Molecular signaling of dioxins

Dioxin derivatives sustain a substantial and versatile toxicity in rodent species, which remains challenging to investigate in human. As exemplified by several recent environmental contaminations reported by the media, humans remain under the threat of being accidentally exposed to dioxins. Firstly, we will describe a molecular signaling pathway that explains mainly the toxic effects of dioxins. It involves a pair of proteins that display a “PAS” active domain: the Aryl-hydrocarbon Receptor (AHR) and its dimerization partner (Arnt). This active dimer transactivates the transcription of a battery of target genes. Nevertheless, their identification does not provide evidence for all toxic actions attributed to dioxins. Transgenic murine models have provided novel physiological and developmental links to this receptor dimer, which appears to be recruited by several dietary chemicals. A recent investigation exposed the connection, at the protein level, between the AHRdioxin pathway and the Estrogen Receptor pathway, thus providing a novel meaning to some puzzling estrogenic effects sustained by dioxin derivatives.Les congénères chimiques de la dioxine déterminent une toxicité considérable et polymorphe chez les rongeurs; son appréciation est plus délicate et confuse chez l'homme. De récents développements médiatiques rappellent que le risque d'exposition humaine est patent et que dans l'attente d'une connaissance plus approfondie des implications en biologie humaine, un légitime principe de précaution s'impose. Suivant une introduction de la problématique, une voie de signalisation moléculaire expliquant une majorité des effets toxiques des dioxines sera présentée. Elle implique deux protéines à domaine fonctionnel PAS: un récepteur activé par les dioxines (AHR) et son partenaire de dimérisation (Arnt). Ce complexe nucléaire transactive une batterie de gènes qui constituent les cibles des dioxines. Cependant leur inventaire actuel n'autorise pas la compréhension exhaustive de la toxicité des dioxines. Des modèles murins déficients permettent d'appréhender certaines fonctions physiologiques et développementales de ce complexe activé par les dioxines. On observe un accroisement des connaissances relatives aux ligands naturels de ce récepteur (molécules alimentaires). De très récentes investigations mettent en lumière l'imbrication de la signalétique moléculaire du AHR avec celle du récepteur aux oestrogènes (ER), expliquant l'origine des surprenants effets oestrogéno-mimétiques produits par les contaminants environnementaux de la famille des dioxines

Molecular cloning, gene structure and expression profile of two mouse peroxisomal 3-ketoacyl-CoA thiolase genes

BACKGROUND: In rats, two peroxisomal 3-ketoacyl-CoA thiolase genes (A and B) have been cloned, whereas only one thiolase gene is found in humans. The aim of this study was thus to clone the different mouse thiolase genes in order to study both their tissue expression and their associated enzymatic activity. RESULTS: In this study, we cloned and characterized two mouse peroxisomal 3-ketoacyl-CoA thiolase genes (termed thiolase A and B). Both thiolase A and B genes contain 12 exons and 11 introns. Using RNA extracted from mouse liver, we cloned the two corresponding cDNAs. Thiolase A and B cDNAs possess an open reading frame of 1272 nucleotides encoding a protein of 424 amino acids. In the coding sequence, the two thiolase genes exhibited ≈97% nucleotide sequence identity and ≈96% identity at the amino acid level. The tissue-specific expression of the two peroxisomal 3-ketoacyl-CoA thiolase genes was studied in mice. Thiolase A mRNA was mainly expressed in liver and intestine, while thiolase B mRNA essentially exhibited hepatic expression and weaker levels in kidney, intestine and white adipose tissue. Thiolase A and B expressions in the other tissues such as brain or muscle were very low though these tissues were chiefly involved in peroxisomal disorders. At the enzymatic level, thiolase activity was detected in liver, kidney, intestine and white adipose tissue but no significant difference was observed between these four tissues. Moreover, thiolase A and B genes were differently induced in liver of mice treated with fenofibrate. CONCLUSION: Two mouse thiolase genes and cDNAs were cloned. Their corresponding transcripts are mostly expressed in the liver of mice and are differently induced by fenofibrate

Issues and special features of animal health research

In the rapidly changing context of research on animal health, INRA launched a collective discussion on the challenges facing the field, its distinguishing features, and synergies with biomedical research. As has been declared forcibly by the heads of WHO, FAO and OIE, the challenges facing animal health, beyond diseases transmissible to humans, are critically important and involve food security, agriculture economics, and the ensemble of economic activities associated with agriculture. There are in addition issues related to public health (zoonoses, xenobiotics, antimicrobial resistance), the environment, and animal welfare

Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease due to mutations in the ABCD1 (ALD) gene, encoding a peroxisomal ATP-binding cassette transporter (ALDP). Overexpression of adrenoleukodystrophy-related protein, an ALDP homologue encoded by the ABCD2 (adrenoleukodystrophy-related) gene, can compensate for ALDP deficiency. 4-Phenylbutyrate (PBA) has been shown to induce both ABCD2 expression and peroxisome proliferation in human fibroblasts. We show that peroxisome proliferation with unusual shapes and clusters occurred in liver of PBA-treated rodents in a PPARα-independent way. PBA activated Abcd2 in cultured glial cells, making PBA a candidate drug for therapy of X-ALD. The Abcd2 induction observed was partially PPARα independent in hepatocytes and totally independent in fibroblasts. We demonstrate that a GC box and a CCAAT box of the Abcd2 promoter are the key elements of the PBA-dependent Abcd2 induction, histone deacetylase (HDAC)1 being recruited by the GC box. Thus, PBA is a nonclassical peroxisome proliferator inducing pleiotropic effects, including effects at the peroxisomal level mainly through HDAC inhibition

Gaia Data Release 2 Mapping the Milky Way disc kinematics

Context. The second Gaia data release (Gaia DR2) contains high-precision positions, parallaxes, and proper motions for 1.3 billion sources as well as line-of-sight velocities for 7.2 million stars brighter than G(RVS) = 12 mag. Both samples provide a full sky coverage. Aims. To illustrate the potential of Gaia DR2, we provide a first look at the kinematics of the Milky Way disc, within a radius of several kiloparsecs around the Sun. Methods. We benefit for the first time from a sample of 6.4 million F-G-K stars with full 6D phase-space coordinates, precise parallaxes (sigma((omega) over bar)/(omega) over bar Results. Gaia DR2 allows us to draw 3D maps of the Galactocentric median velocities and velocity dispersions with unprecedented accuracy, precision, and spatial resolution. The maps show the complexity and richness of the velocity field of the galactic disc. We observe streaming motions in all the components of the velocities as well as patterns in the velocity dispersions. For example, we confirm the previously reported negative and positive galactocentric radial velocity gradients in the inner and outer disc, respectively. Here, we see them as part of a non-axisymmetric kinematic oscillation, and we map its azimuthal and vertical behaviour. We also witness a new global arrangement of stars in the velocity plane of the solar neighbourhood and in distant regions in which stars are organised in thin substructures with the shape of circular arches that are oriented approximately along the horizontal direction in the U - V plane. Moreover, in distant regions, we see variations in the velocity substructures more clearly than ever before, in particular, variations in the velocity of the Hercules stream. Conclusions. Gaia DR2 provides the largest existing full 6D phase-space coordinates catalogue. It also vastly increases the number of available distances and transverse velocities with respect to Gaia DR1. Gaia DR2 offers a great wealth of information on the Milky Way and reveals clear non-axisymmetric kinematic signatures within the Galactic disc, for instance. It is now up to the astronomical community to explore its full potential.Peer reviewe

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Gaia Data Release 2 Observations of solar system objects

CONTEXT: The Gaia spacecraft of the European Space Agency (ESA) has been securing observations of solar system objects (SSOs) since the beginning of its operations. Data Release 2 (DR2) contains the observations of a selected sample of 14,099 SSOs. These asteroids have been already identified and have been numbered by the Minor Planet Center repository. Positions are provided for each Gaia observation at CCD level. As additional information, complementary to astrometry, the apparent brightness of SSOs in the unfiltered G band is also provided for selected observations. AIMS: We explain the processing of SSO data, and describe the criteria we used to select the sample published in Gaia DR2. We then explore the data set to assess its quality. METHODS: To exploit the main data product for the solar system in Gaia DR2, which is the epoch astrometry of asteroids, it is necessary to take into account the unusual properties of the uncertainty, as the position information is nearly one-dimensional. When this aspect is handled appropriately, an orbit fit can be obtained with post-fit residuals that are overall consistent with the a-priori error model that was used to define individual values of the astrometric uncertainty. The role of both random and systematic errors is described. The distribution of residuals allowed us to identify possible contaminants in the data set (such as stars). Photometry in the G band was compared to computed values from reference asteroid shapes and to the flux registered at the corresponding epochs by the red and blue photometers (RP and BP). RESULTS: The overall astrometric performance is close to the expectations, with an optimal range of brightness G ∼ 12 − 17. In this range, the typical transit-level accuracy is well below 1 mas. For fainter asteroids, the growing photon noise deteriorates the performance. Asteroids brighter than G ∼ 12 are affected by a lower performance of the processing of their signals. The dramatic improvement brought by Gaia DR2 astrometry of SSOs is demonstrated by comparisons to the archive data and by preliminary tests on the detection of subtle non-gravitational effects

Gaia Data Release 3. The Galaxy in your preferred colours: Synthetic photometry from Gaia low-resolution spectra

peer reviewedGaia Data Release 3 provides novel flux-calibrated low-resolution spectrophotometry for ≃220 million sources in the wavelength range 330 nm ≤ λ ≤ 1050 nm (XP spectra). Synthetic photometry directly tied to a flux in physical units can be obtained from these spectra for any passband fully enclosed in this wavelength range. We describe how synthetic photometry can be obtained from XP spectra, illustrating the performance that can be achieved under a range of different conditions - for example passband width and wavelength range - as well as the limits and the problems affecting it. Existing top-quality photometry can be reproduced within a few per cent over a wide range of magnitudes and colour, for wide and medium bands, and with up to millimag accuracy when synthetic photometry is standardised with respect to these external sources. Some examples of potential scientific application are presented, including the detection of multiple populations in globular clusters, the estimation of metallicity extended to the very metal-poor regime, and the classification of white dwarfs. A catalogue providing standardised photometry for ≃2.2 × 108 sources in several wide bands of widely used photometric systems is provided (Gaia Synthetic Photometry Catalogue; GSPC) as well as a catalogue of ≃105 white dwarfs with DA/non-DA classification obtained with a Random Forest algorithm (Gaia Synthetic Photometry Catalogue for White Dwarfs; GSPC-WD)