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  • 1
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    Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation (2014)
    Oxford University Press
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    Publication Date: 2014-10-09
    Description: Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn , a novel AMPK–mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn -deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn -deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn -deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn -deficient hearts and indeed, inactivation of Ppargc1a in Flcn -deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn -deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK–mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    The Gaia-ESO Survey: the most metal-poor stars in the Galactic bulge (2014)
    Oxford University Press
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    Publication Date: 2014-11-08
    Description: We present the first results of the EMBLA survey (Extremely Metal-poor BuLge stars with AAOmega), aimed at finding metal-poor stars in the Milky Way bulge, where the oldest stars should now preferentially reside. EMBLA utilizes SkyMapper photometry to pre-select metal-poor candidates, which are subsequently confirmed using AAOmega spectroscopy. We describe the discovery and analysis of four bulge giants with –2.72 ≤ [Fe/H] ≤ –2.48, the lowest metallicity bulge stars studied with high-resolution spectroscopy to date. Using FLAMES/UVES spectra through the Gaia -ESO Survey we have derived abundances of twelve elements. Given the uncertainties, we find a chemical similarity between these bulge stars and halo stars of the same metallicity, although the abundance scatter may be larger, with some of the stars showing unusual [α/Fe] ratios.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 3
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    MetPP: a computational platform for comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry-based metabolomics (2013)
    Oxford University Press
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    Publication Date: 2013-07-06
    Description: Motivation: Due to the high complexity of metabolome, the comprehensive 2D gas chromatography time-of-flight mass spectrometry (GC x GC-TOF MS) is considered as a powerful analytical platform for metabolomics study. However, the applications of GC x GC-TOF MS in metabolomics are not popular owing to the lack of bioinformatics system for data analysis. Results: We developed a computational platform entitled metabolomics profiling pipeline (MetPP) for analysis of metabolomics data acquired on a GC x GC-TOF MS system. MetPP can process peak filtering and merging, retention index matching, peak list alignment, normalization, statistical significance tests and pattern recognition, using the peak lists deconvoluted from the instrument data as its input. The performance of MetPP software was tested with two sets of experimental data acquired in a spike-in experiment and a biomarker discovery experiment, respectively. MetPP not only correctly aligned the spiked-in metabolite standards from the experimental data, but also correctly recognized their concentration difference between sample groups. For analysis of the biomarker discovery data, 15 metabolites were recognized with significant concentration difference between the sample groups and these results agree with the literature results of histological analysis, demonstrating the effectiveness of applying MetPP software for disease biomarker discovery. Availability: The source code of MetPP is available at http://metaopen.sourceforge.net Contact: xiang.zhang@louisville.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 4
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    DySC: software for greedy clustering of 16S rRNA reads (2012)
    Oxford University Press
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    Publication Date: 2012-08-08
    Description: : Pyrosequencing technologies are frequently used for sequencing the 16S ribosomal RNA marker gene for profiling microbial communities. Clustering of the produced reads is an important but time-consuming task. We present Dynamic Seed-based Clustering (DySC), a new tool based on the greedy clustering approach that uses a dynamic seeding strategy. Evaluations based on the normalized mutual information (NMI) criterion show that DySC produces higher quality clusters than UCLUST and CD-HIT at a comparable runtime. Availability and implementation: DySC, implemented in C, is available at http://code.google.com/p/dysc/ under GNU GPL license. Contact: bertil.schmidt@uni-mainz.de Supplementary Information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 5
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    Implementing ecosystem-based fisheries management: from single-species to integrated ecosystem assessment and advice for Baltic Sea fish stocks (2014)
    Oxford University Press
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    Publication Date: 2014-06-18
    Description: Theory behind ecosystem-based management (EBM) and ecosystem-based fisheries management (EBFM) is now well developed. However, the implementation of EBFM exemplified by fisheries management in Europe is still largely based on single-species assessments and ignores the wider ecosystem context and impact. The reason for the lack or slow implementation of EBM and specifically EBFM is a lack of a coherent strategy. Such a strategy is offered by recently developed integrated ecosystem assessments (IEAs), a formal synthesis tool to quantitatively analyse information on relevant natural and socio-economic factors, in relation to specified management objectives. Here, we focus on implementing the IEA approach for Baltic Sea fish stocks. We combine both tactical and strategic management aspects into a single strategy that supports the present Baltic Sea fish stock advice, conducted by the International Council for the Exploration of the Sea (ICES). We first review the state of the art in the development of IEA within the current management framework. We then outline and discuss an approach that integrates fish stock advice and IEAs for the Baltic Sea. We intentionally focus on the central Baltic Sea and its three major fish stocks cod ( Gadus morhua ), herring ( Clupea harengus ), and sprat ( Sprattus sprattus ), but emphasize that our approach may be applied to other parts and stocks of the Baltic, as well as other ocean areas.
    Print ISSN: 1054-3139
    Electronic ISSN: 1095-9289
    Topics: Biology , Geosciences , Physics
    Published by Oxford University Press
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  • 6
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    The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease (2014)
    Oxford University Press
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    Publication Date: 2014-07-05
    Description: HIP14 is the most highly conserved of 23 human palmitoyl acyltransferases (PATs) that catalyze the post-translational addition of palmitate to proteins, including huntingtin (HTT). HIP14 is dysfunctional in the presence of mutant HTT (mHTT), the causative gene for Huntington disease (HD), and we hypothesize that reduced palmitoylation of HTT and other HIP14 substrates contributes to the pathogenesis of the disease. Here we describe the yeast two-hybrid (Y2H) interactors of HIP14 in the first comprehensive study of interactors of a mammalian PAT. Unexpectedly, we discovered a highly significant overlap between HIP14 interactors and 370 published interactors of HTT, 4-fold greater than for control proteins ( P = 8 x 10 –5 ). Nearly half of the 36 shared interactors are already implicated in HD, supporting a direct link between HIP14 and the disease. The HIP14 Y2H interaction set is significantly enriched for palmitoylated proteins that are candidate substrates. We confirmed that three of them, GPM6A, and the Sprouty domain-containing proteins SPRED1 and SPRED3, are indeed palmitoylated by HIP14; the first enzyme known to palmitoylate these proteins. These novel substrates functions might be affected by reduced palmitoylation in HD. We also show that the vesicular cargo adapter optineurin, an established HTT-binding protein, co-immunoprecipitates with HIP14 but is not palmitoylated. mHTT leads to mislocalization of optineurin and aberrant cargo trafficking. Therefore, it is possible that optineurin regulates trafficking of HIP14 to its substrates. Taken together, our data raise the possibility that defective palmitoylation by HIP14 might be an important mechanism that contributes to the pathogenesis of HD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 7
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    Optimization of transcription factor binding map accuracy utilizing knockout-mouse models (2014)
    Oxford University Press
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    Publication Date: 2014-11-28
    Description: Genome-wide assessment of protein–DNA interaction by chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) is a key technology for studying transcription factor (TF) localization and regulation of gene expression. Signal-to-noise-ratio and signal specificity in ChIP-seq studies depend on many variables, including antibody affinity and specificity. Thus far, efforts to improve antibody reagents for ChIP-seq experiments have focused mainly on generating higher quality antibodies. Here we introduce KOIN (knockout implemented normalization) as a novel strategy to increase signal specificity and reduce noise by using TF knockout mice as a critical control for ChIP-seq data experiments. Additionally, KOIN can identify ‘hyper ChIPable regions’ as another source of false-positive signals. As the use of the KOIN algorithm reduces false-positive results and thereby prevents misinterpretation of ChIP-seq data, it should be considered as the gold standard for future ChIP-seq analyses, particularly when developing ChIP-assays with novel antibody reagents.
    Keywords: Chromatin and Epigenetics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Inferring the redshift distribution of the cosmic infrared background (2014)
    Oxford University Press
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    Publication Date: 2014-12-03
    Description: Cross-correlating the Planck High Frequency Instrument maps against quasars from the Sloan Digital Sky Survey DR7, we estimate the intensity distribution of the cosmic infrared background (CIB) over the redshift range 0 〈  z  〈 5. We detect redshift-dependent spatial cross-correlations between the two data sets using the 857, 545, and 353 GHz channels and we obtain upper limits at 217 GHz consistent with expectations. At all frequencies with detectable signal we infer a redshift distribution peaking around z  ~ 1.2 and find the recovered spectrum to be consistent with emission arising from star-forming galaxies. By assuming simple modified blackbody and Kennicutt relations, we estimate dust and star formation rate density as a function of redshift, finding results consistent with earlier multiwavelength measurements over a large portion of cosmic history. However, we note that, lacking mid-infrared coverage, we are not able to make an accurate determination of the mean temperature for the dust responsible for the CIB. Our results demonstrate that clustering-based redshift inference is a valuable tool for measuring the entire evolution history of the cosmic star formation rate from a single and homogeneous data set.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 9
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    A gene expression analysis of cell wall biosynthetic genes in Malus x domestica infected by 'Candidatus Phytoplasma mali' (2012)
    Oxford University Press
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    Publication Date: 2012-11-09
    Description: Apple proliferation (AP) represents a serious threat to several fruit-growing areas and is responsible for great economic losses. Several studies have highlighted the key role played by the cell wall in response to pathogen attack. The existence of a cell wall integrity signaling pathway which senses perturbations in the cell wall architecture upon abiotic/biotic stresses and activates specific defence responses has been widely demonstrated in plants. More recently a role played by cell wall-related genes has also been reported in plants infected by phytoplasmas. With the aim of shedding light on the cell wall response to AP disease in the economically relevant fruit-tree Malus x domestica Borkh., we investigated the expression of the cellulose ( CesA ) and callose synthase ( CalS ) genes in different organs (i.e., leaves, roots and branch phloem) of healthy and infected symptomatic outdoor-grown trees, sampled over the course of two time points (i.e., spring and autumn 2011), as well as in in vitro micropropagated control and infected plantlets. A strong up-regulation in the expression of cell wall biosynthetic genes was recorded in roots from infected trees. Secondary cell wall CesA s showed up-regulation in the phloem tissue from branches of infected plants, while either a down-regulation of some genes or no major changes were observed in the leaves. Micropropagated plantlets also showed an increase in cell wall-related genes and constitute a useful system for a general assessment of gene expression analysis upon phytoplasma infection. Finally, we also report the presence of several ‘knot’-like structures along the roots of infected apple trees and discuss the occurrence of this interesting phenotype in relation to the gene expression results and the modalities of phytoplasma diffusion.
    Print ISSN: 0829-318X
    Electronic ISSN: 1758-4469
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Published by Oxford University Press
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  • 10
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    Structure and properties of the esterase from non-LTR retrotransposons suggest a role for lipids in retrotransposition (2013)
    Oxford University Press
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    Publication Date: 2013-12-07
    Description: Non-LTR retrotransposons are mobile genetic elements and play a major role in eukaryotic genome evolution and disease. Similar to retroviruses they encode a reverse transcriptase, but their genomic integration mechanism is fundamentally different, and they lack homologs of the retroviral nucleocapsid-forming protein Gag. Instead, their first open reading frames encode distinct multi-domain proteins (ORF1ps) presumed to package the retrotransposon-encoded RNA into ribonucleoprotein particles (RNPs). The mechanistic roles of ORF1ps are poorly understood, particularly of ORF1ps that appear to harbor an enzymatic function in the form of an SGNH-type lipolytic acetylesterase. We determined the crystal structures of the coiled coil and esterase domains of the ORF1p from the Danio rerio ZfL2-1 element. We demonstrate a dimerization of the coiled coil and a hydrolytic activity of the esterase. Furthermore, the esterase binds negatively charged phospholipids and liposomes, but not oligo-(A) RNA. Unexpectedly, the esterase can split into two dynamic half-domains, suited to engulf long fatty acid substrates extending from the active site. These properties indicate a role for lipids and membranes in non-LTR retrotransposition. We speculate that Gag-like membrane targeting properties of ORF1ps could play a role in RNP assembly and in membrane-dependent transport or localization processes.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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