Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development

Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals

Explorative visual analytics on interval-based genomic data and their metadata

Background: With the wide-spreading of public repositories of NGS processed data, the availability of user-friendly and effective tools for data exploration, analysis and visualization is becoming very relevant. These tools enable interactive analytics, an exploratory approach for the seamless "sense-making" of data through on-the-fly integration of analysis and visualization phases, suggested not only for evaluating processing results, but also for designing and adapting NGS data analysis pipelines. Results: This paper presents abstractions for supporting the early analysis of NGS processed data and their implementation in an associated tool, named GenoMetric Space Explorer (GeMSE). This tool serves the needs of the GenoMetric Query Language, an innovative cloud-based system for computing complex queries over heterogeneous processed data. It can also be used starting from any text files in standard BED, BroadPeak, NarrowPeak, GTF, or general tab-delimited format, containing numerical features of genomic regions; metadata can be provided as text files in tab-delimited attribute-value format. GeMSE allows interactive analytics, consisting of on-the-fly cycling among steps of data exploration, analysis and visualization that help biologists and bioinformaticians in making sense of heterogeneous genomic datasets. By means of an explorative interaction support, users can trace past activities and quickly recover their results, seamlessly going backward and forward in the analysis steps and comparative visualizations of heatmaps. Conclusions: GeMSE effective application and practical usefulness is demonstrated through significant use cases of biological interest. GeMSE is available at http://www.bioinformatics.deib.polimi.it/GeMSE/ , and its source code is available at https://github.com/Genometric/GeMSEunder GPLv3 open-source license

The effects of spatial legacies following shifting management practices and fire on boreal forest age structure

Forest age structure and its spatial arrangement are important elements of sustainable forestry because of their effects on biodiversity and timber availability. Forest management objectives that include specific forest age structure may not be easily attained due to constraints imposed by the legacies of historical management and natural disturbance. We used a spatially explicit stochastic model to explore the synergetic effects of forest management and fire on boreal forest age structure. Specifically, we examined (1) the duration of spatial legacies of different management practices in the boreal forest, (2) how multiple shifts in management practices affect legacy duration and the spatial trajectories of forest age structure, and (3) how fire influences legacy duration and pattern development in combination with harvesting. Results based on 30 replicates of 500 years for each scenario indicate that (1) spatial legacies persist over 200 years and the rate at which legacies are overcome depends on whether new management targets are in synchrony with existing spatial pattern; (2) age specific goals were met faster after multiple management shifts due to the similar spatial scale of the preceding management types; (3) because large fires can erase the spatial pattern created by smaller disturbances, scenarios with fire had shorter lags than scenarios without fire. These results suggest that forest management goals can be accelerated by applying management at a similar spatial scale as existing spatial patterns. Also, management planning should include careful consideration of historical management as well as current and likely future disturbances

The Increased Activity of TRPV4 Channel in the Astrocytes of the Adult Rat Hippocampus after Cerebral Hypoxia/Ischemia

The polymodal transient receptor potential vanilloid 4 (TRPV4) channel, a member of the TRP channel family, is a calcium-permeable cationic channel that is gated by various stimuli such as cell swelling, low pH and high temperature. Therefore, TRPV4-mediated calcium entry may be involved in neuronal and glia pathophysiology associated with various disorders of the central nervous system, such as ischemia. The TRPV4 channel has been recently found in adult rat cortical and hippocampal astrocytes; however, its role in astrocyte pathophysiology is still not defined. In the present study, we examined the impact of cerebral hypoxia/ischemia (H/I) on the functional expression of astrocytic TRPV4 channels in the adult rat hippocampal CA1 region employing immunohistochemical analyses, the patch-clamp technique and microfluorimetric intracellular calcium imaging on astrocytes in slices as well as on those isolated from sham-operated or ischemic hippocampi. Hypoxia/ischemia was induced by a bilateral 15-minute occlusion of the common carotids combined with hypoxic conditions. Our immunohistochemical analyses revealed that 7 days after H/I, the expression of TRPV4 is markedly enhanced in hippocampal astrocytes of the CA1 region and that the increasing TRPV4 expression coincides with the development of astrogliosis. Additionally, adult hippocampal astrocytes in slices or cultured hippocampal astrocytes respond to the TRPV4 activator 4-alpha-phorbol-12,-13-didecanoate (4αPDD) by an increase in intracellular calcium and the activation of a cationic current, both of which are abolished by the removal of extracellular calcium or exposure to TRP antagonists, such as Ruthenium Red or RN1734. Following hypoxic/ischemic injury, the responses of astrocytes to 4αPDD are significantly augmented. Collectively, we show that TRPV4 channels are involved in ischemia-induced calcium entry in reactive astrocytes and thus, might participate in the pathogenic mechanisms of astroglial reactivity following ischemic insult

Adolescents’ beverage choice at school and the impact on sugar intake

Background/Objectives: To examine students’ beverage choice in school, with reference to its contribution to students’ intake of non-milk extrinsic (NME) sugars. Subjects/Methods: Beverage and food selection data for students aged 11–18 years (n=2461) were collected from two large secondary schools in England, for a continuous period of 145 (school A) and 125 (school B) school days. Descriptive analysis followed by cluster analysis of the beverage data were performed separately for each school. Results: More than a third of all items selected by students were beverages, and juice-based beverages were students’ most popular choice (school A, 38.6%; school B, 35.2%). Mean NME sugars derived from beverages alone was high (school A, 16.7 g/student-day; school B, 12.9 g/student-day). Based on beverage purchases, six clusters of students were identified at each school (school A: ‘juice-based’, ‘assorted’, ‘water’, ‘cartoned flavoured milk’, ‘bottled flavoured milk’, ‘high volume juice-based’; school B: ‘assorted’, ‘water with juice-based’, ‘sparkling juice/juice-based’, ‘water’, ‘high volume water’, ‘high volume juice-based’). Both schools included ‘high volume juice-based’ clusters with the highest NME sugar means from beverages (school A, 28.6 g/student-day; school B, 24.4 g/student-day), and ‘water’ clusters with the lowest. A hierarchy in NME sugars was found according to cluster; students in the ‘high volume juice-based’ cluster returned significantly higher levels of NME sugars than students in other clusters. Conclusions: This study reveals the contribution that school beverages combined with students’ beverage choice behaviour is making to students’ NME sugar intake. These findings inform school food initiatives, and more generally public health policy around adolescents’ dietary intake

Operation and performance of the ATLAS Tile Calorimeter in Run 1

The Tile Calorimeter is the hadron calorimeter covering the central region of the ATLAS experiment at the Large Hadron Collider. Approximately 10,000 photomultipliers collect light from scintillating tiles acting as the active material sandwiched between slabs of steel absorber. This paper gives an overview of the calorimeter’s performance during the years 2008–2012 using cosmic-ray muon events and proton–proton collision data at centre-of-mass energies of 7 and 8TeV with a total integrated luminosity of nearly 30 fb−1. The signal reconstruction methods, calibration systems as well as the detector operation status are presented. The energy and time calibration methods performed excellently, resulting in good stability of the calorimeter response under varying conditions during the LHC Run 1. Finally, the Tile Calorimeter response to isolated muons and hadrons as well as to jets from proton–proton collisions is presented. The results demonstrate excellent performance in accord with specifications mentioned in the Technical Design Report

Search for new particles in events with one lepton and missing transverse momentum in pp collisions at √s = 8 TeV with the ATLAS detector

This paper presents a search for new particles in events with one lepton (electron or muon) and missing transverse momentum using 20.3 fb−¹ of proton-proton collision data at √s=8 TeV recorded by the ATLAS experiment at the Large Hadron Collider. No significant excess beyond Standard Model expectations is observed. A W′ with Sequential Standard Model couplings is excluded at the 95% confidence level for masses up to 3.24 TeV. Excited chiral bosons (W*) with equivalent coupling strengths are excluded for masses up to 3.21 TeV. In the framework of an effective field theory limits are also set on the dark matter-nucleon scattering cross-section as well as the mass scale M* of the unknown mediating interaction for dark matter pair production in association with a leptonically decaying W