Robust Conditional Independence maps of single-voxel Magnetic Resonance Spectra to elucidate associations between brain tumours and metabolites.

The aim of the paper is two-fold. First, we show that structure finding with the PC algorithm can be inherently unstable and requires further operational constraints in order to consistently obtain models that are faithful to the data. We propose a methodology to stabilise the structure finding process, minimising both false positive and false negative error rates. This is demonstrated with synthetic data. Second, to apply the proposed structure finding methodology to a data set comprising single-voxel Magnetic Resonance Spectra of normal brain and three classes of brain tumours, to elucidate the associations between brain tumour types and a range of observed metabolites that are known to be relevant for their characterisation. The data set is bootstrapped in order to maximise the robustness of feature selection for nominated target variables. Specifically, Conditional Independence maps (CI-maps) built from the data and their derived Bayesian networks have been used. A Directed Acyclic Graph (DAG) is built from CI-maps, being a major challenge the minimization of errors in the graph structure. This work presents empirical evidence on how to reduce false positive errors via the False Discovery Rate, and how to identify appropriate parameter settings to improve the False Negative Reduction. In addition, several node ordering policies are investigated that transform the graph into a DAG. The obtained results show that ordering nodes by strength of mutual information can recover a representative DAG in a reasonable time, although a more accurate graph can be recovered using a random order of samples at the expense of increasing the computation time

Obligatory role for PKCδ in PIP2 -mediated activation of store-operated TRPC1 channels in vascular smooth muscle cells.

KEY POINTS: In vascular smooth muscle cells (VSMCs), activation of Ca2+ -permeable store-operated channels (SOCs) composed of canonical transient receptor potential channel 1 (TRPC1) subunits mediate Ca2+ entry pathways which regulate contraction, proliferation and migration that are processes associated with vascular disease. Activation of TRPC1-based SOCs requires protein kinase C (PKC) activity, which is proposed to phosphorylate TRPC1 proteins to promote channel opening by phosphatidylinositol 4,5-bisphosphate (PIP2 ). We investigated the identity of the PKC isoform involved in activating TRPC1-based SOCs in rat mesenteric artery VSMCs. TRPC1-based SOCs were reduced by PKCδ inhibitors and knockdown of PKCδ expression. Store depletion induced interactions between TRPC1 and PKCδ and PKCδ-dependent phosphorylation of TRPC1. Furthermore, generation of store-operated interactions between PIP2 and TRPC1 and activation of TRPC1-based SOCs by PIP2 required PKCδ. These findings reveal that PKCδ activity has an obligatory role in activating TRPC1-based SOCs, through regulating PIP2 -mediated channel opening. ABSTRACT: In vascular smooth muscle cells (VMSCs), stimulation of Ca2+ -permeable canonical transient receptor potential channel 1 (TRPC1)-based store-operated channels (SOCs) mediate Ca2+ entry pathways which regulate cell contraction, proliferation and migration that are processes associated with vascular disease. It is therefore important to understand how TRPC1-based SOCs are activated. Stimulation of TRPC1-based SOCs requires protein kinase C (PKC) activity, with store-operated PKC-dependent phosphorylation of TRPC1 essential for channel opening by phosphatidylinositol 4,5-bisphosphate (PIP2 ). Experimental protocols used to activate TRPC1-based SOCs suggest that the PKC isoform involved requires diacylglycerol (DAG) but is Ca2+ -insensitive, which are characteristics of the novel group of PKC isoforms (δ, ε, η, θ). Hence the present study examines if a novel PKC isoform(s) is involved in activating TRPC1-based SOCs in contractile rat mesenteric artery VSMCs. Store-operated whole-cell cation currents were blocked by Pico145, a highly selective and potent TRPC1/4/5 channel blocker and T1E3, a TRPC1 blocking antibody. PKCδ was expressed in VSMCs, and selective PKCδ inhibitory peptides and knockdown of PKCδ expression with morpholinos oligomers inhibited TRPC1-based SOCs. TRPC1 and PKCδ interactions and phosphorylation of TRPC1 induced by store depletion were both reduced by pharmacological inhibition and PKCδ knockdown. In addition, store-operated PIP2 and TRPC1 interactions were blocked by PKCδ inhibition, and PKCδ was required for PIP2 -mediated activation of TRPC1 currents. These results identify involvement of PKCδ in stimulation of TRPC1-based SOCs and highlights that store-operated PKCδ activity is obligatory for channel opening by PIP2 , the likely activating ligand. This article is protected by copyright. All rights reserved

Why should we care about quantum discord?

Entanglement is a central feature of quantum theory. Mathematical properties and physical applications of pure state entanglement make it a template to study quantum correlations. However, an extension of entanglement measures to mixed states in terms of separability does not always correspond to all the operational aspects. Quantum discord measures allow an alternative way to extend the idea of quantum correlations to mixed states. In many cases these extensions are motivated by physical scenarios and quantum information protocols. In this chapter we discuss several settings involving correlated quantum systems, ranging from distributed gates to detectors testing quantum fields. In each setting we show how entanglement fails to capture the relevant features of the correlated system, and discuss the role of discord as a possible alternative.Comment: Written for "Lectures on general quantum correlations and their applications

Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis

The preterm gut microbiome is a complex dynamic community influenced by genetic and environmental factors and is implicated in the pathogenesis of necrotising enterocolitis (NEC) and sepsis. We aimed to explore the longitudinal development of the gut microbiome in preterm twins to determine how shared environmental and genetic factors may influence temporal changes and compared this to the expressed breast milk (EBM) microbiome. Stool samples (n = 173) from 27 infants (12 twin pairs and 1 triplet set) and EBM (n = 18) from 4 mothers were collected longitudinally. All samples underwent PCR-DGGE (denaturing gradient gel electrophoresis) analysis and a selected subset underwent 454 pyrosequencing. Stool and EBM shared a core microbiome dominated by Enterobacteriaceae, Enterococcaceae, and Staphylococcaceae. The gut microbiome showed greater similarity between siblings compared to unrelated individuals. Pyrosequencing revealed a reduction in diversity and increasing dominance of Escherichia sp. preceding NEC that was not observed in the healthy twin. Antibiotic treatment had a substantial effect on the gut microbiome, reducing Escherichia sp. and increasing other Enterobacteriaceae. This study demonstrates related preterm twins share similar gut microbiome development, even within the complex environment of neonatal intensive care. This is likely a result of shared genetic and immunomodulatory factors as well as exposure to the same maternal microbiome during birth, skin contact and exposure to EBM. Environmental factors including antibiotic exposure and feeding are additional significant determinants of community structure, regardless of host genetics

Proto-oncogene HER-2 in normal, dysplastic and tumorous feline mammary glands: an immunohistochemical and chromogenic in situ hybridization study

<p>Abstract</p> <p>Background</p> <p>Feline mammary carcinoma has been proposed as a natural model of highly aggressive, hormone-independent human breast cancer. To further explore the utility of the model by adding new similarities between the two diseases, we have analyzed the oncogene HER-2 status at both the protein and the gene levels.</p> <p>Methods</p> <p>Formalin-fixed, paraffin-embedded tissue samples from 30 invasive carcinomas, 7 benign lesions and two normal mammary glands were analyzed. Tumour features with prognostic value were recorded. The expression of protein HER-2 was analyzed by immunohistochemistry and the number of gene copies by means of DNA chromogenic <it>in situ </it>hybridization.</p> <p>Results</p> <p>Immunohistochemical HER-2 protein overexpression was found in 40% of feline mammary carcinomas, a percentage higher to that observed in human breast carcinoma. As in women, feline tumours with HER-2 protein overexpression had pathological features of high malignancy. However, amplification of HER-2 was detected in 16% of carcinomas with protein overexpression, a percentage much lower than that observed in their human counterpart.</p> <p>Conclusion</p> <p>Feline mammary carcinoma would be a suitable natural model of that subset of human breast carcinomas with HER-2 protein overexpression without gene amplification.</p

Genetic Analysis of the Individual Contribution to Virulence of the Type III Effector Inventory of Pseudomonas syringae pv. phaseolicola

Several reports have recently contributed to determine the effector inventory of the sequenced strain Pseudomonas syringae pv. phaseolicola (Pph) 1448a. However, the contribution to virulence of most of these effectors remains to be established. Genetic analysis of the contribution to virulence of individual P. syringae effectors has been traditionally hindered by the lack of phenotypes of the corresponding knockout mutants, largely attributed to a high degree of functional redundancy within their effector inventories. In support of this notion, effectors from Pseudomonas syringae pv. tomato (Pto) DC3000 have been classified into redundant effector groups (REGs), analysing virulence of polymutants in the model plant Nicotiana benthamiana. However, using competitive index (CI) as a virulence assay, we were able to establish the individual contribution of AvrPto1PtoDC3000 to Pto DC3000 virulence in tomato, its natural host, even though typically, contribution to virulence of AvrPto1 is only shown in strains also lacking AvrPtoB (also called HopAB2), a member of its REG. This report raised the possibility that even effectors targeting the same defence signalling pathway may have an individual contribution to virulence, and pointed out to CI assays as the means to establish such a contribution for individual effectors. In this work, we have analysed the individual contribution to virulence of the majority of previously uncharacterised Pph 1448a effectors, by monitoring the development of disease symptoms and determining the CI of single knockout mutants at different stages of growth within bean, its natural host. Despite their potential functional redundancy, we have found individual contributions to virulence for six out of the fifteen effectors analysed. In addition, we have analysed the functional relationships between effectors displaying individual contribution to virulence, highlighting the diversity that these relationships may present, and the interest of analysing their functions within the context of the infection

Buses, cars, bicycles and walkers the influence of the type of human transport on the flight responses of waterbirds

One way to manage disturbance to waterbirds in natural areas where humans require access is to promote the occurrence of stimuli for which birds tolerate closer approaches, and so cause fewer responses. We conducted 730 experimental approaches to 39 species of waterbird, using five stimulus types (single walker, three walkers, bicycle, car and bus) selected to mimic different human management options available for a controlled access, Ramsar-listed wetland. Across species, where differences existed (56% of 25 cases), motor vehicles always evoked shorter flight-initiation distances (FID) than humans on foot. The influence of stimulus type on FID varied across four species for which enough data were available for complete cross-stimulus analysis. All four varied FID in relation to stimuli, differing in 4 to 7 of 10 possible comparisons. Where differences occurred, the effect size was generally modest, suggesting that managing stimulus type (e.g. by requiring people to use vehicles) may have species-specific, modest benefits, at least for the waterbirds we studied. However, different stimulus types have different capacities to reduce the frequency of disturbance (i.e. by carrying more people) and vary in their capacity to travel around important habita

Debris Disks: Probing Planet Formation

Debris disks are the dust disks found around ~20% of nearby main sequence stars in far-IR surveys. They can be considered as descendants of protoplanetary disks or components of planetary systems, providing valuable information on circumstellar disk evolution and the outcome of planet formation. The debris disk population can be explained by the steady collisional erosion of planetesimal belts; population models constrain where (10-100au) and in what quantity (>1Mearth) planetesimals (>10km in size) typically form in protoplanetary disks. Gas is now seen long into the debris disk phase. Some of this is secondary implying planetesimals have a Solar System comet-like composition, but some systems may retain primordial gas. Ongoing planet formation processes are invoked for some debris disks, such as the continued growth of dwarf planets in an unstirred disk, or the growth of terrestrial planets through giant impacts. Planets imprint structure on debris disks in many ways; images of gaps, clumps, warps, eccentricities and other disk asymmetries, are readily explained by planets at >>5au. Hot dust in the region planets are commonly found (<5au) is seen for a growing number of stars. This dust usually originates in an outer belt (e.g., from exocomets), although an asteroid belt or recent collision is sometimes inferred.Comment: Invited review, accepted for publication in the 'Handbook of Exoplanets', eds. H.J. Deeg and J.A. Belmonte, Springer (2018

Review of Recent Developments in the Random-Field Ising Model

A lot of progress has been made recently in our understanding of the random-field Ising model thanks to large-scale numerical simulations. In particular, it has been shown that, contrary to previous statements: the critical exponents for different probability distributions of the random fields and for diluted antiferromagnets in a field are the same. Therefore, critical universality, which is a perturbative renormalization-group prediction, holds beyond the validity regime of perturbation theory. Most notably, dimensional reduction is restored at five dimensions, i.e., the exponents of the random-field Ising model at five dimensions and those of the pure Ising ferromagnet at three dimensions are the same.Comment: 11 pages, 4 figures, updated and extended version, to be published in J. Stat. Phy

Cyclic Tetrapyrrolic Photosensitisers from the leaves of Phaeanthus ophthalmicus

<p>Abstract</p> <p>Background</p> <p>Twenty-seven extracts from 26 plants were identified as photo-cytotoxic in the course of our bioassay guided screening program for photosensitisers from 128 extracts prepared from 64 terrestrial plants in two different collection sites in Malaysia - Royal Belum Forest Reserve in the State of Perak and Gunung Nuang in the State of Selangor. One of the photo-cytotoxic extracts from the leaves of <it>Phaeanthus ophtalmicus </it>was further investigated.</p> <p>Results</p> <p>The ethanolic extract of the leaves from <it>Phaeanthus ophtalmicus </it>was able to reduce the <it>in vitro </it>viability of leukaemic HL60 cells to < 50% when exposed to 9.6 J/cm²of a broad spectrum light at a concentration of 20 μg/mL. Dereplication of the photo-cytotoxic fractions from <it>P. ophthalmicus </it>extracts based on TLC R_fvalues and HPLC co-injection of reference tetrapyrrolic compounds enabled quick identification of known photosensitisers, pheophorbide-<it>a</it>, pheophorbide-<it>a </it>methyl ester, 13²-hydroxypheophorbide-<it>a </it>methyl ester, pheophytin-<it>a </it>and 15¹-hydroxypurpurin 7-lactone dimethyl ester. In addition, compound <b>1 </b>which was not previously isolated as a natural product was also identified as 7-formyl-15¹-hydroxypurpurin-7-lactone methyl ester using standard spectroscopic techniques.</p> <p>Conclusions</p> <p>Our results suggest that the main photosensitisers in plants are based on the cyclic tetrapyrrole structure and photosensitisers with other structures, if present, are present in very minor amounts or are not as active as those with the cyclic tetrapyrrole structure.</p