Pro-oxidant effect of ALA is implicated in mitochondrial dysfunction of HepG2 cells

Heme biosynthesis begins in the mitochondrion with the formation of delta-aminolevulinic acid (ALA). In acute intermittent porphyria, hereditary tyrosinemia type I and lead poisoning patients, ALA is accumulated in plasma and in organs, especially the liver. These diseases are also associated with neuromuscular dysfunction and increased incidence of hepatocellular carcinoma. Many studies suggest that this damage may originate from ALA-induced oxidative stress following its accumulation. Using the MnSOD as an oxidative stress marker, we showed here that ALA treatment of cultured cells induced ROS production, increasing with ALA concentration. The mitochondrial energetic function of ALA-treated HepG2 cells was further explored. Mitochondrial respiration and ATP content were reduced compared to control cells. For the 300 μM treatment, ALA induced a mitochondrial mass decrease and a mitochondrial network imbalance although neither necrosis nor apoptosis were observed. The up regulation of PGC-1, Tfam and ND5 genes was also found; these genes encode mitochondrial proteins involved in mitochondrial biogenesis activation and OXPHOS function. We propose that ALA may constitute an internal bioenergetic signal, which initiates a coordinated upregulation of respiratory genes, which ultimately drives mitochondrial metabolic adaptation within cells. The addition of an antioxidant, Manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), resulted in improvement of maximal respiratory chain capacity with 300 μM ALA. Our results suggest that mitochondria, an ALA-production site, are more sensitive to pro-oxidant effect of ALA, and may be directly involved in pathophysiology of patients with inherited or acquired porphyria

The XMM-LSS Survey: A well controlled X-ray cluster sample over the D1 CFHTLS area

We present the XMM-LSS cluster catalogue corresponding to the CFHTLS D1 area. The list contains 13 spectroscopically confirmed, X-ray selected galaxy clusters over 0.8 deg2 to a redshift of unity and so constitutes the highest density sample of clusters to date. Cluster X-ray bolometric luminosities range from 0.03 to 5x10^{44} erg/s. In this study, we describe our catalogue construction procedure: from the detection of X-ray cluster candidates to the compilation of a spectroscopically confirmed cluster sample with an explicit selection function. The procedure further provides basic X-ray products such as cluster temperature, flux and luminosity. We detected slightly more clusters with a (0.5-2.0 keV) X-ray fluxes of >2x10^{-14} erg/s/cm^{-2} than we expected based on expectations from deep ROSAT surveys. We also present the Luminosity-Temperature relation for our 9 brightest objects possessing a reliable temperature determination. The slope is in good agreement with the local relation, yet compatible with a luminosity enhancement for the 0.15 < z< 0.35 objects having 1 < T < 2 keV, a population that the XMM-LSS is identifying systematically for the first time. The present study permits the compilation of cluster samples from XMM images whose selection biases are understood. This allows, in addition to studies of large-scale structure, the systematic investigation of cluster scaling law evolution, especially for low mass X-ray groups which constitute the bulk of our observed cluster population. All cluster ancillary data (images, profiles, spectra) are made available in electronic form via the XMM-LSS cluster database.Comment: 12 pages 5 figures, MNRAS accepted. The paper with full resolution cluster images is available at http://vela.astro.ulg.ac.be/themes/spatial/xmm/LSS/rel_pub_e.htm

The XMM-LSS catalogue: X-ray sources and associated optical data. Version I

Following the presentation of the XMM-LSS X-ray source detection package by Pacaud et al., we provide the source lists for the first 5.5 surveyed square degrees. The catalogues pertain to the [0.5-2] and [2-10] keV bands and contain in total 3385 point-like or extended sources above a detection likelihood of 15 in either band. The agreement with deep logN-logS is excellent. The main parameters considered are position, countrate, source extent with associated likelihood values. A set of additional quantities such as astrometric corrections and fluxes are further calculated while errors on the position and countrate are deduced from simulations. We describe the construction of the band-merged catalogue allowing rapid sub-sample selection and easy cross-correlation with external multi-wavelength catalogues. A small optical CFHTLS multi-band subset of objects is associated wich each source along with an X-ray/optical overlay. We make the full X-ray images available in FITS format. The data are available at CDS and, in a more extended form, at the Milan XMM-LSS database.Comment: 13 pages, 7 figures and 11 tables (fig. 1 and 6 are enclosed in reduced resolution), MNRAS Latex, accepted by MNRA

AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages

Reticular dysgenesis is a human severe combined immunodeficiency that is primarily characterized by profound neutropenia and lymphopenia. The condition is caused by mutations in the adenylate kinase 2 (AK2) gene, resulting in the loss of mitochondrial AK2 protein expression. AK2 regulates the homeostasis of mitochondrial adenine nucleotides (ADP, ATP and AMP) by catalyzing the transfer of high-energy phosphate. Our present results demonstrate that AK2-knocked-down progenitor cells have poor proliferative and survival capacities and are blocked in their differentiation toward lymphoid and granulocyte lineages. We also observed that AK2 deficiency impaired mitochondrial function in general and oxidative phosphorylation in particular - showing that AK2 is critical in the control of energy metabolism. Loss of AK2 disrupts this regulation and leads to a profound block in lymphoid and myeloid cell differentiation

Draft Genome Sequence of the Marine Streptomyces sp. Strain PP-C42, Isolated from the Baltic Sea

Streptomyces, a branch of aerobic Gram-positive bacteria represents the largest genus of actinobacteria. The streptomycetes are characterized by a complex secondary metabolism and produce over two-thirds of the clinically used natural antibiotics today. Here we report the draft genome sequence of a Streptomyces strain PP-C42 isolated from the marine environment. A subset of unique genes and gene clusters for diverse secondary metabolites as well as antimicrobial peptides (AMPs) could be identified from the genome, showing great promise as a source for novel bioactive compound

Draft Genome Sequence of the Marine Streptomyces sp. Strain PP-C42, Isolated from the Baltic Sea

Streptomyces, a branch of aerobic Gram-positive bacteria represents the largest genus of actinobacteria. The streptomycetes are characterized by a complex secondary metabolism and produce over two-thirds of the clinically used natural antibiotics today. Here we report the draft genome sequence of a Streptomyces strain PP-C42 isolated from the marine environment. A subset of unique genes and gene clusters for diverse secondary metabolites as well as antimicrobial peptides (AMPs) could be identified from the genome, showing great promise as a source for novel bioactive compound

An optimization procedure of the start-up of Combined Cycle Power Plants

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Nerve excitability changes related to muscle weakness in chronic progressive external ophthalmoplegia

Objective: To explore potential spreading to peripheral nerves of the mitochondrial dysfunction in chronic progressive external ophthalmoplegia (CPEO) by assessing axonal excitability. Methods: CPEO patients (n = 13) with large size deletion of mitochondrial DNA and matching healthy controls (n = 22) were included in a case-control study. Muscle strength was quantified using MRC sum-score and used to define two groups of patients: CPEO-weak and CPEO-normal (normal strength). Nerve excitability properties of median motor axons were assessed with the TROND protocol and changes interpreted with the aid of a model. Results: Alterations of nerve excitability strongly correlated with scores of muscle strength. CPEO-weak displayed abnormal nerve excitability compared to CPEO-normal and healthy controls, with increased superexcitability and responses to hyperpolarizing current. Modeling indicated that the CPEO-weak recordings were best explained by an increase in the ‘Barrett-Barrett’ conductance across the myelin sheath. Conclusion: CPEO patients with skeletal weakness presented sub-clinical nerve excitability changes, which were not consistent with axonal membrane depolarization, but suggested Schwann cell involvement. Significance: This study provides new insights into the spreading of large size deletion of mitochondrial DNA to Schwann cells in CPEO patients

The XMM-LSS survey: the Class 1 cluster sample over the initial 5 square degrees and its cosmological modelling

We present a sample of 29 galaxy clusters from the XMM-LSS survey over an area of some 5deg2 out to a redshift of z=1.05. The sample clusters, which represent about half of the X-ray clusters identified in the region, follow well defined X-ray selection criteria and are all spectroscopically confirmed. For all clusters, we provide X-ray luminosities and temperatures as well as masses. The cluster distribution peaks around z=0.3 and T =1.5 keV, half of the objects being groups with a temperature below 2 keV. Our L-T(z) relation points toward self-similar evolution, but does not exclude other physically plausible models. Assuming that cluster scaling laws follow self-similar evolution, our number density estimates up to z=1 are compatible with the predictions of the concordance cosmology and with the findings of previous ROSAT surveys. Our well monitored selection function allowed us to demonstrate that the inclusion of selection effects is essential for the correct determination of the evolution of the L-T relation, which may explain the contradictory results from previous studies. Extensive simulations show that extending the survey area to 10deg2 has the potential to exclude the non-evolution hypothesis, but that constraints on more refined ICM models will probably be limited by the large intrinsic dispersion of the L-T relation. We further demonstrate that increasing the dispersion in the scaling laws increases the number of detectable clusters, hence generating further degeneracy [in addition to sigma8, Omega_m, L(M,z) and T(M,z)] in the cosmological interpretation of the cluster number counts. We provide useful empirical formulae for the cluster mass-flux and mass-count-rate relations as well as a comparison between the XMM-LSS mass sensitivity and that of forthcoming SZ surveys.Comment: Accepted for publication by MNRAS. Full resolution images as well as additional cluster data are available through a dedicated database at http://l3sdb.in2p3.fr:8080/l3sdb