Ribavirin enhances IFN-α signalling and MxA expression: a novel immune modulation mechanism during treatment of HCV

The nucleoside analogue Ribavirin significantly increases patient response to IFN-α treatment of HCV, by directly inhibiting viral replication. Recent studies indicate that Ribavirin also regulates immunity and we propose that Ribavirin enhances specific interferon sensitive gene (ISG) expression by amplifying the IFN-α-JAK/STAT pathway. We found that IFN-α-induced STAT1 and STAT3 phosphorylation was increased in hepatocytes co-treated with Ribavirin and IFN-α, compared to IFN-α alone. Ribavirin specifically enhanced IFN-α induced mRNA and protein of the anti-viral mediator MxA, which co-localised with HCV core protein. These novel findings indicate for the first time that Ribavirin, in addition to its viral incorporation, also enhances IFN-α-JAK/STAT signalling, leading to a novel MxA-mediated immuno-modulatory mechanism that may enhance IFN-α anti-viral activity against HCV.     

Assessing lower-body peak power in elite rugby-union players

Resistance training at the load that maximizes peak power (Pmax) may produce greater increases in peak power than other loads. Pmax for lower-body lifts can occur with no loading but whether Pmax can be increased further with negative loading is unclear. The purpose of this investigation was therefore to determine lower-body Pmax (jump squat) using a spectrum of loads. Box squat 1 repetition maximum (1RM) was measured in 18 elite rugby-union players. Pmax was then determined using loads of -28 to 60%1RM. Elastic bands were used to unload body weight for negative loads. Jump squat Pmax occurred with no loading (body weight: 8,880 ± 2,186 W) in all but 2 subjects. There was a discontinuity in the power-load relationship for the jump squat, possibly because of the increased countermovement in the body weight jump. The self-selected depth (dip) before the propulsive phase of the jump was greater by 24 ± 11 to 40 ± 16% (moderate to large effect size) than all positive loads. These findings highlight methodological issues that need to be taken into consideration when comparing power outputs of loaded and unloaded jumps.     

Phylogenetic generalised dissimilarity modelling: a new approach to analysing and predicting spatial turnover in the phylogenetic composition of communities

Compared to species turnover, patterns of phylogenetic turnover provide extra information about the spatial structure of biodiversity, for example providing more informative comparisons between the biota of sites which share no species. To harness this information for broad‐scale spatial analysis, we present phylo‐GDM, a technique for interpolating the spatial structure of phylogenetic turnover between sampled locations in relation to environment, based on generalised dissimilarity modelling (GDM). Using a database of over 150 000 location records for 114 myobatrachid frog species in Australia, linked to a species‐level phylogeny inferred from 2467 base pairs of mitochondrial DNA, we calculated species and phylogenetic turnover between pairs of sites. We show how phylogenetic turnover extended the range of informative comparison of compositional turnover to more biologically and environmentally dissimilar sites. We generated GDM models which predict species and phylogenetic turnover across Australia, and tested the fit of models for different ages within the phylogeny to find the phylogenetic tree depth at which the relationship to current day environment is greatest. We also incorporated explanatory variables based on biogeographic patterns, to represent broad‐scale turnover resulting from divergent evolutionary histories. We found that while the predictive power of our models was lower for full phylogenetic turnover than for species turnover, models based on the more recent components of the phylogeny (closer to the tips) outperformed species models and full phylogenetic models. Phylo‐GDM has considerable potential as a method for incorporating phylogenetic relationships into biodiversity analyses in ways not previously possible. Because phylogenies do not require named taxa, phylo‐GDM may also provide a means of including lineages with poorly resolved taxonomy (e.g. from metagenomic sequencing) into biodiversity planning and phylogeographic analysis.     

Evaluating fossil calibrations for dating phylogenies in light of rates of molecular evolution: a comparison of three approaches

Evolutionary and biogeographic studies increasingly rely on calibrated molecular clocks to date key events. Although there has been significant recent progress in development of the techniques used for molecular dating, many issues remain. In particular, controversies abound over the appropriate use and placement of fossils for calibrating molecular clocks. Several methods have been proposed for evaluating candidate fossils; however, few studies have compared the results obtained by different approaches. Moreover, no previous study has incorporated the effects of nucleotide saturation from different data types in the evaluation of candidate fossils. In order to address these issues, we compared three approaches for evaluating fossil calibrations: the single-fossil cross-validation method of Near, Meylan, and Shaffer (2005. Assessing concordance of fossil calibration points in molecular clock studies: an example using turtles. Am. Nat. 165:137-146), the empirical fossil coverage method of Marshall (2008. A simple method for bracketing absolute divergence times on molecular phylogenies using multiple fossil calibration points. Am. Nat. 171:726-742), and the Bayesian multicalibration method of Sanders and Lee (2007. Evaluating molecular clock calibrations using Bayesian analyses with soft and hard bounds. Biol. Lett. 3:275-279) and explicitly incorporate the effects of data type (nuclear vs. mitochondrial DNA) for identifying the most reliable or congruent fossil calibrations. We used advanced (Caenophidian) snakes as a case study; however, our results are applicable to any taxonomic group with multiple candidate fossils, provided appropriate taxon sampling and sufficient molecular sequence data are available. We found that data type strongly influenced which fossil calibrations were identified as outliers, regardless of which method was used. Despite the use of complex partitioned models of sequence evolution and multiple calibrations throughout the tree, saturation severely compressed basal branch lengths obtained from mitochondrial DNA compared with nuclear DNA. The effects of mitochondrial saturation were not ameliorated by analyzing a combined nuclear and mitochondrial data set. Although removing the third codon positions from the mitochondrial coding regions did not ameliorate saturation effects in the single-fossil cross-validations, it did in the Bayesian multicalibration analyses. Saturation significantly influenced the fossils that were selected as most reliable for all three methods evaluated. Our findings highlight the need to critically evaluate the fossils selected by data with different rates of nucleotide substitution and how data with different evolutionary rates affect the results of each method for evaluating fossils. Our empirical evaluation demonstrates that the advantages of using multiple independent fossil calibrations significantly outweigh any disadvantages.     

Live cell image analysis of cell-cell interactions reveals the specific targeting of vascular smooth muscle cells by fetal trophoblasts

In early pregnancy, fetal trophoblasts selectively invade and remodel maternal spiral arteries. A healthy pregnancy is dependent on this adaptation to allow sufficient maternal blood to reach the placenta and the developing fetus. However, little is known of the role played by trophoblasts in this adaptation process. In this study, the interactions between trophoblast cells (TC) and vascular smooth muscle cells (VSMC) were examined using novel live cell image analysis methods which allow quantitative assessment of the behaviour of these two cell types in co-culture. TC and VSMC were simultaneously tracked in co-culture and, for each cell type, directionality, speed and the cell-cell interaction were assessed. The overall migratory behaviour of TC was markedly different in the presence of VSMC with co-cultured TC migrating further with directional movement while mono-cultured TC moved more randomly. Furthermore, TC were shown to specifically target VSMC, suggesting that invading TC may initiate targeted vascular remodelling. Analysis of movement behaviour and cell-cell attraction will be useful in other co-culture systems in addition to answering important questions in the reproductive field.     

The contribution of volume, technique, and load to single-repetition and total-repetition kinematics and kinetics in response to three loading schemes

This study examined the effect of volume, technique, and load upon single-repetition and total-repetition kinematics and kinetics during three loading schemes. Eleven recreationally trained males each performed a power (8 sets of 6 repetitions at 45% of one-repetition maximum [1RM], 3-minute rest periods, explosive and ballistic movements), hypertrophy (10 sets of 10 repetitions at 75% 1RM, 2-minute rest periods, controlled movements), and maximal strength (6 sets of 4 repetitions at 88% 1RM, 4-minute rest periods, explosive intent) scheme involving squats. Examination of repetition data showed that load intensity (% 1RM) generally had a direct effect on forces, contraction times, impulses, and work (i.e., increasing with load), whereas power varied across loads (p < 0.001). However, total-repetition forces, contraction times, impulses, work, and power were all greater in the hypertrophy scheme (p < 0.001), because of the greater number of repetitions performed (volume) as well as lifting technique. No differences in total forces were found between the equal-volume power and maximal strength schemes, but the former did produce greater total contraction times, work, and power (p < 0.001), which may also be attributed to repetition and technique differences. Total impulses were the only variable greater in the maximal strength scheme (p < 0.001). Thus, the interaction of load, volume, and technique plays an important role in determining the mechanical responses (stimuli) afforded by these workouts. These findings may explain disparities cited within research, regarding the effectiveness of different loading strategies for hypertrophy, maximal strength, and power adaptation.     

Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology

Signaling through Toll-like receptors (TLR) activates dendritic cell (DC) maturation and IL-12 production, which directs the induction of Th1 cells. We found that the production of IL-10, in addition to inflammatory cytokines and chemokines, was significantly reduced in DCs from TLR4-defective C3H/HeJ mice in response to Bordetella pertussis. TLR4 was also required for B. pertussis LPS-induced maturation of DCs, but other B. pertussis components stimulated DC maturation independently of TLR4. The course of B. pertussis infection was more severe in C3H/HeJ than in C3H/HeN mice. Surprisingly, Ab- and Ag-specific IFN-gamma responses were enhanced at the peak of infection, whereas Ag-specific IL-10-producing T cells were significantly reduced in C3H/HeJ mice. This was associated with enhanced inflammatory cytokine production, cellular infiltration, and severe pathological changes in the lungs of TLR4-defective mice. Our findings suggest that TLR-4 signaling activates innate IL-10 production in response to B. pertussis, which both directly, and by promoting the induction of IL-10-secreting type 1 regulatory T cells, may inhibit Th1 responses and limit inflammatory pathology in the lungs during infection with B. pertussis.     

Monitoring and Mining Animal Sounds in Visual Space

Monitoring animals by the sounds they produce is an important and challenging task, whether the application is outdoors in a natural habitat, or in the controlled environment of a laboratory setting. In the former case, the density and diversity of animal sounds can act as a measure of biodiversity. In the latter case, researchers often create control and treatment groups of animals, expose them to different interventions, and test for different outcomes. One possible manifestation of different outcomes may be changes in the bioacoustics of the animals. With such a plethora of important applications, there have been significant efforts to build bioacoustic classification tools. However, we argue that most current tools are severely limited. They often require the careful tuning of many parameters (and thus huge amounts of training data), are either too computationally expensive for deployment in resource-limited sensors, specialized for a very small group of species, or are simply not accurate enough to be useful. In this work we introduce a novel bioacoustic recognition/classification framework that mitigates or solves all of the above problems. We propose to classify animal sounds in the visual space, by treating the texture of their sonograms as an acoustic fingerprint using a recently introduced parameter-free texture measure as a distance measure. We further show that by searching for the most representative acoustic fingerprint, we can significantly outperform other techniques in terms of speed and accuracy.     

The complement component C1s catalysed hydrolysis of peptide 4-nitroanilide substrates

The kinetic parameter kcat/Km has been determined for the hydrolysis of peptide 4-nitroanilides, catalysed by complement component C1s. Substrates based on the C-terminal sequence of human C4a (Leu-Gln-Arg) were synthesised. Replacement of the glutamine residue by glycine or serine increased kcat/Km. Substitution of valine for the leucine residue increased kcat/Km, while substitution of glycine or lysine for the leucine residue decreased kcat/Km slightly. D-Val-Ser-Arg 4-nitroanilide is the most reactive 4-nitroanilide substrate towards C1s, so far. These results are discussed in relation to the amino acid sequences near the bonds cleaved by C1s in C4, C2 and C1 inhibitor.