TREEOME: A framework for epigenetic and transcriptomic data integration to explore regulatory interactions controlling transcription

Motivation: Predictive modelling of gene expression is a powerful framework for the in silico exploration of transcriptional regulatory interactions through the integration of high-throughput -omics data. A major limitation of previous approaches is their inability to handle conditional and synergistic interactions that emerge when collectively analysing genes subject to different regulatory mechanisms. This limitation reduces overall predictive power and thus the reliability of downstream biological inference. Results: We introduce an analytical modelling framework (TREEOME: tree of models of expression) that integrates epigenetic and transcriptomic data by separating genes into putative regulatory classes. Current predictive modelling approaches have found both DNA methylation and histone modification epigenetic data to provide little or no improvement in accuracy of prediction of transcript abundance despite, for example, distinct anti-correlation between mRNA levels and promoter-localised DNA methylation. To improve on this, in TREEOME we evaluate four possible methods of formulating gene-level DNA methylation metrics, which provide a foundation for identifying gene-level methylation events and subsequent differential analysis, whereas most previous techniques operate at the level of individual CpG dinucleotides. We demonstrate TREEOME by integrating gene-level DNA methylation (bisulfite-seq) and histone modification (ChIP-seq) data to accurately predict genome-wide mRNA transcript abundance (RNA-seq) for H1-hESC and GM12878 cell lines. Availability: TREEOME is implemented using open-source software and made available as a pre-configured bootable reference environment. All scripts and data presented in this study are available online at http://sourceforge.net/projects/budden2015treeome/.Comment: 14 pages, 6 figure

Force field feature extraction for ear biometrics

The overall objective in defining feature space is to reduce the dimensionality of the original pattern space, whilst maintaining discriminatory power for classification. To meet this objective in the context of ear biometrics a new force field transformation treats the image as an array of mutually attracting particles that act as the source of a Gaussian force field. Underlying the force field there is a scalar potential energy field, which in the case of an ear takes the form of a smooth surface that resembles a small mountain with a number of peaks joined by ridges. The peaks correspond to potential energy wells and to extend the analogy the ridges correspond to potential energy channels. Since the transform also turns out to be invertible, and since the surface is otherwise smooth, information theory suggests that much of the information is transferred to these features, thus confirming their efficacy. We previously described how field line feature extraction, using an algorithm similar to gradient descent, exploits the directional properties of the force field to automatically locate these channels and wells, which then form the basis of characteristic ear features. We now show how an analysis of the mechanism of this algorithmic approach leads to a closed analytical description based on the divergence of force direction, which reveals that channels and wells are really manifestations of the same phenomenon. We further show that this new operator, with its own distinct advantages, has a striking similarity to the Marr-Hildreth operator, but with the important difference that it is non-linear. As well as addressing faster implementation, invertibility, and brightness sensitivity, the technique is also validated by performing recognition on a database of ears selected from the XM2VTS face database, and by comparing the results with the more established technique of Principal Components Analysis. This confirms not only that ears do indeed appear to have potential as a biometric, but also that the new approach is well suited to their description, being robust especially in the presence of noise, and having the advantage that the ear does not need to be explicitly extracted from the background

SGR 1806-20 Is a Set of Independent Relaxation Systems

The Soft Gamma Repeater 1806-20 produced patterns of bursts during its 1983 outburst that indicate multiple independent energy accumulation sites, each driven by a continuous power source, with sudden, incomplete releases of the accumulated energy. The strengths of the power sources and their durations of activity vary over several orders of magnitude.Comment: Accepted ApJLett, 15 pages, 3 figure

Nonsolar astronomy with the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI)

The Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) is a NASA Small Explorer satellite designed to study hard x-ray and gamma-ray emission from solar flares. In addition, its high-resolution array of germanium detectors can see photons from high-energy sources throughout the Universe. Here we discuss the various algorithms necessary to extract spectra, lightcurves, and other information about cosmic gamma-ray bursts, pulsars, and other astrophysical phenomena using an unpointed, spinning array of detectors. We show some preliminary results and discuss our plans for future analyses. All RHESSI data are public, and scientists interested in participating should contact the principal author

Neuroprotective role for RORA in Parkinson’s disease revealed by analysis of post-mortem brain and a dopaminergic cell line

Parkinson's disease (PD) is almost twice as prevalent in men, which has largely been attributed to neuroprotective effect of oestradiol in women. RORA (retinoic acid receptor-related orphan receptor alpha) regulates the transcription of central aromatase, the enzyme responsible for local oestradiol synthesis, simultaneously, RORA expression is regulated by sex hormones. Moreover, RORA protects neurones against oxidative stress, a key mechanism contributing to the loss of dopaminergic neurones in PD. Therefore, we hypothesized that there would be sex differences in RORA expression in the substantia nigra pars compacta (SNpc), which could contribute to sex differences observed in PD prevalence and pathogenesis. In a case control study, qPCR and western blot analyses were used to quantify gene and protein expression in the SNpc of post-mortem brains (n = 14 late-stage PD and 11 age and sex matched controls). The neuroprotective properties of a RORA agonist were then investigated directly using a cell culture toxin-based model of PD coupled with measures of viability, mitochondrial function and apoptosis. RORA was expressed at significantly higher levels in the SNpc from control females' brains compared to males. In PD, we found a significant increase in SNpc RORA expression in male PD compared to female PD. Treatment with a RORA agonist showed a significant neuroprotection in our cell culture model of PD and revealed significant effects on intracellular factors involved in neuronal survival and demise. This study is the first to demonstrate a sex specific pattern of RORA protein and gene expression in the SNpc of controls post-mortem human brains, and to show that this is differentially altered in male and female PD subjects, thus supporting a role for RORA in sex-specific aspects of PD. Furthermore, our in vitro PD model indicates mechanisms whereby a RORA agonist exerts its neuroprotective effect, thereby highlighting the translational potential for RORA ligands in PD

Pituitary Adenylate-Cyclase Activating Polypeptide Regulates Hunger- and Palatability-Induced Binge Eating

While pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the hypothalamic ventromedial nuclei (VMN) has been shown to regulate feeding, a challenge in unmasking a role for this peptide in obesity is that excess feeding can involve numerous mechanisms including homeostatic (hunger) and hedonic-related (palatability) drives. In these studies, we first isolated distinct feeding drives by developing a novel model of binge behavior in which homeostatic-driven feeding was temporally separated from feeding driven by food palatability. We found that stimulation of the VMN, achieved by local microinjections of AMPA, decreased standard chow consumption in food-restricted rats (e.g., homeostatic feeding); surprisingly, this manipulation failed to alter palatable food consumption in satiated rats (e.g., hedonic feeding). In contrast, inhibition of the nucleus accumbens (NAc), through local microinjections of GABA receptor agonists baclofen and muscimol, decreased hedonic feeding without altering homeostatic feeding. PACAP microinjections produced the site-specific changes in synaptic transmission needed to decrease feeding via VMN or NAc circuitry. PACAP into the NAc mimicked the actions of GABA agonists by reducing hedonic feeding without altering homeostatic feeding. In contrast, PACAP into the VMN mimicked the actions of AMPA by decreasing homeostatic feeding without affecting hedonic feeding. Slice electrophysiology recordings verified PACAP excitation of VMN neurons and inhibition of NAc neurons. These data suggest that the VMN and NAc regulate distinct circuits giving rise to unique feeding drives, but that both can be regulated by the neuropeptide PACAP to potentially curb excessive eating stemming from either drive

Immunocompromise in Gnotobiotic Pigs Induced by Verotoxin-Producing \u3ci\u3eEscherichia coli\u3c/i\u3e (O111:NM)

A verotoxin-producing Escherichia coli serotype O111:NM strain (strain 10049; verotoxin 1 positive) persistently infected experimentally inoculated gnotobiotic pigs, causing attaching-effacing intestinal lesions and chronic diarrhea. Experiments were performed to determine whether persistent infection might be associated with immunocompromise of the host by this organism. Pigs inoculated with this strain had a significant reduction in peripheral blood lymphocytes and lower antibody titers to sheep erythrocytes compared with control pigs. Compared with pigs given a verotoxin-negative pathogenic strain of the same serotype (O111:NM, strain 2430), pigs inoculated with the verotoxin-positive strain had lower peripheral lymphocyte counts and proliferative responses to concanavalin A, phytohemagglutinin, and pokeweed mitogens. The results of this study suggest that strain 10049 has an immunocompromising effect on gnotobiotic pigs

Immunocompromise in Gnotobiotic Pigs Induced by Verotoxin-Producing \u3ci\u3eEscherichia coli\u3c/i\u3e (O111:NM)

A verotoxin-producing Escherichia coli serotype O111:NM strain (strain 10049; verotoxin 1 positive) persistently infected experimentally inoculated gnotobiotic pigs, causing attaching-effacing intestinal lesions and chronic diarrhea. Experiments were performed to determine whether persistent infection might be associated with immunocompromise of the host by this organism. Pigs inoculated with this strain had a significant reduction in peripheral blood lymphocytes and lower antibody titers to sheep erythrocytes compared with control pigs. Compared with pigs given a verotoxin-negative pathogenic strain of the same serotype (O111:NM, strain 2430), pigs inoculated with the verotoxin-positive strain had lower peripheral lymphocyte counts and proliferative responses to concanavalin A, phytohemagglutinin, and pokeweed mitogens. The results of this study suggest that strain 10049 has an immunocompromising effect on gnotobiotic pigs