Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates TH2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

Background

Severe asthma is associated with T helper (T_H) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.

Objective

To determine the anti-inflammatory potential of anthraquinones in-vivo.

Methods

BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.

Results

Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of T_H2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

Conclusion

Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.     

Biosynthesis of Vitamins and Cofactors in Bacterium-Harbouring Trypanosomatids Depends on the Symbiotic Association as Revealed by Genomic Analyses

Some non-pathogenic trypanosomatids maintain a mutualistic relationship with a betaproteobacterium of the Alcaligenaceae family. Intensive nutritional exchanges have been reported between the two partners, indicating that these protozoa are excellent biological models to study metabolic co-evolution. We previously sequenced and herein investigate the entire genomes of five trypanosomatids which harbor a symbiotic bacterium (SHTs for Symbiont-Haboring Trypanosomatids) and the respective bacteria (TPEs for Trypanosomatid Proteobacterial Endosymbiont), as well as two trypanosomatids without symbionts (RTs for Regular Trypanosomatids), for the presence of genes of the classical pathways for vitamin biosynthesis. Our data show that genes for the biosynthetic pathways of thiamine, biotin, and nicotinic acid are absent from all trypanosomatid genomes. This is in agreement with the absolute growth requirement for these vitamins in all protozoa of the family. Also absent from the genomes of RTs are the genes for the synthesis of pantothenic acid, folic acid, riboflavin, and vitamin B_6. This is also in agreement with the available data showing that RTs are auxotrophic for these essential vitamins. On the other hand, SHTs are autotrophic for such vitamins. Indeed, all the genes of the corresponding biosynthetic pathways were identified, most of them in the symbiont genomes, while a few genes, mostly of eukaryotic origin, were found in the host genomes. The only exceptions to the latter are: the gene coding for the enzyme ketopantoate reductase (EC:1.1.1.169) which is related instead to the Firmicutes bacteria; and two other genes, one involved in the salvage pathway of pantothenic acid and the other in the synthesis of ubiquinone, that are related to Gammaproteobacteria. Their presence in trypanosomatids may result from lateral gene transfer. Taken together, our results reinforce the idea that the low nutritional requirement of SHTs is associated with the presence of the symbiotic bacterium, which contains most genes for vitamin production.     

The Impact of Healthcare-Associated Infection on Mortality: Failure in Clinical Recognition Is Related with Inadequate Antibiotic Therapy

Purpose

To understand if clinicians can tell apart patients with healthcare-associated infections (HCAI) from those with community-acquired infections (CAI) and to determine the impact of HCAI in the adequacy of initial antibiotic therapy and hospital mortality.

Methods

One-year prospective cohort study including all consecutive infected patients admitted to a large university tertiary care hospital.

Results

A total of 1035 patients were included in this study. There were 718 patients admitted from the community: 225 (31%) with HCAI and 493 (69%) with CAI. Total microbiologic documentation rate of infection was 68% (n = 703): 56% in CAI, 73% in HCAI and 83% in hospital-acquired infections (HAI). Antibiotic therapy was inadequate in 27% of patients with HCAI vs. 14% of patients with CAI (p<0.001). Among patients with HCAI, 47% received antibiotic therapy in accordance with international recommendations for treatment of CAI. Antibiotic therapy was inadequate in 36% of patients with HCAI whose treatment followed international recommendations for CAI vs. 19% in the group of HCAI patients whose treatment did not follow these guidelines (p = 0.014). Variables independently associated with inadequate antibiotic therapy were: decreased functional capacity (adjusted OR = 2.24), HCAI (adjusted OR = 2.09) and HAI (adjusted OR = 2.24). Variables independently associated with higher hospital mortality were: age (adjusted OR = 1.05, per year), severe sepsis (adjusted OR = 1.92), septic shock (adjusted OR = 8.13) and inadequate antibiotic therapy (adjusted OR = 1.99).

Conclusions

HCAI was associated with an increased rate of inadequate antibiotic therapy but not with a significant increase in hospital mortality. Clinicians need to be aware of healthcare-associated infections among the group of infected patients arriving from the community since the existing guidelines regarding antibiotic therapy do not apply to this group and they will otherwise receive inadequate antibiotic therapy which will have a negative impact on hospital outcome.     

The Synergistic Effect of Combined Immunization with a DNA Vaccine and Chimeric Yellow Fever/Dengue Virus Leads to Strong Protection against Dengue

The dengue envelope glycoprotein (E) is the major component of virion surface and its ectodomain is composed of domains I, II and III. This protein is the main target for the development of a dengue vaccine with induction of neutralizing antibodies. In the present work, we tested two different vaccination strategies, with combined immunizations in a prime/booster regimen or simultaneous inoculation with a DNA vaccine (pE1D2) and a chimeric yellow fever/dengue 2 virus (YF17D-D2). The pE1D2 DNA vaccine encodes the ectodomain of the envelope DENV2 protein fused to t-PA signal peptide, while the YF17D-D2 was constructed by replacing the prM and E genes from the 17D yellow fever vaccine virus by those from DENV2. Balb/c mice were inoculated with these two vaccines by different prime/booster or simultaneous immunization protocols and most of them induced a synergistic effect on the elicited immune response, mainly in neutralizing antibody production. Furthermore, combined immunization remarkably increased protection against a lethal dose of DENV2, when compared to each vaccine administered alone. Results also revealed that immunization with the DNA vaccine, regardless of the combination with the chimeric virus, induced a robust cell immune response, with production of IFN-γ by CD8+ T lymphocytes.     

Instrumental Rotation for Persistent Fetal Occiput Posterior Position: A Way to Decrease Maternal and Neonatal Injury?

Objective

To evaluate immediate perineal and neonatal morbidity associated with instrumental rotations performed with Thierry’s spatulas for the management of persistent posterior occiput (OP) positions.

Methods

Retrospective study including all persistent occiput posterior positions with vaginal OP delivery, from August 2006 to September 2007. Occiput anterior deliveries following successful instrumental rotation were included as well. We compared maternal and neonatal immediate outcomes between spontaneous deliveries, rotational and non rotational assisted deliveries, using χ² and Anova tests.

Results

157 patients were enrolled, comprising 46 OP spontaneous deliveries, 58 assisted OP deliveries and 53 deliveries after rotational procedure. Instrumental rotation failed in 9 cases. Mean age and parity were significantly higher in the spontaneous delivery group, while labor duration was shorter. There were no significant differences in the rate of severe perineal tears and neonatal adverse outcomes between the 3 groups.

Conclusion

Instrumental rotation using Thierry’s spatulas was not associated with a reduced risk of maternal and neonatal morbidity for persistent OP deliveries. Further studies are required to define the true interest of such procedure in modern obstetrics.     

Relative Amino Acid Composition Signatures of Organisms and Environments

Background

Identifying organism-environment interactions at the molecular level is crucial to understanding how organisms adapt to and change the chemical and molecular landscape of their habitats. In this work we investigated whether relative amino acid compositions could be used as a molecular signature of an environment and whether such a signature could also be observed at the level of the cellular amino acid composition of the microorganisms that inhabit that environment.

Methodologies/Principal Findings

To address these questions we collected and analyzed environmental amino acid determinations from the literature, and estimated from complete genomic sequences the global relative amino acid abundances of organisms that are cognate to the different types of environment. Environmental relative amino acid abundances clustered into broad groups (ocean waters, host-associated environments, grass land environments, sandy soils and sediments, and forest soils), indicating the presence of amino acid signatures specific for each environment. These signatures correlate to those found in organisms. Nevertheless, relative amino acid abundance of organisms was more influenced by GC content than habitat or phylogeny.

Conclusions

Our results suggest that relative amino acid composition can be used as a signature of an environment. In addition, we observed that the relative amino acid composition of organisms is not highly determined by environment, reinforcing previous studies that find GC content to be the major factor correlating to amino acid composition in living organisms.     

Carvedilol Decrease IL-1β and TNF-α, Inhibits MMP-2, MMP-9, COX-2, and RANKL Expression,and Up-Regulates OPG in a Rat Model of Periodontitis

Periodontal diseases are initiated primarily by Gram-negative, tooth-associated microbial biofilms that elicit a host response that causes osseous and soft tissue destruction. Carvedilol is a β-blocker used as a multifunctional neurohormonal antagonist that has been shown to act not only as an anti-oxidant but also as an anti-inflammatory drug. This study evaluated whether Carvedilol exerted a protective role against ligature-induced periodontitis in a rat model and defined how Carvedilol affected metalloproteinases and RANKL/RANK/OPG expression in the context of bone remodeling. Rats were randomly divided into 5 groups (n = 10/group): (1) non-ligated (NL), (2) ligature-only (LO), and (3) ligature plus Carvedilol (1, 5 or 10 mg/kg daily for 10 days). Periodontal tissue was analyzed for histopathlogy and using immunohistochemical analysis characterized the expression profiles of MMP-2, MMP-9, COX-2, and RANKL/RANK/OPG and determined the presence of IL-1β, IL-10 and TNF-α, myeloperoxidase (MPO), malonaldehyde (MDA) and, glutathione (GSH). MPO activity in the group with periodontal disease was significantly increased compared to the control group (p<0.05). Rats treated with 10 mg/kg Carvedilol presented with significantly reduced MPO and MDA concentrations (p<0.05) in addition to presenting with reduced levels of the pro-inflammatory cytokines IL-1 β and TNF-α (p<0.05). IL-10 levels in Carvedilol-treated rats remained unaltered. Immunohistochemical analysis demonstrated reduced expression of MMP-2, MMP-9, RANK, RANKL, COX-2, and OPG in rats treated with 10 mg/kg Carvedilol. This study demonstrated that Carvedilol affected bone formation/destruction and anti-inflammatory activity in a rat model of periodontitis.     

Overview of the Distribution,Habitat Association and Impact of Exotic Ants on Native Ant Communities in New Caledonia

Ants are among the most ubiquitous and harmful invaders worldwide, but there are few regional studies of their relationships with habitat and native ant communities. New Caledonia has a unique and diverse ant fauna that is threatened by exotic ants, but broad-scale patterns of exotic and native ant community composition in relation to habitat remain poorly documented. We conducted a systematic baiting survey of 56 sites representing the main New Caledonian habitat types: rainforest on ultramafic soils (15 sites), rainforest on volcano-sedimentary soils (13), maquis shrubland (15), Melaleuca-dominated savannas (11) and Acacia spirorbis thickets (2). We collected a total of 49 species, 13 of which were exotic. Only five sites were free of exotic species, and these were all rainforest. The five most abundant exotic species differed in their habitat association, with Pheidole megacephala associated with rainforests, Brachymyrmex cf. obscurior with savanna, and Wasmannia auropunctata and Nylanderia vaga present in most habitats. Anoplolepis gracilipes occurred primarily in maquis-shrubland, which contrasts with its rainforest affinity elsewhere. Multivariate analysis of overall ant species composition showed strong differentiation of sites according to the distribution of exotic species, and these patterns were maintained at the genus and functional group levels. Native ant composition differed at invaded versus uninvaded rainforest sites, in the absence of differences in habitat variables. Generalised Myrmicinae and Forest Opportunists were particularly affected by invasion. There was a strong negative relationship between the abundance of W. auropunctata and native ant abundance and richness. This emphasizes that, in addition to dominating many ant communities numerically, some exotic species, and in particular W. auropunctata, have a marked impact on native ant communities.     

Chemical preservation of tail feathers from Anchiornis huxleyi,a theropod dinosaur from the Tiaojishan Formation (Upper Jurassic,China)

A panel of geochemical techniques is used here to investigate the taphonomy of fossil feathers preserved in association with the skeleton of the Jurassic theropod Anchiornis huxleyi. Extant feathers were analysed in parallel to test whether the soft tissues morphologically preserved in the fossil also exhibit a high degree of chemical preservation. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) indicate that clays and iron oxide pseudomorphs occur in the surrounding sediment and also reveal the preservation of melanosome-like microbodies in the fossil. Carbon gradient along a depth profile and co-occurrence of carbon and sulphur are shown in the fossil by elastic backscattering (EBS) and particle-induced x-ray emission (PIXE), which are promising techniques for the elemental analysis of fossil soft tissues. The molecular composition of modern and fossil soft tissues was assessed from micro-attenuated total reflectance fourier transform infrared spectroscopy (micro-ATR FTIR), solid-state ¹³C nuclear magnetic resonance (CP-MAS ¹³C NMR) and pyrolysis gas chromatography mass spectrometry in the presence of TMAH (TMAH-Py-GC-MS). Results indicate that the proteinaceous material that comprises the modern feathers is not present in the fossil feathers. The fossil feathers and the embedding sediment exhibit a highly aliphatic character. However, substantial differences exist between these samples, revealing that the organic matter of the fossil feathers is, at least partially, derived from original constituents of the feathers. Our results suggest that, despite the morphological preservation of Anchiornis feathers, original proteins, that is keratin, were probably not preserved in the 160-myr-old feathers.     

Babassu palm (Attalea speciosa Mart.) super-dominance shapes its surroundings via multiple biotic,soil chemical,and physical interactions and accumulates soil carbon: a case study in eastern Amazonia

Plant and Soil - Aggressive ruderal plant species pose an increasing problem in anthropically degraded lands. They both affect and are affected by other vegetation and by soil fertility in their...