Cholesterol 24S-Hydroxylase overexpression inhibits the liver X receptor (LXR) pathway by activating small guanosine triphosphate-binding proteins (sGTPases) in neuronal cells

The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATP-binding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominant-negative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.

Using social semantic knowledge to improve annotations in personal photo collections

Instituto Politécnico de Lisboa (IPL) e Instituto Superior de Engenharia de Lisboa (ISEL)apoio concedido pela bolsa SPRH/PROTEC/67580/2010, que apoiou parcialmente este trabalho

Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis.

RATIONALE: Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and the IL-1 receptor 1 (IL-1R1) signaling pathway. The molecular mechanisms by which lung injury triggers IL-1beta production, inflammation, and fibrosis remain poorly understood. OBJECTIVES: To determine if lung injury depends on the NALP3 inflammasome and if bleomycin (BLM)-induced lung injury triggers local production of uric acid, thereby activating the NALP3 inflammasome in the lung. Methods: Inflammation upon BLM administration was evaluated in vivo in inflammasome-deficient mice. Pulmonary uric acid accumulation, inflammation, and fibrosis were analyzed in mice treated with the inhibitor of uric acid synthesis or with uricase, which degrades uric acid. MEASUREMENTS AND MAIN RESULTS: Lung injury depends on the NALP3 inflammasome, which is triggered by uric acid locally produced in the lung upon BLM-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase leads to a decrease in BLM-induced IL-1beta production, lung inflammation, repair, and fibrosis. Local administration of exogenous uric acid crystals recapitulates lung inflammation and repair, which depend on the NALP3 inflammasome, MyD88, and IL-1R1 pathways and Toll-like receptor (TLR)2 and TLR4 for optimal inflammation but are independent of the IL-18 receptor. CONCLUSIONS: Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology.

ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1.

Sodium transport via epithelial sodium channels (ENaC) expressed in alveolar epithelial cells (AEC) provides the driving force for removal of fluid from the alveolar space. The membrane-bound channel-activating protease 1 (CAP1/Prss8) activates ENaC in vitro in various expression systems. To study the role of CAP1/Prss8 in alveolar sodium transport and lung fluid balance in vivo, we generated mice lacking CAP1/Prss8 in the alveolar epithelium using conditional Cre-loxP-mediated recombination. Deficiency of CAP1/Prss8 in AEC induced in vitro a 40% decrease in ENaC-mediated sodium currents. Sodium-driven alveolar fluid clearance (AFC) was reduced in CAP1/Prss8-deficient mice, due to a 48% decrease in amiloride-sensitive clearance, and was less sensitive to beta(2)-agonist treatment. Intra-alveolar treatment with neutrophil elastase, a soluble serine protease activating ENaC at the cell surface, fully restored basal AFC and the stimulation by beta(2)-agonists. Finally, acute volume-overload increased alveolar lining fluid volume in CAP1/Prss8-deficient mice. This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance.

L'Archiviste : revue historique et documentaire publiée d'après des documents tirés des collections publiques et privées de la France et de l'étranger / sous la direction de L. Séché

1892/12 (T1,N1)-1893/06 (T1,N9).

L'Archiviste : revue historique et documentaire publiée d'après des documents tirés des collections publiques et privées de la France et de l'étranger / sous la direction de L. Séché

1893/07 (T2,N10)-1893/10 (T2,N13).

[4 phot. de monuments musulmans en France, 3 du cimetière musulman au Père-Lachaise à Paris, 1 d'une gravure représentant la mosquée Mahomet à Buzancy (Ardennes), le tout dû à la Photogravure parisienne de monuments historiques, 30, boulevard Saint-Germain. Des collections du prince R. Bonaparte]

Donateur : Bonaparte, Roland (1858-1924)

[Vases grecs de diverses collections] : [relevés d'objets et de décors] / [recueillis par Aubin-Louis Millin]

Collectionneur : Millin, Aubin-Louis (1759-1818)

Mémoires authentiques de Jacques-Nompar de Caumont, duc de La Force,... et de ses deux fils, les marquis de Montpouillan et de Castelnaut, suivis de documents curieux et de correspondances inédites de Jeanne d'Albret, Henri III, Henri IV, Catherine de Bourbon,... et autres personnages marquants, depuis la Saint-Barthélemy jusqu'à la Fronde, pour faire suite à toutes les collections de mémoires sur l'histoire de France / recueillis, mis en ordre et précédés d'une introduction, par le Mis de La Grange,...

Comprend : [Correspondance inédite] ; Lettres ; Correspondances inédites...

Mémoires authentiques de Jacques-Nompar de Caumont, duc de La Force,... et de ses deux fils, les marquis de Montpouillan et de Castelnaut, suivis de documents curieux et de correspondances inédites de Jeanne d'Albret, Henri III, Henri IV, Catherine de Bourbon,... et autres personnages marquants, depuis la Saint-Barthélemy jusqu'à la Fronde, pour faire suite à toutes les collections de mémoires sur l'histoire de France / recueillis, mis en ordre et précédés d'une introduction, par le Mis de La Grange,...

Comprend : [Correspondance inédite] ; Lettres ; Correspondances inédites...

Mémoires authentiques de Jacques-Nompar de Caumont, duc de La Force,... et de ses deux fils, les marquis de Montpouillan et de Castelnaut, suivis de documents curieux et de correspondances inédites de Jeanne d'Albret, Henri III, Henri IV, Catherine de Bourbon,... et autres personnages marquants, depuis la Saint-Barthélemy jusqu'à la Fronde, pour faire suite à toutes les collections de mémoires sur l'histoire de France / recueillis, mis en ordre et précédés d'une introduction, par le Mis de La Grange,...

Comprend : [Correspondance inédite] ; Lettres ; Correspondances inédites...

Collections canoniques.

Notice des cités de la Gaule (1v). Glossaire canonique, renfermant des mots germaniques (12v). Collection de Denys le Petit (17v). Pénitentiel de Théodore (153). Canons de Martin de Brague (156v). Canons remis par Adrien Ier à Angilramnus, év. de Metz (163), suivis d'une adhésion de Hincmar (166v). Extraits du Code théodosien (187v).