A Computational Screen for Regulators of Oxidative Phosphorylation Implicates SLIRP in Mitochondrial RNA Homeostasis

The human oxidative phosphorylation (OxPhos) system consists of approximately 90 proteins encoded by nuclear and mitochondrial genomes and serves as the primary cellular pathway for ATP biosynthesis. While the core protein machinery for OxPhos is well characterized, many of its assembly, maturation, and regulatory factors remain unknown. We exploited the tight transcriptional control of the genes encoding the core OxPhos machinery to identify novel regulators. We developed a computational procedure, which we call expression screening, which integrates information from thousands of microarray data sets in a principled manner to identify genes that are consistently co-expressed with a target pathway across biological contexts. We applied expression screening to predict dozens of novel regulators of OxPhos. For two candidate genes, CHCHD2 and SLIRP, we show that silencing with RNAi results in destabilization of OxPhos complexes and a marked loss of OxPhos enzymatic activity. Moreover, we show that SLIRP plays an essential role in maintaining mitochondrial-localized mRNA transcripts that encode OxPhos protein subunits. Our findings provide a catalogue of potential novel OxPhos regulators that advance our understanding of the coordination between nuclear and mitochondrial genomes for the regulation of cellular energy metabolism

Discovery of Genes Essential for Heme Biosynthesis through Large-Scale Gene Expression Analysis

SummaryHeme biosynthesis consists of a series of eight enzymatic reactions that originate in mitochondria and continue in the cytosol before returning to mitochondria. Although these core enzymes are well studied, additional mitochondrial transporters and regulatory factors are predicted to be required. To discover such unknown components, we utilized a large-scale computational screen to identify mitochondrial proteins whose transcripts consistently coexpress with the core machinery of heme biosynthesis. We identified SLC25A39, SLC22A4, and TMEM14C, which are putative mitochondrial transporters, as well as C1orf69 and ISCA1, which are iron-sulfur cluster proteins. Targeted knockdowns of all five genes in zebrafish resulted in profound anemia without impacting erythroid lineage specification. Moreover, silencing of Slc25a39 in murine erythroleukemia cells impaired iron incorporation into protoporphyrin IX, and vertebrate Slc25a39 complemented an iron homeostasis defect in the orthologous yeast mtm1Δ deletion mutant. Our results advance the molecular understanding of heme biosynthesis and offer promising candidate genes for inherited anemias

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

Gamma-ray and radio properties of six pulsars detected by the fermi large area telescope

We report the detection of pulsed γ-rays for PSRs J0631+1036, J0659+1414, J0742-2822, J1420-6048, J1509-5850, and J1718-3825 using the Large Area Telescope on board the Fermi Gamma-ray Space Telescope (formerly known as GLAST). Although these six pulsars are diverse in terms of their spin parameters, they share an important feature: their γ-ray light curves are (at least given the current count statistics) single peaked. For two pulsars, there are hints for a double-peaked structure in the light curves. The shapes of the observed light curves of this group of pulsars are discussed in the light of models for which the emission originates from high up in the magnetosphere. The observed phases of the γ-ray light curves are, in general, consistent with those predicted by high-altitude models, although we speculate that the γ-ray emission of PSR J0659+1414, possibly featuring the softest spectrum of all Fermi pulsars coupled with a very low efficiency, arises from relatively low down in the magnetosphere. High-quality radio polarization data are available showing that all but one have a high degree of linear polarization. This allows us to place some constraints on the viewing geometry and aids the comparison of the γ-ray light curves with high-energy beam models

Author Correction: Drivers of seedling establishment success in dryland restoration efforts

1 Pág. Correción errata.In the version of this Article originally published, the surname of author Tina Parkhurst was incorrectly written as Schroeder. This has now been corrected.Peer reviewe

Complications of transvenous right ventricular endomyocardial biopsy in adult patients with cardiomyopathy: A seven-year survey of 546 consecutive diagnostic procedures in a tertiary referral center

AbstractTo determine the incidence, nature and subsequent management of complications occurring during right ventricular endomyocardial biopsy in patients with cardiomyopathy, all events occurring during 546 procedures in 464 consecutive patients were prospectively recorded. The internal jugular vein was the primary site of introduction in 96% of cases. A total of 33 complications (6%) occurred: 15 (2.7%) during catheter insertion including 12 arterial punctures (2%), 2 vasovagal reactions (0.4%) and 1 episode of prolonged bleeding (0.2%), all without sequelae; 18 (3.3%) during biopsy included 6 arrhythmias (1.1%), 5 conduction abnormalities (1%), 4 possible perforations (0.7%) and 3 definite perforations (0.5%) (pericardial fluid). Two (0.4%) of the three patients with a perforation died.There was no secular trend in the complication rate, nor were complications associated with specific clinical or hemodynamic characteristics. It is concluded that the overall rate of endomyocardial biopsy complications (6%) is low, but mortality may occur

Influence of dilated cardiomyopathy, myocarditis and cardiac transplantation on the relation between plasma atrial natriuretic factor and atrial pressures

To determine whether dilated cardiomyopathy, myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures, right atrial plasma ANF concentration, pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48), dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however, the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms, respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ ml/mm Hg (95% confidence interval (CI), 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI, 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI, 72 to 100%) of patients with right atrial pressure ≥ 8 mm Hg having ANF ≥ 150 pg/ml, but only 56% (CI, 42 to 69%) with pressure < 8 mm Hg having ANF < 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis), cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean ± standard deviation, 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy. Factors other than filling pressures influence circulating ANF in a significant number of patients with cardiomyopathy and in all transplant recipients

Abstract 1753: Transcriptomic based Biomarkers Contain Diagnostic and Prognostic Information about Patients with new onset Heart Failure

INTRODUCTION: One of the clinical dilemmas in cardiology is to accurately diagnose the etiology of patients with new onset heart failure such as to differentiate between potentially reversible myocarditis from idiopathic dilated cardiomyopathy (IDCM). Furthermore, it is difficult to predict the clinical trajectory of patients with IDCM. We hypothesized that the transcriptomic signatures generated from endomyocardial biopsies, obtained from patients at first presentation of heart failure, could serve as novel biomarkers to distinguish between myocarditis and IDCM as well as to predict the prognosis of patients classified as having IDCM. METHODS AND RESULTS: Endomyocardial biopsy samples were collected from 68 patients with new onset heart failure due to IDCM (n=49) and myocarditis (n=19). The average follow-up was 5 years and included information on mortality, need for left ventricular assist device (LVAD), or heart transplant. We used the U133 Plus 2.0 microarray (Affymetrix) and data analysis was performed with Significance Analysis of Microarrays (SAM) and Prediction Analysis of Microarrays (PAM). First, we identified a molecular signature of 39 genes in our training cohort (n=25 IDCM and n=8 myocarditis). When tested in independent patients (myocarditis: n=11; IDCM: n=11), this signature performed with 97% accuracy. Next, we identified a transcriptomic signature of 45 genes in a group of patients with IDCM that delineated between patients classified as having a good prognosis (event free survival > 5 years; n=18) vs a bad prognosis (death or requirement for insertion of LVAD or tx within 2 years of presentation; n=12). We tested this biomarker in independent samples and were able to predict prognosis with 87% accuracy. The transcriptomic biomarker was substantially more accurate in assigning prognosis than the Seattle Heart Failure Score (p=0.011). CONCLUSION: Together these findings illustrate the potential utility of using transcriptomic biomarkers generated from a single endomyocardial biopsy to improve the accuracy of diagnosis and prognosis in patients with new onset heart failure. This creates novel modalities to enhance management and identification of patients at highest risk for complications of heart failure in the short term