Dissecting the specificity of protein-protein interaction in bacterial two-component signaling: orphans and crosstalks

Predictive understanding of the myriads of signal transduction pathways in a cell is an outstanding challenge of systems biology. Such pathways are primarily mediated by specific but transient protein-protein interactions, which are difficult to study experimentally. In this study, we dissect the specificity of protein-protein interactions governing two-component signaling (TCS) systems ubiquitously used in bacteria. Exploiting the large number of sequenced bacterial genomes and an operon structure which packages many pairs of interacting TCS proteins together, we developed a computational approach to extract a molecular interaction code capturing the preferences of a small but critical number of directly interacting residue pairs. This code is found to reflect physical interaction mechanisms, with the strongest signal coming from charged amino acids. It is used to predict the specificity of TCS interaction: Our results compare favorably to most available experimental results, including the prediction of 7 (out of 8 known) interaction partners of orphan signaling proteins in Caulobacter crescentus. Surveying among the available bacterial genomes, our results suggest 15～25% of the TCS proteins could participate in out-of-operon "crosstalks". Additionally, we predict clusters of crosstalking candidates, expanding from the anecdotally known examples in model organisms. The tools and results presented here can be used to guide experimental studies towards a system-level understanding of two-component signaling.     

Full genome sequencing and genetic characterization of Eubenangee viruses identify Pata virus as a distinct species within the genus Orbivirus

Eubenangee virus has previously been identified as the cause of Tammar sudden death syndrome (TSDS). Eubenangee virus (EUBV), Tilligery virus (TILV), Pata virus (PATAV) and Ngoupe virus (NGOV) are currently all classified within the Eubenangee virus species of the genus Orbivirus, family Reoviridae. Full genome sequencing confirmed that EUBV and TILV (both of which are from Australia) show high levels of aa sequence identity (>92%) in the conserved polymerase VP1(Pol), sub-core VP3(T2) and outer core VP7(T13) proteins, and are therefore appropriately classified within the same virus species. However, they show much lower amino acid (aa) identity levels in their larger outer-capsid protein VP2 (<53%), consistent with membership of two different serotypes - EUBV-1 and EUBV-2 (respectively). In contrast PATAV showed significantly lower levels of aa sequence identity with either EUBV or TILV (with <71% in VP1(Pol) and VP3(T2), and <57% aa identity in VP7(T13)) consistent with membership of a distinct virus species. A proposal has therefore been sent to the Reoviridae Study Group of ICTV to recognise 'Pata virus' as a new Orbivirus species, with the PATAV isolate as serotype 1 (PATAV-1). Amongst the other orbiviruses, PATAV shows closest relationships to Epizootic Haemorrhagic Disease virus (EHDV), with 80.7%, 72.4% and 66.9% aa identity in VP3(T2), VP1(Pol), and VP7(T13) respectively. Although Ngoupe virus was not available for these studies, like PATAV it was isolated in Central Africa, and therefore seems likely to also belong to the new species, possibly as a distinct 'type'. The data presented will facilitate diagnostic assay design and the identification of additional isolates of these viruses.     

Lack of association between the rs2294008 polymorphism in the prostate stem cell antigen gene and colorectal neoplasia: a case-control and immunohistochemical study

ABSTRACT: BACKGROUND: Prostate stem cell antigen (PSCA) has been implicated in the pathogenesis of several solid tumours, either due to changes in protein expression, or through association with the rs2294008 polymorphism in the PSCA gene. To our knowledge, the role of PSCA in the development of colorectal neoplasia has not been explored. We performed a genotyping study to assess for associations between the rs2294008 polymorphism and risk of adenomatous polyps and colorectal cancer. DNA samples were available from 388 individuals with colorectal neoplasia and 496 controls, all of whom had undergone screening colonoscopy. In addition, we performed immunohistochemical staining for PSCA in colonic tissue representing all stages of the adenoma-carcinoma sequence. RESULTS: No genotypic associations were found between the rs2294008 polymorphism and the risk of colorectal adenomata or cancer. Immunohistochemical staining did not reveal any alteration in PSCA expression accompanying the adenoma-carcinoma sequence. CONCLUSION: From these data it seems unlikely that PSCA has a role in the initiation or progression of colorectal neoplasia.     

The relationship between impulsive choice and impulsive action: a cross-species translational study

Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.     

Fluid and particle passage in three duiker species

Ruminants are characterised by two different types of reticulorumen (RR) physiology. ‘Cattle-type’ ruminants have, amongst other features such as RR contents stratification and a heterogenous intraruminal papillation, a distinct difference between the mean retention time (MRT) of small particles and fluids (the ratio is called the selectivity factor, SF). ‘Moose-type’ ruminants have RR contents that are less stratified, a more homogenous intraruminal papillation and low SFs, indicating less difference in the MRT of small particles and fluids. To date, physiological data indicating a ‘moose-type’ physiology have only been measured in giraffids and Odocoilean cervids, raising the question whether it is limited to these taxonomic groups only. Here, we measured MRTs of fluids and particles in five duikers (Bovidae, Cephalophinae) from three species (Sylvicapra grimmia, Cephalophus monticola and Cephalophus sylvicultor) and found SFs in the RR of 1.27 ± 0.18—well within the range of these other browsers. These results are the first physiological indication that a ‘moose-type’ physiology may also occur in bovid species and thus might represent a true convergent adaptation.     

Effects of Organic Enrichment of Mine Spoil on Growth and Nutrient Uptake in Oak Seedlings Inoculated with Selected Ectomycorrhizal Fungi

Abstract Poor growth of Quercus robur L. (oak) trees has been reported on mine sites where overburden and subsoil have been used in the reinstatement of surface layers. This stunting has been attributed to a lack of macronutrients and to an adverse soil environment for root growth and mycorrhizal development. Growth, mineral nutrition, and ectomycorrhizal colonization of Q. robur seedlings were studied in an experiment carried out under controlled growing conditions in which mine spoil material was enriched with a leaf litter mulch. Enrichment of mine spoil material was found to produce a significant increase in growth and foliar N concentrations of oak seedlings. Inoculation with three taxa of ectomycorrhizal fungi did not benefit seedlings when mine spoil was the only substrate, possibly due to the poor physical properties of the unamended spoil and lack of nutrients. Inoculation with two taxa, Laccaria laccata and Hebeloma crustuliniforme, isolated from 3‐year‐old trees produced a significant stimulation of growth in the organically enriched treatment, which was believed to be due to greater uptake of mineralized N. However, Cortinarius anomalus isolated from fruit bodies associated with a 15‐year‐old tree did not increase biomass. The presence of organic matter was found to result in a significant stimulation of mycorrhizal infection by both inoculum and contaminant mycobionts. Recommendations are made for improving the establishment and growth of oak seedlings on reinstated sites.     

The effects of care bundles on patient outcomes: a systematic review and meta-analysis

Background

Care bundles are a set of three to five evidence-informed practices performed collectively and reliably to improve the quality of care. Care bundles are used widely across healthcare settings with the aim of preventing and managing different health conditions. This is the first systematic review designed to determine the effects of care bundles on patient outcomes and the behaviour of healthcare workers in relation to fidelity with care bundles.

Methods

This systematic review is reported in line with the PRISMA statement for reporting systematic reviews and meta-analyses. A total of 5796 abstracts were retrieved through a systematic search for articles published between January 1, 2001, to February 4, 2017, in the Cochrane Central Register for Controlled Trials, MEDLINE, EMBASE, British Nursing Index, CINAHL, PsychInfo, British Library, Conference Proceeding Citation Index, OpenGrey trials (including cluster-randomised trials) and non-randomised studies (comprising controlled before-after studies, interrupted time series, cohort studies) of care bundles for any health condition and any healthcare settings were considered. Following the removal of duplicated studies, two reviewers independently screen 3134 records. Three authors performed data extraction independently. We compared the care bundles with usual care to evaluate the effects of care bundles on the risk of negative patient outcomes. Random-effect models were used to further explore the effects of subgroups.

Results

In total, 37 studies (6 randomised trials, 31 controlled before-after studies) were eligible for inclusion. The effect of care bundles on patient outcomes is uncertain. For randomised trial data, the pooled relative risk of negative effects between care bundle and control groups was 0.97 [95% CI 0.71 to 1.34; 2049 participants]. The relative risk of negative patient outcomes from controlled before-after studies favoured the care bundle treated groups (0.66 [95% CI 0.59 to 0.75; 119,178 participants]). However, using GRADE, we assessed the certainty of all of the evidence to be very low (downgraded for risk of bias, inconsistency, indirectness).

Conclusions

Very low quality evidence from controlled before-after studies suggests that care bundles may reduce the risk of negative outcomes when compared with usual care. By contrast, the better quality evidence from six randomised trials is more uncertain.

Trial registration

PROSPERO, CRD42016033175