Differential binding of the transcription factors Sp1, AP-1, and NFI to the promoter of the human α5 integrin gene dictates its transcriptional activity

Purpose. Damage to the corneal epithelium results in the massive secretion of fibronectin (FN) shortly after injury and induces the expression of its integrin receptor α5β1. The authors reported previously that FN induces α5 expression in human corneal epithelial cells and rabbit corneal epithelial cells by altering the binding of the transcription factor (TF) Sp1 to a regulatory element from the α5 promoter that it is also flanked by binding sites for the TFs NFI and AP-1. Here, they assessed the function of NFI and AP-1 on α5 gene expression and evaluated the contribution of FN to their overall regulatory influence. Methods. TF binding to the α5 promoter was evaluated in vitro by electrophoretic mobility shift assays and in vivo by ligation-mediated PCR or chromatin immunoprecipitation. TFs expression was monitored by Western blot, whereas their influence was assessed by transfection and RNAi analyses. Results. Coexpression of Sp1, NFI, and AP-1 was demonstrated in all cell types, and each TF was shown to bind efficiently to the α5 promoter. Whereas both AP-1 and Sp1 activated expression directed by the α5 promoter, NFI functioned as a potent repressor of that gene. Interestingly, FN could either promote or repress α5 promoter activity in a cell density–dependent manner by differentially altering the ratio of these TFs. Conclusions. These results suggest that α5 gene expression is likely dictated by subtle alterations in the nuclear ratio of TFs that either repress (NFI) or activate (Sp1 and AP-1) α5 transcription in corneal epithelial cells

Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: Application to acetaminophen injury

International audienceWe have analyzed transcriptomic, proteomic and metabolomic profiles of hepatoma cells cultivated inside a microfluidic biochip with or without acetaminophen (APAP). Without APAP, the results show an adaptive cellular response to the microfluidic environment, leading to the induction of anti-oxidative stress and cytoprotective pathways. In presence of APAP, calcium homeostasis perturbation, lipid peroxidation and cell death are observed. These effects can be attributed to APAP metabolism into its highly reactive metabolite. N-acetyl-p-benzoquinone imine (NAPQI). That toxicity pathway was confirmed by the detection of GSH-APAP, the large production of 2-hydroxybutyrate and 3-hydroxybutyrate, and methionine, cystine, and histidine consumption in the treated biochips. Those metabolites have been reported as specific biomarkers of hepatotoxicity and glutathione depletion in the literature. In addition, the integration of the metabolomic, transcriptomic and proteomic collected profiles allowed a more complete reconstruction of the APAP injury pathways. To our knowledge, this work is the first example of a global integration of microfluidic biochip data in toxicity assessment. Our results demonstrate the potential of that new approach to predictive toxicology

Delayed Treatment with Systemic (S)-Roscovitine Provides Neuroprotection and Inhibits In Vivo CDK5 Activity Increase in Animal Stroke Models

Although quite challenging, neuroprotective therapies in ischemic stroke remain an interesting strategy to counter mechanisms of ischemic injury and reduce brain tissue damage. Among potential neuroprotective drug, cyclin-dependent kinases (CDK) inhibitors represent interesting therapeutic candidates. Increasing evidence indisputably links cell cycle CDKs and CDK5 to the pathogenesis of stroke. Although recent studies have demonstrated promising neuroprotective efficacies of pharmacological CDK inhibitors in related animal models, none of them were however clinically relevant to human treatment.In the present study, we report that systemic delivery of (S)-roscovitine, a well known inhibitor of mitotic CDKs and CDK5, was neuroprotective in a dose-dependent manner in two models of focal ischemia, as recommended by STAIR guidelines. We show that (S)-roscovitine was able to cross the blood brain barrier. (S)-roscovitine significant in vivo positive effect remained when the compound was systemically administered 2 hrs after the insult. Moreover, we validate one of (S)-roscovitine in vivo target after ischemia. Cerebral increase of CDK5/p25 activity was observed 3 hrs after the insult and prevented by systemic (S)-roscovitine administration. Our results show therefore that roscovitine protects in vivo neurons possibly through CDK5 dependent mechanisms.Altogether, our data bring new evidences for the further development of pharmacological CDK inhibitors in stroke therapy

No caminho para o urbanismo. Saturnino de Brito e Édouard Imbeaux, trajetórias profissionais entre Brasil e França

The aim of this work is to establish a dialogue between the professional trajectories of two engineers: Saturnino de Brito (1864-1929) and Édouard Imbeaux (1861-1943). They both focussed on the city as object of action and reflection based on an innovative knowledge of hygiene and sanitation issues. The specificity of these trajectories is the association of practice, theoretical reflection and dissemination: these two professionals respectively contributed, in their countries, to the construction of Town planning as a discipline, in particular in relation to its technical approach. The international scene is an important dimension of their activity as it made possible the circulation / comparison of technical knowledge between Europe and Brazil and it contributed to find a specific and appropriate response to the problems of the city. The interaction of local, national and international scene allows another perspective of the professional trajectories of Saturnino de Brito and Edouard Imbeaux.O objetivo deste trabalho é estabelecer um diálogo entre duas trajetórias profissionais, a de Saturnino de Brito (1864-1929) e a de Édouard Imbeaux (1861-1943), que privilegiaram a cidade como objeto de ação e de reflexão, as quais são construídas a partir de um conhecimento inovador sobre as questões de higiene e saneamento. A especificidade desses percursos é a associação da prática com a reflexão teórica e sua difusão: estes dois profissionais contribuíram, assim, cada um em seu país, para a construção da disciplina urbanística, especialmente em sua abordagem técnica. O cenário internacional constitui uma dimensão importante de sua ação, que tornou possível a circulação/confronto de saberes técnicos entre Europa e Brasil e contribuiu com a pesquisa de uma resposta concreta e adaptada aos problemas da cidade. A interação do cenário local, nacional e internacional permite trazer um outro olhar sobre as trajetórias profissionais de Saturnino de Brito e Édouard Imbeaux

Urbanisme national-socialiste en France, les projets pour le « Nouveau Strasbourg », 1940-1944

National-socialist urbanisation in France, schemes for the “Nouveau Strasbourg ” (1940-1944). After their victory in June 1940, the nazis started a new political reorganisation which included the annexation of the Alsace region to the Bade Land and a new status for Strasbourg as the capital of the New Upper Rhine province. A competition was organised by Albert Speer in January 1941 for the plan of the “Nouveau Strasbourg”, Hitler himself had made a sketch. The drawings and representations of five of the eight projects then proposed have been kept ; they are unequalled as a testimony of the nazi techniques and architectural designs on the French territory.Leclerc Bénédicte. Urbanisme national-socialiste en France, les projets pour le « Nouveau Strasbourg », 1940-1944. In: Histoire de l'art, N°1-2, 1988. Architecture. pp. 61-74

L'héritage de J.C.N. Forestier dans l'œuvre de MA. Quevedo

From Paris to Mexico, through Morocco, Spain, Portugal, Argentina, Cuba or the United States, Jean-Claude Nicolas Forestier (1861-1920), preserver of the promenades in Paris and a prominent figure at the French School of Urbanism, refined, through the concept of "park systems", the tools of urban planning from the dawn of the 20th century. They were put into use starting in 1911 by another engineer who became friends with Forestier, Miguel Angel de Quevedo (1862-1946) when he proposed the "Piano del Distrito Federal con indicaciones de las réservas forestales de la ciudad de México".De Paris à Mexico, via le Maroc, l'Espagne, le Portugal, l'Argentine, Cuba ou les USA, Jean-Claude Nicolas Forestier (1861-1930), Conservateur des promenades de Paris, figure tutélaire de l'Ecole française d'urbanisme, affine, à travers le concept de système de parcs, des outils de planification de la forme urbaine au début du XXe siècle. Ceux-ci sont mis en œuvre, dès 1911 par un autre ingénieur devenu son ami, Miguel Angel de Quevedo (1862-1946) lorsque celui-ci propose le «Piano del Distrito Federal con indicaciones de las réservas forestales de la ciudad de México ».De Paris a México, a través de Marruecos, Espana, Portugal, Argentina, Cuba o Estados Unidos, Jean-Claude Nicolas Forestier (1861-1920), conservador de los paseos de París y figura tutelar de la Escuela francesa de urbanismo, refina, a través del concepto de «sistema de parques», las herramientas de la planificación de la forma urbana desde los inicios del siglo XX. Éstas ponen en marcha desde 1911 por otro ingeniero que se convirtió en su amigo, Miguel Ángel de Quevedo (1862-1946) al proponer el «Plano del Distrito Federal con indicaciones de las reservas forestales de la ciudad de México».Leclerc Bénédicte. L'héritage de J.C.N. Forestier dans l'œuvre de MA. Quevedo. In: Villes en parallèle, n°45-46, juin 2012. Paris – Mexico en reflet. pp. 284-309

La herencia de J.C.N. Forestier a travès de Miguel Ángel de Quevedo

Leclerc Bénédicte. La herencia de J.C.N. Forestier a travès de Miguel Ángel de Quevedo. In: Villes en parallèle, n°45-46, juin 2012. Paris – Mexico en reflet. pp. 310-313

L’accueil des très jeunes enfants dans la Manche [Des tensions localisées dans le Sud-Manche]

Leclerc Bénédicte, Piveteau Bruno. L’accueil des très jeunes enfants dans la Manche [Des tensions localisées dans le Sud-Manche]. In: Recherches et Prévisions, n°80, 2005. Acteurs et politiques de la petite enfance. Permanences et mutations. pp. 125-132

Transformation urbaine et projet architectural: I. Le Wacken dans "la ceinture verte" de Strasbourg. II. Les fronts du Neudorf dans "la ceinture verte" de Strasbourg. III. La "ceinture verte" de Strasbourg

Étude de l'évolution urbaine et architecturale de la zone de Wacken et de la ceinture verte à Strasbourg, depuis la fin du XVIIe siècle jusqu'à nos jours à partir des archives de la vill

FiberGrowth Pipeline: A Framework Toward Predicting Fiber-Specific Growth From Human Gut Bacteroidetes Genomes

International audienceDietary fibers impact gut colonic health, through the production of short-chain fatty acids. A low-fiber diet has been linked to lower bacterial diversity, obesity, type 2 diabetes, and promotion of mucosal pathogens. Glycoside hydrolases (GHs) are important enzymes involved in the bacterial catabolism of fiber into short-chain fatty acids. However, the GH involved in glycan breakdown (adhesion, hydrolysis, and fermentation) are organized in polysaccharide utilization loci (PUL) with complex modularity. Our goal was to explore how the capacity of strains, from the Bacteroidetes phylum, to grow on fiber could be predicted from their genome sequences. We designed an in silico pipeline called FiberGrowth and independently validated it for seven different fibers, on 28 genomes from Bacteroidetes-type strains. To do so, we compared the existing GH annotation tools and built PUL models by using published growth and gene expression data. FiberGrowth’s prediction performance in terms of true positive rate (TPR) and false positive rate (FPR) strongly depended on available data and fiber: arabinoxylan (TPR: 0.89 and FPR: 0), inulin (0.95 and 0.33), heparin (0.8 and 0.22) laminarin (0.38 and 0.17), levan (0.3 and 0.06), mucus (0.13 and 0.38), and starch (0.73 and 0.41). Being able to better predict fiber breakdown by bacterial strains would help to understand their impact on human nutrition and health. Assuming further gene expression experiment along with discoveries on structural analysis, we hope computational tools like FiberGrowth will help researchers prioritize and design in vitro experiments