Multi-scale mechanistic modelling of the host defence in invasive aspergillosis reveals leucocyte activation and iron acquisition as drivers of infection outcome

Aspergillus species are ubiquitous environmental moulds, with spores inhaled daily by most humans. Immunocompromised hosts can develop an invasive infection resulting in high mortality. There is, therefore, a pressing need for host-centric therapeutics for this infection. To address it, we created a multi-scale computational model of the infection, focused on its interaction with the innate immune system and iron, a critical nutrient for the pathogen. The model, parameterized using published data, was found to recapitulate a wide range of biological features and was experimentally validated in vivo. Conidial swelling was identified as critical in fungal strains with high growth, whereas the siderophore secretion rate seems to be an essential prerequisite for the establishment of the infection in low-growth strains. In immunocompetent hosts, high growth, high swelling probability and impaired leucocyte activation lead to a high conidial germination rate. Similarly, in neutropenic hosts, high fungal growth was achieved through synergy between high growth rate, high swelling probability, slow leucocyte activation and high siderophore secretion. In summary, the model reveals a small set of parameters related to fungal growth, iron acquisition and leucocyte activation as critical determinants of the fate of the infection.     

In vitro β‐Carotene Bioaccessibility and Lipid Digestion in Emulsions: Influence of Pectin Type and Degree of Methyl‐Esterification

Citrus pectin (CP) and sugar beet pectin (SBP) were demethoxylated and fully characterized in terms of pectin properties in order to investigate the influence of the pectin degree of methyl‐esterification (DM) and the pectin type on the in vitro β‐carotene bioaccessibility and lipid digestion in emulsions. For the CP based emulsions containing β‐carotene enriched oil, water and pectin, the β‐carotene bioaccessibility, and lipid digestion were higher in the emulsions with pectin with a higher DM (57%; “CP57 emulsion”) compared to the emulsions with pectin with a lower DM (30%; “CP30 emulsion”) showing that the DM plays an important role. In contrast, in SBP‐based emulsions, nor β‐carotene bioaccessibility nor lipid digestion were dependent on pectin DM. Probably here, other pectin properties are more important factors. It was observed that β‐carotene bioaccessibility and lipid digestion were lower in the CP30 emulsion in comparison with the CP57, SBP32, and SBP58 emulsions. However, the β‐carotene bioaccessibility of CP57 emulsion was similar to that of the SBP emulsions, whereas the lipid digestion was not. It seems that pectin type and pectin DM (in case of CP) are determining which components can be incorporated into micelles. Because carotenoids and lipids have different structures and polarities, their incorporation may be different. This knowledge can be used to engineer targeted (digestive) functionalities in food products. If both high β‐carotene bioaccessibility and high lipid digestion are targeted, SBP emulsions are the best options. The CP57 emulsion can be chosen if high β‐carotene bioaccessibility but lower lipid digestion is desired.     

Lipid specificity and location of the sterol carrier protein-2 fatty acid-binding site: A fluorescence displacement and energy transfer study

Although it was recently recognized that sterol carrier protein-2 (SCP-2) interacts with fatty acids, little is known regarding the specificity of SCP-2 for long-chain fatty acids or branched-chain fatty-acid-like molecules. Likewise the location of the fatty-acid binding site within SCP-2 is unresolved. A fluorescent cis-parinaric acid displacement assay was used to show that SCP-2 optimally interacted with 14–22 carbon chain lipidic molecules: polyunsaturated fatty acids > monounsaturated, saturated > branched-chain isoprenoids > branched-chain phytol-derived fatty acids. In contrast, the other major fatty-acid binding protein in liver, fatty-acid binding protein (L-FABP), displayed a much narrower carbon chain preference in general: polyunsaturated fatty acids > branched-chain phytol-derived fatty acids > 14- and 16-carbon saturated > branched-chain isoprenoids. However, both SCP-2 and l-FABP displayed a very similar unsaturated fatty-acid specificity profile. The presence and location of the SCP-2 lipid binding site were investigated by fluorescence energy transfer. The distance between the SCP-2 Trp⁵⁰ and bound cis-parinaric acid was determined to be 40 Å. Thus, the SCP-2 fatty-acid binding site appeared to be located on the opposite side of the SCP-2 Trp⁵⁰. These findings not only contribute to our understanding of the SCP-2 ligand binding site but also provide evidence suggesting a potential role for SCP-2 and/or L-FABP in metabolism of branched-chain fatty acids and isoprenoids.     

Mercury in the Arctic atmosphere: an analysis of eight years of measurements of GEM at Alert (Canada) and a comparison with observations at Amderma (Russia) and Kuujjuarapik (Canada)

Eight years of gaseous elemental mercury (GEM) concentration measurements from Alert, Nunavut, Canada (between 1995 and 2002) is presented. The annual time series shows a distinct repeating seasonal pattern with an overall annual median concentration for this time period of 1.58 (S.D.=0.04 ng m(-3)). Strong seasonal variation was observed throughout the years with springtime displaying strong variability in the GEM and overall lower median concentrations due to the so-called mercury depletion events (MDEs). Summer concentrations are higher than the annual average and show a decrease in variability. Fall and winter concentrations are distributed around the annual median concentrations and show little variability. The relationship between the springtime depression and the summer increase shows a change in the behaviour of mercury between 1995 and 2002. Preliminary results suggest that during this period an increasing amount of the mercury lost from the atmosphere in the spring is not returned to atmosphere in summer. A comparison of GEM concentration data from three sites--Alert (Canada), Amderma (Russia) and Kuujjuarapik (Canada)--demonstrated similar monthly distribution of GEM between Alert and Amderma, with the latter not showing as high summer concentrations. Monthly distribution of GEM at Kuujjuarapik varied considerably from the other two sites. MDEs were found to occur at each site in the spring yet displayed different characteristics. MDEs appear to start at Alert shortly after polar sunrise but in Amderma their initiation is delayed approximately 2 months following polar sunrise. MDEs occur in Kuujjuarapik in the springtime despite an incomplete development of the polar day-night cycle. In spring, as soon as air temperature attained temperatures consistently above 0 degrees C, MDEs ended immediately at all three sites. Continued studies into MDEs are warranted, but clearly an important component of future studies must focus on the origins of the variation of GEM behaviour at different sites.     

Efficiency of 4,4′‐bis(N,N‐diethylamino) benzophenone for the polymerization of dimethacrylate resins in thick sections

The efficiency of 4,4′‐bis(N,N‐diethylamino)benzophenone (DEABP) for the polymerization of dimethacrylate monomers in thick sections ( 1 – 2 mm) was studied. DEABP (λ_max = 365 nm) represents a complete initiating system as it contains both ketone and amine functional groups. During irradiation, DEABP photobleaches at a fast rate causing deeper penetration of light through the underlying layers, but the photoinitiation efficiency (rate of polymerization per photon absorption rate) is relatively poor. As a result, irradiation of methacrylate monomers at 365 nm results in a slow average polymerization rate and a reduced monomer conversion for thick sections due to the light attenuation caused by the high absorptivity of DEABP and photolysis products. These results highlight the inherent interlinking of light attenuation and photobleaching rate in polymerization of thick sections. Copyright © 2011 Society of Chemical Industry     

High Dietary Fat Exacerbates Weight Gain and Obesity in Female Liver Fatty Acid Binding Protein Gene-Ablated Mice

Since liver fatty acid binding protein (L-FABP) facilitates uptake/oxidation of long-chain fatty acids in cultured transfected cells and primary hepatocytes, loss of L-FABP was expected to exacerbate weight gain and/or obesity in response to high dietary fat. Male and female wild-type (WT) and L-FABP gene-ablated mice, pair-fed a defined isocaloric control or high fat diet for 12 weeks, consumed equal amounts of food by weight and kcal. Male WT mice gained weight faster than their female WT counterparts regardless of diet. L-FABP gene ablation enhanced weight gain more in female than male mice—an effect exacerbated by high fat diet. Dual emission X-ray absorptiometry revealed high-fat fed male and female WT mice gained mostly fat tissue mass (FTM). L-FABP gene ablation increased FTM in female, but not male, mice—an effect also exacerbated by high fat diet. Concomitantly, L-FABP gene ablation decreased serum β-hydroxybutyrate in male and female mice fed the control diet and, even more so, on the high-fat diet. Thus, L-FABP gene ablation decreased fat oxidation and sensitized all mice to weight gain as whole body FTM and LTM—with the most gain observed in FTM of control vs high-fat fed female L-FABP null mice. Taken together, these results indicate loss of L-FABP exacerbates weight gain and/or obesity in response to high dietary fat.     

Contribution of combined sewer overflows to trace contaminant loads in urban streams

The present study examines the contribution of combined sewer overflows (CSO) to loads and concentrations of trace contaminants in receiving surface water. A simple method to assess the ratio of CSO to wastewater treatment plant (WWTP) effluents was applied to the urban River Spree in Berlin, Germany. The assessment indicated that annual loads are dominated by CSO for substances with removal in WWTP above ∼95%. Moreover, it showed that substances with high removal in WWTP can lead to concentration peaks in the river during CSO events. The calculated results could be verified based on eight years of monitoring data from the River Spree, collected between 2000 and 2007. Substances that are well removed in WWTP such as NTA (nitrilotriacetic acid) were found to occur in significantly increased concentration during CSO, while the concentration of substances that are poorly removable in WWTP such as EDTA (ethylenediaminetetraacetic acid) decreased in CSO-influenced samples due to dilution effects. The overall results indicate the potential importance of the CSO pathway of well-removable sewage-based trace contaminants to rivers. In particular, high concentrations during CSO events may be relevant for aquatic organisms. Given the results, it is suggested to include well-removable, sewage-based trace contaminants, a substance group often neglected in the past, in future studies on urban rivers in case of combined sewer systems. The presented methodology is suggested for a first assessment, since it is based solely on urban drainage data, which is available in most cities.