Synthesis and biological evaluation of new active For‐Met‐Leu‐Phe‐OMe analogues containing para‐substituted Phe residues

In the present study, we report synthesis and biological evaluation of the N‐Boc‐protected tripeptides 4a–l and N‐For protected tripeptides 5a–l as new For‐Met‐Leu‐Phe‐OMe (fMLF‐OMe) analogues. All the new ligands are characterized by the C‐terminal Phe residue variously substituted at position 4 of the aromatic ring. The agonism of 5a–l and the antagonism of 4a–l (chemotaxis, superoxide anion production, lysozyme release as well as receptor binding affinity) have been examined on human neutrophils. No synthesized compounds has higher activity than the standard fMLF‐OMe tripeptide to stimulate chemotaxis, although compounds 5a and 5c with ‐CH₃ and ‐C(CH₃)₃, respectively, in position 4 on the aromatic ring, are better than the standard tripeptide to stimulate the production of superoxide anion, in higher concentration. Compounds 4f and 4i , containing ‐F and ‐I in position 4, respectively, on the aromatic ring of phenylalanine, exhibit significant chemotactic antagonism. The influence of the different substitution at the position 4 on the aromatic ring of phenylalanine is discussed. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.     

Structure and polymorphism of the human gene for the interferon-induced p78 protein (MX1): evidence of association with alopecia areata in the Down syndrome region

Alopecia areata (AA) is a chronic inflammatory disease characterised by patchy hair loss with T cell infiltration of hair follicles. AA occurs in approximately 0.1% of the general population, but this is increased to 9% in Down syndrome (DS). DS is associated with an additional copy (full or partial) of chromosome 21, and the DS region may potentially include genes involved in the pathogenesis of AA. MX1 is the gene encoding the interferon-induced p78 protein (MxA). MxA protein confers resistance to influenza viruses, and we have previously shown that MxA protein is strongly expressed in lesional anagen hair bulbs from patients with AA but not in normal follicles. We therefore studied the possible involvement of MX1 in the pathogenesis of AA. To establish markers in the MX1 region which could be screened by PCR-based methods, we defined the human MX1 exon/intron organisation and screened the exons and the introns by conformation-sensitive gel electrophoresis. We found that the MX1 gene contains 17 exons extending over 33 kb. The size and sequence of the region from exon 6 to exon 16 are highly conserved between human and mouse. Screening of 4747 bp within the MX1 gene revealed four single nucleotide polymorphisms in intron 6. These polymorphisms are concentrated within 147 bp and show strong linkage disequilibrium. In a case-control association study for the MX1 (+9959) polymorphism in 165 AA patients and 510 controls we found a significant association of this marker with AA (odds ratio 1.79, 95% CI 1.21-2.66, chi2 = 8.464, P = 0.0036). The risk of disease was greater for patchy AA (mild disease) and with early age at onset (odds ratio 2.34, 95% CI 1.24-4.43, P = 0.0072), providing new evidence of genetic heterogeneity in AA. Our demonstration of genetic association between the MX1 gene and disease supports the hypothesis that this is a new candidate gene in AA.     

Design of a Virtual Player for Joint Improvisation with Humans in the Mirror Game

Joint improvisation is often observed among humans performing joint action tasks. Exploring the underlying cognitive and neural mechanisms behind the emergence of joint improvisation is an open research challenge. This paper investigates jointly improvised movements between two participants in the mirror game, a paradigmatic joint task example. First, experiments involving movement coordination of different dyads of human players are performed in order to build a human benchmark. No designation of leader and follower is given beforehand. We find that joint improvisation is characterized by the lack of a leader and high levels of movement synchronization. Then, a theoretical model is proposed to capture some features of their interaction, and a set of experiments is carried out to test and validate the model ability to reproduce the experimental observations. Furthermore, the model is used to drive a computer avatar able to successfully improvise joint motion with a human participant in real time. Finally, a convergence analysis of the proposed model is carried out to confirm its ability to reproduce joint movements between the participants.     

Long-Term Exposure to Primary Traffic Pollutants and Lung Function in Children: Cross-Sectional Study and Meta-Analysis

Background

There is widespread concern about the possible health effects of traffic-related air pollution. Nitrogen dioxide (NO₂) is a convenient marker of primary pollution. We investigated the associations between lung function and current residential exposure to a range of air pollutants (particularly NO₂, NO, NOx and particulate matter) in London children. Moreover, we placed the results for NO₂ in context with a meta-analysis of published estimates of the association.

Methods and Findings

Associations between primary traffic pollutants and lung function were investigated in 4884 children aged 9–10 years who participated in the Child Heart and Health Study in England (CHASE). A systematic literature search identified 13 studies eligible for inclusion in a meta-analysis. We combined results from the meta-analysis with the distribution of the values of FEV₁ in CHASE to estimate the prevalence of children with abnormal lung function (FEV₁<80% of predicted value) expected under different scenarios of NO₂ exposure. In CHASE, there were non-significant inverse associations between all pollutants except ozone and both FEV1 and FVC. In the meta-analysis, a 10 μg/m³ increase in NO₂ was associated with an 8 ml lower FEV₁ (95% CI: -14 to -1 ml; p: 0.016). The observed effect was not modified by a reported asthma diagnosis. On the basis of these results, a 10 μg/m³ increase in NO₂ level would translate into a 7% (95% CI: 4% to 12%) increase of the prevalence of children with abnormal lung function.

Conclusions

Exposure to traffic pollution may cause a small overall reduction in lung function and increase the prevalence of children with clinically relevant declines in lung function.     

A Link between Arabinose Utilization and Oxalotrophy in Bradyrhizobium japonicum

Rhizobia have a versatile catabolism that allows them to compete successfully with other microorganisms for nutrients in the soil and in the rhizosphere of their respective host plants. In this study, Bradyrhizobium japonicum USDA 110 was found to be able to utilize oxalate as the sole carbon source. A proteome analysis of cells grown in minimal medium containing arabinose suggested that oxalate oxidation extends the arabinose degradation branch via glycolaldehyde. A mutant of the key pathway genes oxc (for oxalyl-coenzyme A decarboxylase) and frc (for formyl-coenzyme A transferase) was constructed and shown to be (i) impaired in growth on arabinose and (ii) unable to grow on oxalate. Oxalate was detected in roots and, at elevated levels, in root nodules of four different B. japonicum host plants. Mixed-inoculation experiments with wild-type and oxc-frc mutant cells revealed that oxalotrophy might be a beneficial trait of B. japonicum at some stage during legume root nodule colonization.     

c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability

c-FLIP (cellular FLICE-like inhibitory protein) protein is mostly known as an apoptosis modulator. However, increasing data underline that c-FLIP plays multiple roles in cellular homoeostasis, influencing differently the same pathways depending on its expression level and isoform predominance. Few and controversial data are available regarding c-FLIP function in autophagy. Here we show that autophagic flux is less effective in c-FLIP−/− than in WT MEFs (mouse embryonic fibroblasts). Indeed, we show that the absence of c-FLIP compromises the expression levels of pivotal factors in the generation of autophagosomes. In line with the role of c-FLIP as a scaffold protein, we found that c-FLIP_L interacts with Beclin-1 (BECN1: coiled-coil, moesin-like BCL2-interacting protein), which is required for autophagosome nucleation. By a combination of bioinformatics tools and biochemistry assays, we demonstrate that c-FLIP_L interaction with Beclin-1 is important to prevent Beclin-1 ubiquitination and degradation through the proteasomal pathway. Taken together, our data describe a novel molecular mechanism through which c-FLIP_L positively regulates autophagy, by enhancing Beclin-1 protein stability.Subject terms: Biochemistry, Autophagy     

Trophic ecology and metabolism of two species of nonnative freshwater stingray (Chondrichthyes: Potamotrygonidae)

The stingrays Potamotrygon amandae and Potamotrygon falkneri are nonnative species established in the Upper Paraná basin. Although they are widely distributed, few studies on their diets or respective metabolic responses exist. Therefore, the aim was to evaluate the dietary composition, trophic niche breadth and lipid/protein concentrations in muscle and hepatic tissues of these two species, as well as the interrelationships between them. The individuals were collected in two areas on the Upper Paraná River. The stomachs and samples of muscle and liver tissues were taken for analysis. A broad dietary spectrum was observed for both species, along with differences in dietary composition, with a higher consumption of detritus by P. amandae and Baetidae by P. falkneri. No differences were observed in the trophic niche breadth. Regarding the metabolic variables, differences were only found in the hepatic protein, with a higher content observed in P. falkneri. A significant positive correlation was observed between items of animal origin and detritus with muscle protein for this species. This shows that such feeding habits, which are characteristic of a generalist, influenced the metabolism of the species and possibly contributed to the successful adjustment of the species to new habitats in the Upper Paraná River.