A novel inhibitor of channel activating proteases: Putting the CAP on ENaC

Background: Excessive activation of epithelial sodium channels (ENaC) contributes to CF lung pathophysiology due to the resultant dehydration of the airway surface liquid (ASL) and impaired mucociliary clearance. Regulated proteolysis of the endogenous α and γ subunits of ENaC by apical membrane-bound Channel Activating Proteases (CAPs) is a fundamental regulatory mechanism for channel activity. In the CF lung a stark imbalance between the levels of CAPs and their natural inhibitors drives the activation of normally inactive ENaC. On this basis inhibition of CAPs-ENaC signalling represents a potential therapeutic intervention. To this end we have developed a novel cell impermeable active-site directed compound (QUB-TL1) designed to inactivate key trypsin-like CAPs highly relevant in this regard. Objectives & Methods: Utilize differentiated non-CF and CF human airway epithelial cells to assess the impact of QUB-TL1 on a range of parameters including surface CAP activities, ENaC subunit processing/channel activity, ASL height and mucociliary clearance. Results: Treatment of airway epithelial cells with QUB-TL1 results in the significant downregulation of key endogenous CAP activities found to be excessively active at the surface of CF cultures. QUB-TL1-mediated CAP inhibition subsequently causes the internalisation of a pool of processed (active) ENaCγ prominent at the apical surface of CF cultures which correlates with a decline in channel activity. This downregulation of ENaC activity results in an increase in ASL height and improved mucociliary clearance in CF cells. We further find QUB-TL1 uniquely inhibits the ENaC activating enzyme furin, which is in contrast to the alternate trypsin-like CAP inhibitors camostat mesylate and aprotinin. QUB-TL1-mediated furin inhibition correlates with a reduction in neutrophil elastase-induced ENaC activation. Moreover we find QUB-TL1 treatment protects CF cultures from Pseudomonas aeruginosa exotoxin A-induced cytotoxicity. Pseudomonas aeruginosa exotoxin A is a major toxic product activated by furin and positively associated with mortality. Conclusion: The novel inhibitor (QUB-TL1) dampens CAPs-ENaC signalling which improves hydration status mucociliary clearance in CF airway epithelial cell cultures. Moreover this compound provides additional benefit by preventing Pseudomonas aeruginosa exotoxin A-induced cytotoxicity.

Libraries and Canon-Formation: the Case of English in the Collections of the Library of the Faculty of Humanities, Lisbon University

Abstract: The project for researching the role played by libraries in canon-formation (namely through their policies regarding the creation, organization, preservation, and utilization of the collections) will be presented and discussed. We selected the Library of the Faculty of Humanities, Lisbon University, a modern academic library, created in 1859, by royal decree of D. Pedro V, following his canonical choice. Actually, the two contemporary rulers of new Britannia— Prince Albert, his cousin, and Queen Victoria—held this king in high consideration for his outstanding contribution to Portuguese modernisation. Representing various fields of study, the collections were decisive to canon-formation in the Faculty of Humanities. Thus, we have been trying to answer the following questions: who has been creating, organizing, preserving, and utilizing the collections, from the mid-nineteenth century onwards? When, where and how? Presently, we are studying the collections in English, namely the works belonging or referring to the long nineteenth century. Richard Garnett’s “The International Library of Famous Literature” (London, 1899) is our first case-study. The anthology determined the Western literary, cultural and visual canon at the turning of the century, as evidenced by comparing it to the Portuguese and Spanish editions, published at the beginning of the twentieth century.

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...