Low-dose inhalation of an endothelin-A receptor antagonist in experimental acute lung injury: ET-1 plasma concentration and pulmonary inflammation

Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET(A) receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO2) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO2, 319 +/- 44 mm Hg vs. 57 +/- 3 mm Hg; MPAP, 32 +/- 2 mm Hg vs. 41 +/- 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 +/- 0.06 fmol/ml after induction of ALI to a maximum of 1.17 +/- 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 +/- 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET(A) receptor antagonist.     

Endothelin-1 influences the efficacy of inhaled nitric oxide in experimental acute lung injury

Beneficial effects of inhaled nitric oxide (iNO) on arterial oxygenation in acute lung injury (ALI) suggest the presence of vasoconstriction in ventilated lung regions and this may be influenced by endothelin-1 (ET-1). We studied a possible interaction between ET-1 and iNO in experimental ALI. Sixteen piglets were anesthetized and mechanically ventilated (inspired O2 fraction, 1.0). After induction of ALI by surfactant depletion, animals were randomly assigned to either inhale 30 ppm NO (iNO group, n = 8), or to receive no further intervention (controls, n = 8). Measurements were performed during the following 4 hrs. In all animals, induction of ALI significantly decreased arterial oxygen tension (PaO2) from 569 +/- 15 (prelavage) to 58 +/- 3 mm Hg. Inhaled NO significantly increased PaO2 when compared with controls (iNO group: 265 +/- 51 mm Hg; controls: 50 +/- 4 mm Hg, values at 4 hrs, P < 0.01). Prelavage ET-1 plasma levels were comparable between groups (iNO: 0.74 +/- 0.03, controls: 0.71 +/- 0.03 fmol/ml, NS). During the protocol, the ET-1 levels increased and were different at 3 hrs (iNO: 0.93 +/- 0.06, controls: 1.25 +/- 0.09 fmol/ml; P < 0.05). PaO2 changes induced by iNO revealed a moderate and significant correlation with ET-1 plasma levels (R = 0.548, P = 0.001). Our data suggest that endogenous ET-1 production influences the efficacy of iNO in ALI. Furthermore, iNO reduced ET-1 plasma levels, possibly indicating anti-inflammatory properties of iNO in the early phase of ALI.     

A temporal comparison of a benthic infaunal community southwest of St. Lawrence Island, Bering Sea between 2006 and 1970–1974

Benthic infaunal biomass and abundance may be changing in Bering Sea communities. This study compared benthic infaunal biomass, abundance, and community composition southwest of St. Lawrence Island in an important forage area for benthic-feeding birds and mammals between 1970–1974 and 2006. Invertebrate biomass and abundance were significantly greater in 2006 than in 1970–1974 primarily due to high nuculid (Bivalvia) biomass and abundance that contributed 13.2% (biomass) and 8.5% (abundance) to differences in community structure between the sampling periods. This is in contrast to St. Lawrence Island Polynya studies conducted in the 1980s and 1990s that documented decreases in benthic biomass and abundance. Spatial scale of sampling, selective predation, a strong recruitment event, and/or sampling design may account for the difference in trends among the studies.     

Ecosystem restoration with teeth: what role for predators?

Recent advances highlight the potential for predators to restore ecosystems and confer resilience against globally threatening processes, including climate change and biological invasions. However, releasing the ecological benefits of predators entails significant challenges. Here, we discuss the economic, environmental and social considerations affecting predator-driven ecological restoration programmes, and suggest approaches for reducing the undesirable impacts of predators. Because the roles of predators are context dependent, we argue for increased emphasis on predator functionality in ecosystems and less on the identities and origins of species and genotypes. We emphasise that insufficient attention is currently given to the importance of variation in the social structures and behaviours of predators in influencing the dynamics of trophic interactions. Lastly, we outline experiments specifically designed to clarify the ecological roles of predators and their potential utility in ecosystem restoration.     

Engineering mammalian mucin-type O-glycosylation in plants

Mucin-type O-glycosylation is an important post-translational modification that confers a variety of biological properties and functions to proteins. This post-translational modification has a particularly complex and differentially regulated biosynthesis rendering prediction and control of where O-glycans are attached to proteins, and which structures are formed, difficult. Because plants are devoid of GalNAc-type O-glycosylation, we have assessed requirements for establishing human GalNAc O-glycosylation de novo in plants with the aim of developing cell systems with custom-designed O-glycosylation capacity. Transient expression of a Pseudomonas aeruginosa Glc(NAc) C4-epimerase and a human polypeptide GalNAc-transferase in leaves of Nicotiana benthamiana resulted in GalNAc O-glycosylation of co-expressed human O-glycoprotein substrates. A chimeric YFP construct containing a 3.5 tandem repeat sequence of MUC1 was glycosylated with up to three and five GalNAc residues when co-expressed with GalNAc-T2 and a combination of GalNAc-T2 and GalNAc-T4, respectively, as determined by mass spectrometry. O-Glycosylation was furthermore demonstrated on a tandem repeat of MUC16 and interferon α2b. In plants, prolines in certain classes of proteins are hydroxylated and further substituted with plant-specific O-glycosylation; unsubstituted hydroxyprolines were identified in our MUC1 construct. In summary, this study demonstrates that mammalian type O-glycosylation can be established in plants and that plants may serve as a host cell for production of recombinant O-glycoproteins with custom-designed O-glycosylation. The observed hydroxyproline modifications, however, call for additional future engineering efforts.     

Grassland plant species diversity decreases invasion by increasing resource use

Species richness of plant communities has been demonstrated to provide resistance to invasion by unsown species, though the relationship with resource availability varies between studies. The present work involved five grassland species grown in monocultures and in four-species mixtures sown in accordance with a simplex design. The species used represented different functional groups (i.e. grasses, legumes and non-N(2)-fixing species), each of which differed internally in terms of competitiveness. I hypothesized that sown diversity would negatively affect invader performance by decreasing the availability of light and soil nitrogen (N) for invading species, and that functional composition of the sown diversity would affect the functional composition of the invading flora. The experimental plots were harvested for two years, and were fertilized with 100 kg N ha(-1) each year. The number of unsown species (classified into four functional groups) invading each plot and their proportion of the biomass harvested were recorded. The penetration of incoming light through the canopy, the apparent N uptake by the sown species from the soil, and the mineral N content in the soil were measured. I found that diverse communities captured more resources both above- and belowground, and the number of invading species and their biomass production were smaller in mixed than in monoculture plots. However, the sampling effect of one grass was also strong. These results suggest that increased resource use in diverse communities can reduce invasion.     

A systematic critical review on MRI in spondyloarthritis

Introduction

Magnetic resonance imaging (MRI) has been proven capable of showing inflammatory and structural changes in patients with spondyloarthritis (SpA) and has become widely used in the diagnosis of SpA. Despite this, no systematic reviews evaluate the diagnostic utility of MRI for SpA. Therefore, the objective of this systematic review was to determine the evidence for the utility of MRI in the clinical diagnosis of SpA. The aims were to identify which MRI findings are associated with the diagnosis of SpA and to quantify this association.

Methods

MEDLINE and EMBASE were electronically searched. Inclusion criteria were cross-sectional or longitudinal case-control or cohort MRI studies. The studies required a group with either SpA or inflammatory back pain (IBP) and a non-case group without SpA or IBP. Each group required a minimum of 20 participants. The included articles had to report results containing raw numbers suitable for the construction of two-by-two tables or report results by sensitivity and specificity for cross-sectional studies or odds ratios, relative risk ratios, or likelihood ratios for longitudinal studies. Method quality was assessed by using criteria based on the QUADAS tool.

Results

In total, 2,395 articles were identified in MEDLINE and EMBASE before November 2011. All articles were reviewed by title and abstract. Seventy-seven articles were reviewed by full text, and 10 met the inclusion criteria. Two were considered of high quality: one evaluated the sacroiliac joints, and the other, the spine. Because of the small number of high-quality studies, a meta-analysis was not performed. The two high-quality studies found a positive association between MRI findings (bone marrow edema, erosions, fat infiltrations, global assessment of sacroiliitis, and ankylosis) and the diagnosis of IBP and SpA.

Conclusion

In this review, several MRI findings were found to be associated with SpA. However, because of the small number of high-quality studies, the evidence for the utility of MRI in the diagnosis of SpA must be considered limited. Therefore, caution should be taken to ensure that inflammatory and structural MRI findings are not interpreted as being more specific for SpA than is supported by research.     

Novel fusion of MYST/Esa1-associated factor 6 and PHF1 in endometrial stromal sarcoma

Rearrangement of chromosome band 6p21 is recurrent in endometrial stromal sarcoma (ESS) and targets the PHF1 gene. So far, PHF1 was found to be the 3' partner in the JAZF1-PHF1 and EPC1-PHF1 chimeras but since the 6p21 rearrangements involve also other chromosomal translocation partners, other PHF1-fusions seem likely. Here, we show that PHF1 is recombined with a novel fusion partner, MEAF6 from 1p34, in an ESS carrying a t(1;6)(p34;p21) translocation as the sole karyotypic anomaly. 5'-RACE, RT-PCR, and sequencing showed the presence of an MEAF6-PHF1 chimera in the tumor with exon 5 of MEAF6 being fused in-frame to exon 2 of PHF1 so that the entire PHF1 coding region becomes the 3' terminal part of the MEAF6-PHF1 fusion. The predicted fusion protein is composed of 750 amino acids and contains the histone acetyltransferase subunit NuA4 domain of MEAF6 and the tudor, PHD zinc finger, and MTF2 domains of PHF1. Although the specific functions of the MEAF6 and PHF1 proteins and why they are targeted by a neoplasia-specific gene fusion are not directly apparent, it seems that rearrangement of genes involved in acetylation (EPC1, MEAF6) and methylation (PHF1), resulting in aberrant gene expression, is a common theme in ESS pathogenesis.     

"Ménage à trois": the presence/absence of thyme shapes the mutualistic interaction between the host plant Medicago truncatula (Fabaceae) and its symbiotic bacterium Sinorhizobium meliloti

The long-term maintenance of specialized mutualisms remains an evolutionary puzzle. Recent focus has been on factors governing the stability of these mutualisms, including sanctions by the host, partner choice, and coevolutionary constraint, that is, the genetic correlation (r(G)) between fitness of both partners. So far these studies have been typically carried out in a single environment. Here, we ask if the genetic correlation between fitness of the host plant Medicago truncatula (Fabaceae) and its bacterial symbiont Sinorhizobium meliloti is affected by the presence/absence of a monoterpene (carvacrol) leached into the soil by Thymus vulgaris-a common plant of the Mediterranean vegetation, often co-occuring with Medicago. We show that the presence of carvacrol in the soil dramatically affects fitness of the rhizobial partner and increases the magnitude of r(G) between plant and rhizobia fitness (r(G) = 0.02 ± 0.05 vs. r(G) = 0.57 ± 0.02). This finding emphasizes the importance of heterogeneity in the biotic environment for understanding the evolution of species interactions.     

Tracing of norovirus outbreak strains in mussels collected near sewage effluents

Noroviruses from mussels collected near sewage effluents were compared with local patient outbreak strains. Sequence analyses of RNA polymerase-capsid-poly(A)-3' (3.1-kilobase) regions confirmed the 99.9% similarity between genotype I.1 strains from mussels and patient strains from recreational-bathing outbreaks, indicating the potential usefulness of sentinel norovirus mussel studies in tracing human norovirus contamination of coastal waters.