Mathematical Modeling of Respiratory System Mechanics in the Newborn Lamb

In this paper, a mathematical model of the respiratory mechanics is used to reproduce experimental signal waveforms acquired from three newborn lambs. As the main challenge is to determine specific lamb parameters, a sensitivity analysis has been realized to find the most influent parameters, which are identified using an evolutionary algorithm. Results show a close match between experimental and simulated pressure and flow waveforms obtained during spontaneous ventilation and pleural pressure variations acquired during the application of positive pressure, since root mean square errors equal to 0.0119, 0.0052 and 0.0094. The identified parameters were discussed in light of previous knowledge of respiratory mechanics in the newborn.     

Effects of surfactin on membrane models displaying lipid phase separation

Surfactin, a bacterial amphiphilic lipopeptide is attracting more and more attention in view of its bioactive properties which are in relation with its ability to interact with lipids of biological membranes. In this work, we investigated the effect of surfactin on membrane structure using model of membranes, vesicles as well as supported bilayers, presenting coexistence of fluid-disordered (DOPC) and gel (DPPC) phases. A range of complementary methods was used including AFM, ellipsometry, dynamic light scattering, fluorescence measurements of Laurdan, DPH, calcein release, and octadecylrhodamine B dequenching. Our findings demonstrated that surfactin concentration is critical for its effect on the membrane. The results suggest that the presence of rigid domains can play an essential role in the first step of surfactin insertion and that surfactin interacts both with the membrane polar heads and the acyl chain region. A mechanism for the surfactin lipid membrane interaction, consisting of three sequential structural and morphological changes, is proposed. At concentrations below the CMC, surfactin inserted at the boundary between gel and fluid lipid domains, inhibited phase separation and stiffened the bilayer without global morphological change of liposomes. At concentrations close to CMC, surfactin solubilized the fluid phospholipid phase and increased order in the remainder of the lipid bilayer. At higher surfactin concentrations, both the fluid and the rigid bilayer structures were dissolved into mixed micelles and other structures presenting a wide size distribution.     

A fast growing spectrum of biological functions of γ-secretase in development and disease

γ-secretase, which assembles as a tetrameric complex, is an aspartyl protease that proteolytically cleaves substrate proteins within their membrane-spanning domain; a process also known as regulated intramembrane proteolysis (RIP). RIP regulates signaling pathways by abrogating or releasing signaling molecules. Since the discovery, already > 15 years ago, of its catalytic component, presenilin, and even much earlier with the identification of amyloid precursor protein as its first substrate, γ-secretase has been commonly associated with Alzheimer's disease. However, starting with Notch and thereafter a continuously increasing number of novel substrates, γ-secretase is becoming linked to an equally broader range of biological processes. This review presents an updated overview of the current knowledge on the diverse molecular mechanisms and signaling pathways controlled by γ-secretase, with a focus on organ development, homeostasis and dysfunction. This article is part of a Special Issue entitled: Intramembrane Proteases.     

Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)

A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria.     

Eucalypts face increasing climate stress

Global climate change is already impacting species and ecosystems across the planet. Trees, although long‐lived, are sensitive to changes in climate, including climate extremes. Shifts in tree species' distributions will influence biodiversity and ecosystem function at scales ranging from local to landscape; dry and hot regions will be especially vulnerable. The Australian continent has been especially susceptible to climate change with extreme heat waves, droughts, and flooding in recent years, and this climate trajectory is expected to continue. We sought to understand how climate change may impact Australian ecosystems by modeling distributional changes in eucalypt species, which dominate or codominate most forested ecosystems across Australia. We modeled a representative sample of Eucalyptus and Corymbia species (n = 108, or 14% of all species) using newly available Representative Concentration Pathway (RCP) scenarios developed for the 5th Assessment Report of the IPCC, and bioclimatic and substrate predictor variables. We compared current, 2025, 2055, and 2085 distributions. Overall, Eucalyptus and Corymbia species in the central desert and open woodland regions will be the most affected, losing 20% of their climate space under the mid‐range climate scenario and twice that under the extreme scenario. The least affected species, in eastern Australia, are likely to lose 10% of their climate space under the mid‐range climate scenario and twice that under the extreme scenario. Range shifts will be lateral as well as polewards, and these east–west transitions will be more significant, reflecting the strong influence of precipitation rather than temperature changes in subtropical and midlatitudes. These net losses, and the direction of shifts and contractions in range, suggest that many species in the eastern and southern seaboards will be pushed toward the continental limit and that large tracts of currently treed landscapes, especially in the continental interior, will change dramatically in terms of species composition and ecosystem structure.     

Temporal Variability of Antibiotics Fluxes in Wastewater and Contribution from Hospitals

Significant quantities of antibiotics are used in all parts of the globe to treat diseases with bacterial origins. After ingestion, antibiotics are excreted by the patient and transmitted in due course to the aquatic environment. This study examined temporal fluctuations (monthly time scale) in antibiotic sources (ambulatory sales and data from a hospital dispensary) for Lausanne, Switzerland. Source variability (i.e., antibiotic consumption, monthly data for 2006–2010) were examined in detail for nine antibiotics – azithromycin, ciprofloxacin, clarithromycin, clindamycin, metronidazole, norfloxacin, ofloxacin, sulfamethoxazole and trimethoprim, from which two main conclusions were reached. First, some substances – azithromycin, clarithromycin, ciprofloxacin – displayed high seasonality in their consumption, with the winter peak being up to three times higher than the summer minimum. This seasonality in consumption resulted in seasonality in Predicted Environmental Concentrations (PECs). In addition, the seasonality in PECs was also influenced by that in the base wastewater flow. Second, the contribution of hospitals to the total load of antibiotics reaching the Lausanne Wastewater Treatment Plant (WTP) fluctuated markedly on a monthly time scale, but with no seasonal pattern detected. That is, there was no connection between fluctuations in ambulatory and hospital consumption for the substances investigated.     

Chronic Endocannabinoid System Stimulation Induces Muscle Macrophage and Lipid Accumulation in Type 2 Diabetic Mice Independently of Metabolic Endotoxaemia

Aims

Obesity and type 2 diabetes are characterised by low-grade inflammation, metabolic endotoxaemia (i.e., increased plasma lipopolysaccharides [LPS] levels) and altered endocannabinoid (eCB)-system tone. The aim of this study was to decipher the specific role of eCB-system stimulation or metabolic endotoxaemia in the onset of glucose intolerance, metabolic inflammation and altered lipid metabolism.

Methods

Mice were treated with either a cannabinoid (CB) receptor agonist (HU210) or low-dose LPS using subcutaneous mini-pumps for 6 weeks. After 3 weeks of the treatment under control (CT) diet, one-half of each group of mice were challenged with a high fat (HF) diet for the following 3-week period.

Results

Under basal conditions (control diet), chronic CB receptor agonist treatment (i.e., 6 weeks) induced glucose intolerance, stimulated metabolic endotoxaemia, and increased macrophage infiltration (CD11c and F4/80 expression) in the muscles; this phenomenon was associated with an altered lipid metabolism (increased PGC-1α expression and decreased CPT-1b expression) in this tissue. Chronic LPS treatment tended to increase the body weight and fat mass, with minor effects on the other metabolic parameters. Challenging mice with an HF diet following pre-treatment with the CB agonist exacerbated the HF diet-induced glucose intolerance, the muscle macrophage infiltration and the muscle''s lipid content without affecting the body weight or the fat mass.

Conclusion

Chronic CB receptor stimulation under basal conditions induces glucose intolerance, stimulates metabolic inflammation and alters lipid metabolism in the muscles. These effects worsen following the concomitant ingestion of an HF diet. Here, we highlight the central roles played by the eCB system and LPS in the pathophysiology of several hallmarks of obesity and type 2 diabetes.     

Socioeconomic Inequalities in Smoking and Smoking Cessation Due to a Smoking Ban: General Population-Based Cross-Sectional Study in Luxembourg

This study aimed to measure changes in socioeconomic inequalities in smoking and smoking cessation due to the 2006 smoking ban in Luxembourg. Data were derived from the PSELL3/EU-SILC (Panel Socio-Economique Liewen Zu Letzebuerg/European Union—Statistic on Income and Living Conditions) survey, which was a representative survey of the general population aged ≥16 years conducted in Luxembourg in 2005, 2007, and 2008. Smoking prevalence and smoking cessation due to the 2006 smoking ban were used as the main smoking outcomes. Two inequality measures were calculated to assess the magnitude and temporal trends of socioeconomic inequalities in smoking: the prevalence ratio and the disparity index. Smoking cessation due to the smoking ban was considered as a positive outcome. Three multiple logistic regression models were used to assess social inequalities in smoking cessation due to the 2006 smoking ban. Education level, income, and employment status served as proxies for socioeconomic status. The prevalence of smoking decreased by 22.5% between 2005 and 2008 (from 23.1% in 2005 to 17.9% in 2008), but socioeconomic inequalities in smoking persisted. Smoking prevalence decreased by 24.2% and 20.2% in men and women, respectively; this difference was not statistically significant. Smoking cessation in daily smokers due to the 2006 smoking ban was associated with education level, employment status, and income, with higher percentages of quitters among those with a lower socioeconomic status. The decrease in smoking prevalence after the 2006 law was also associated with a reduction in socioeconomic inequalities, including differences in education level, income, and employment status. Although the smoking ban contributed to a reduction of such inequalities, they still persist, indicating the need for a more targeted approach of smoke-free policies directed toward lower socioeconomic groups.     

CD45 Isoform Profile Identifies Natural Killer (NK) Subsets with Differential Activity

The leucocyte-specific phosphatase CD45 is present in two main isoforms: the large CD45RA and the short CD45RO. We have recently shown that distinctive expression of these isoforms distinguishes natural killer (NK) populations. For example, co-expression of both isoforms identifies in vivo the anti tumor NK cells in hematological cancer patients. Here we show that low CD45 expression associates with less mature, CD56^bright, NK cells. Most NK cells in healthy human donors are CD45RA⁺CD45RO^-. The CD45RA^-RO⁺ phenotype, CD45RO cells, is extremely uncommon in B or NK cells, in contrast to T cells. However, healthy donors possess CD45RA^dimRO^- (CD45RA^dim cells), which show immature markers and are largely expanded in hematopoietic stem cell transplant patients. Blood borne cancer patients also have more CD45RA^dim cells that carry several features of immature NK cells. However, and in opposition to their association to NK cell progenitors, they do not proliferate and show low expression of the transferrin receptor protein 1/CD71, suggesting low metabolic activity. Moreover, CD45RA^dim cells properly respond to in vitro encounter with target cells by degranulating or gaining CD69 expression. In summary, they are quiescent NK cells, with low metabolic status that can, however, respond after encounter with target cells.