 2 increase or decrease relative to the mean level. The Im and Sm galaxies have extensive gas reservoirs and can maintain star formation at the current rate for more than another Hubble time. The average spatial distribution of star formation in the Im galaxies, and to a lesser extent the Sm galaxies, is very similar to that of the older stellar population traced by the red light.Comment: 8 pages, 7 figures, accepted for publication in Astronomy & Astrophysic

Detectors for the James Webb Space Telescope Near-Infrared Spectrograph I: Readout Mode, Noise Model, and Calibration Considerations

We describe how the James Webb Space Telescope (JWST) Near-Infrared Spectrograph's (NIRSpec's) detectors will be read out, and present a model of how noise scales with the number of multiple non-destructive reads sampling-up-the-ramp. We believe that this noise model, which is validated using real and simulated test data, is applicable to most astronomical near-infrared instruments. We describe some non-ideal behaviors that have been observed in engineering grade NIRSpec detectors, and demonstrate that they are unlikely to affect NIRSpec sensitivity, operations, or calibration. These include a HAWAII-2RG reset anomaly and random telegraph noise (RTN). Using real test data, we show that the reset anomaly is: (1) very nearly noiseless and (2) can be easily calibrated out. Likewise, we show that large-amplitude RTN affects only a small and fixed population of pixels. It can therefore be tracked using standard pixel operability maps.Comment: 55 pages, 10 figure

Nonlinear spectral calculus and super-expanders

Nonlinear spectral gaps with respect to uniformly convex normed spaces are shown to satisfy a spectral calculus inequality that establishes their decay along Cesaro averages. Nonlinear spectral gaps of graphs are also shown to behave sub-multiplicatively under zigzag products. These results yield a combinatorial construction of super-expanders, i.e., a sequence of 3-regular graphs that does not admit a coarse embedding into any uniformly convex normed space.Comment: Typos fixed based on referee comments. Some of the results of this paper were announced in arXiv:0910.2041. The corresponding parts of arXiv:0910.2041 are subsumed by the current pape