Opposing effects of retinoic acid and FGF9 on Nanos2 expression and meiotic entry of mouse germ cells

In the mouse, three genes that are homologous to the Drosophila Nanos (Nos) gene have been identified. Deletion of one of these genes, Nanos2, results in male sterility, owing to loss of germ cells during fetal life. Before apoptosis, Nanos2-null gonocytes enter meiosis, suggesting that Nanos2 functions as a meiotic repressor. Here, we show that Nanos2 is continuously expressed in male germ cells from fetal gonocytes to postnatal spermatogonial stem cells. We observed that the promeiotic factor AtRA, an analog of retinoic acid (RA), downregulates NANOS2 levels, in both fetal and postnatal gonocytes, while promoting meiosis. Interestingly, FGF9, a growth factor crucial for sex differentiation and survival of fetal gonocytes, upregulates levels of NANOS2 in both male and female primordial germ cells (PGCs) and in premeiotic spermatogonia. This effect was paralleled by an impairment of meiotic entry, suggesting that FGF9 acts as an inhibitor of meiosis through the upregulation of Nanos2. We found that NANOS2 interacts with PUM2, and that these two proteins colocalize in the ribonucleoparticle and polysomal fractions on sucrose gradients, supporting the notion that they bind RNA. Finally, we found that recombinant NANOS2 binds to two spermatogonial mRNAs, Gata2 and Taf7l, which are involved in germ-cell differentiation

Rapport de sondages et d'analyses, Le Kilian et les carrières anciennes de trachyte dans la Chaîne des Puys (Puy-de-Dôme)

En 2008, l'existence de carrières souterraines médiévales avait été mise en évidence dans la pente ouest du Bois de Manson qui domine la dépression du Cratère Kilian, au pied sud du puy de Dôme. En 2009-2010, des sondages et prospections ont été étendus à tout l'ensemble du Kilian de façon à préciser l'étendue et, si possible, la chronologie de son exploitation dans le passé. Ces travaux ont permis d'observer, dans le fond du cratère et sur son flanc interne ouest, des amoncellements de déblais d'un volume considérable, témoignant d'une extraction de roche à grande échelle durant le haut Moyen Âge et très probablement aussi à l'époque gallo-romaine. Une nouvelle carrière souterraine a été découverte dans la pente interne ouest du cratère. La base du remplissage de cette carrière a livré des charbons datés entre la fin du IV e siècle et le début du VI e siècle par le radiocarbone, tandis que le sommet du remplissage contenait des tessons de céramique datables, par leur typologie, de la fin du V e siècle au début du VIII e siècle. L'état actuel des investigations conduit à faire l'hypothèse que les gallo-romains ont exploité, au fond du cratère, un trachyte compact dont on ne trouve aujourd'hui que les déchets de taille, et dont les affleurements sont masqués par les déblais, tandis que les artisans du Moyen Âge ont recherché un trachyte plus tendre dans les pentes hautes du cratère. Le Kilian doit donc s'ajouter aux trois sources actuellement connues de trachyte d'oeuvre dans le passé, à savoir les volcans Sarcoui, Aumône (ou petit Suchet) et Cliersou. Dès cette découverte, en 2008, s'est posée la question de savoir quelle part éventuelle le trachyte du Kilian avait pu prendre dans la construction du temple de Mercure au sommet du puy de Dôme et dans l'agglomération gallo-romaine située au col de Ceyssat. Pour y répondre, une campagne d'analyses géochimiques et pétrographiques été engagée pour caractériser, aux fins de comparaison, non seulement les trachytes du Kilian et ceux des ruines gallo-romaines, mais, de plus, les trachytes du Cliersou, de l'Aumône et du Sarcoui. Ces analyses ont finalement montré qu'il est possible de faire une discrimination statistiquement significative entre les différents trachytes étudiés, à l'exception de ceux du couple Cliersou-Aumône dont les laves sont très peu différentes les unes des autres. Le résultat le plus remarquable est que tous les trachytes gallo-romains échantillonnés (dont 10 échantillons distincts au temple de Mercure et 10 au col de Ceyssat) se rattachent sans ambiguïté au Kilian. En toute rigueur, ces nouvelles données ne permettent pas d'exclure sans appel la possibilité d'utilisation à l'époque gallo-romaine, au temple de Mercure et au col de Ceyssat, de trachytes provenant d'autres sources que le Kilian (cas des chaperons de mur du col de Ceyssat, provenant du puy de Dôme). Cependant, il faut ajouter qu'un examen visuel des trachytes d'oeuvre dans ces deux sites, portant sur un nombre de moellons et d'éléments architecturaux bien supérieur au nombre de ceux qui ont été analysés, conduit à conclure que leur source est probablement commune. Cette conclusion est basée sur un faciès minéralogique particulier, observable à l'oeil nu ou à la loupe

Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin

<p>Abstract</p> <p>Background</p> <p>The natural polyether ionophorous antibiotics are used for the treatment of coccidiosis in poultry and ruminants. They are effective agents against infections caused by Gram-positive microorganisms. On the other hand, it was found that some of these compounds selectively bind lead(II) ions in <it>in vivo </it>experiments, despite so far no Pb(II)-containing compounds of defined composition have been isolated and characterized. To assess the potential of polyether ionophores as possible antidotes in the agriculture, a detailed study on their <it>in vitro </it>complexation with toxic metal ions is required. In the present paper we report for the first time the preparation and the structure elucidation of salinomycin complexes with ions of cadmium(II) and lead(II).</p> <p>Results</p> <p>New metal(II) complexes of the polyether ionophorous antibiotic salinomycin with Cd(II) and Pb(II) ions were prepared and structurally characterized by IR, FAB-MS and NMR techniques. The spectroscopic information and elemental analysis data reveal that sodium salinomycin (SalNa) undergoes a reaction with heavy metal(II) ions to form [Cd(Sal)₂(H₂O)₂] (<b>1</b>) and [Pb(Sal)(NO₃)] (<b>2</b>), respectively. Abstraction of sodium ions from the cavity of the antibiotic is occurring during the complexation reaction. Salinomycin coordinates with cadmium(II) ions as a bidentate monoanionic ligand through the deprotonated carboxylic moiety and one of the hydroxyl groups to yield <b>1</b>. Two salinomycin anions occupy the equatorial plane of the Cd(II) center, while two water molecules take the axial positions of the inner coordination sphere of the metal(II) cation. Complex <b>2 </b>consists of monoanionic salinomycin acting in polydentate coordination mode in a molar ratio of 1: 1 to the metal ion with one nitrate ion for charge compensation.</p> <p>Conclusion</p> <p>The formation of the salinomycin heavy metal(II) complexes indicates a possible antidote activity of the ligand in case of chronic/acute intoxications likely to occur in the stock farming.</p

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Blood progenitors within the lymph gland, a larval organ that supports hematopoiesis in Drosophila melanogaster, are maintained by integrating signals emanating from niche-like cells and those from differentiating blood cells. We term the signal from differentiating cells the ‘equilibrium signal’ in order to distinguish it from the ‘niche signal’. Earlier we showed that equilibrium signaling utilizes Pvr (the Drosophila PDGF/VEGF receptor), STAT92E, and adenosine deaminase-related growth factor A (ADGF-A) (Mondal et al., 2011). Little is known about how this signal initiates during hematopoietic development. To identify new genes involved in lymph gland blood progenitor maintenance, particularly those involved in equilibrium signaling, we performed a genetic screen that identified bip1 (bric à brac interacting protein 1) and Nucleoporin 98 (Nup98) as additional regulators of the equilibrium signal. We show that the products of these genes along with the Bip1-interacting protein RpS8 (Ribosomal protein S8) are required for the proper expression of Pvr. DOI: http://dx.doi.org/10.7554/eLife.03626.00

Macrocyclic 14-membered ring diketal diamines: Synthesis, conformational analysis and 99m Tc radiolabeling evaluation

Chiral and achiral macrocyclic diketal diamines, analogs of cyclams, were synthesized from the previously obtained corresponding diketal dilactams by reduction with lithium aluminum hydride in the presence of a trace amount of triethylamine. In the (15-30) × 10-3 M concentration range, the reaction led mainly to the expected doubly reduced compounds except in the trans-OMe substituted series (R = Ph, Me), in which it partially stopped at the single reduction stage. A conformational study conducted by liquid NMR spectroscopy and molecular mechanics calculations showed that the most stable conformations were either set in a rectangular [3434]-type structure for trans-OMe compounds 7b (R = Me) and 10b (R = H) or stabilized by two intramolecular NH···O hydrogen bonds for all the other macrocyclic diamines. Tc-99m radiolabeling with the nitrido-technetium core [TcN]2+ gave 10-20 % exchange yield

Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Prkar1a Knockout Mice

Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD