Design of the citadel of Bonifacio urban area through experimental and numerical assessment of pedestrian comfort

International audienceThis paper presented a study on the optimization of the pedestrian comfort in the citadel of Bonifacio, the windiest city of Europe. Urbalterre, the urban architect agency in charge of the project combined Wind Tunnel and CFD simulations to assess and optimize the pedestrian wind comfort. The first step was an evaluation of the wind statistics at the district location. Weather data from the nearest weather station was extrapolated to Bonifacio using CFD simulations on a domain of several kilometers to take into account the local orography and roughness. The design of the district was then performed in three steps. A first assessment was carried out in wind tunnel using Particle Image Velocimetry. To our knowledge, very few studies used this type of measurements to assess wind comfort. This kind of measurements indeed requires special care to obtain sufficient accuracy due to the proximity of the laser sheet from the ground. Velocity measurements were combined with weather data to compute a wind comfort criterion. Results highlighted severe comfort issues which require an optimization of the district. A second step consists of optimization carried out by the urban architects of Urbalterre themselves thanks to the UrbaWind CFD solution. Good correlations between wind tunnel and CFD results were observed. On some locations, CFD results presented lower wind mean speed values for some Venturi effects compared to the wind tunnel results. CFD tool allowed the urban architects to iterate several versions of the district and to convergence towards an optimal solution. The use of vegetation leads to an optimized version of the district which was finally tested again in the wind tunnel. Final adjustments were performed directly in the wind tunnel using PIV measurements to optimize a Venturi effect between two buildings. The main interest of this study is the combination of PIV measurements, which proved to be a very efficient tool to assess wind comfort in wind tunnel, and CFD simulations which were carried out by the urban architects themselves to iterate various solutions. The configuration of the Montlaur Citadel, due its location above 60m cliffs and the impressive statistics of the wind blowing on the South of Corsica Island, was a tough challenge regarding the optimization of pedestrian wind comfort. Again, the use of the vegetation has proven to be one of the most efficient way to optimize pedestrian wind comfort when designing a urban area

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Numerical coupling model to compute the microclimate parameters inside a street canyon. Part II: Experimental validation of air temperature and airflow

International audienc

Global Decrease of Histone H3K27 Acetylation in ZEB1-Induced Epithelial to Mesenchymal Transition in Lung Cancer Cells

cancer

The final assembly of trehalose polyphleates takes place within the outer layer of the mycobacterial cell envelope

International audienc

Solution structure of the type I polyketide synthase Pks13 from Mycobacterium tuberculosis

International audienceBackground: Type I polyketide synthases (PKSs) are multifunctional enzymes responsible for the biosynthesis of a group of diverse natural compounds with biotechnological and pharmaceutical interest called polyketides. The diversity of polyketides is impressive despite the limited set of catalytic domains used by PKSs for biosynthesis, leading to considerable interest in deciphering their structure-function relationships, which is challenging due to high intrinsic flexibility. Among nineteen polyketide synthases encoded by the genome of Mycobacterium tuberculosis, Pks13 is the condensase required for the final condensation step of two long acyl chains in the biosynthetic pathway of mycolic acids, essential components of the cell envelope of Corynebacterineae species. It has been validated as a promising druggable target and knowledge of its structure is essential to speed up drug discovery to fight against tuberculosis. Results: We report here a quasi-atomic model of Pks13 obtained using small-angle X-ray scattering of the entire protein and various molecular subspecies combined with known high-resolution structures of Pks13 domains or structural homologues. As a comparison, the low-resolution structures of two other mycobacterial polyketide synthases, Mas and PpsA from Mycobacterium bovis BCG, are also presented. This study highlights a monomeric and elongated state of the enzyme with the apo-and holo-forms being identical at the resolution probed. Catalytic domains are segregated into two parts, which correspond to the condensation reaction per se and to the release of the product, a pivot for the enzyme flexibility being at the interface. The two acyl carrier protein domains are found at opposite sides of the ketosynthase domain and display distinct characteristics in terms of flexibility. Conclusions: The Pks13 model reported here provides the first structural information on the molecular mechanism of this complex enzyme and opens up new perspectives to develop inhibitors that target the interactions with its enzymatic partners or between catalytic domains within Pks13 itself

Solution structure of the type I polyketide synthase Pks13 from Mycobacterium tuberculosis

BackgroundType I polyketide synthases (PKSs) are multifunctional enzymes responsible for the biosynthesis of a group of diverse natural compounds with biotechnological and pharmaceutical interest called polyketides. The diversity of polyketides is impressive despite the limited set of catalytic domains used by PKSs for biosynthesis, leading to considerable interest in deciphering their structure‐function relationships, which is challenging due to high intrinsic flexibility. Among nineteen polyketide synthases encoded by the genome of Mycobacterium tuberculosis, Pks13 is the condensase required for the final condensation step of two long acyl chains in the biosynthetic pathway of mycolic acids, essential components of the cell envelope of Corynebacterineae species. It has been validated as a promising druggable target and knowledge of its structure is essential to speed up drug discovery to fight against tuberculosis.ResultsWe report here a quasi-atomic model of Pks13 obtained using small-angle X-ray scattering of the entire protein and various molecular subspecies combined with known high-resolution structures of Pks13 domains or structural homologues. As a comparison, the low-resolution structures of two other mycobacterial polyketide synthases, Mas and PpsA from Mycobacterium bovis BCG, are also presented. This study highlights a monomeric and elongated state of the enzyme with the apo- and holo-forms being identical at the resolution probed. Catalytic domains are segregated into two parts, which correspond to the condensation reaction per se and to the release of the product, a pivot for the enzyme flexibility being at the interface. The two acyl carrier protein domains are found at opposite sides of the ketosynthase domain and display distinct characteristics in terms of flexibility.ConclusionsThe Pks13 model reported here provides the first structural information on the molecular mechanism of this complex enzyme and opens up new perspectives to develop inhibitors that target the interactions with its enzymatic partners or between catalytic domains within Pks13 itself

The downregulation of BAP1 expression by BCR-ABL reduces the stability of BRCA1 in chronic myeloid leukemia.

BCR ABLInternational audienceBCR-ABL induces an intrinsic genetic instability in chronic myeloid leukemia (CML). The protein breast cancer 1, early onset (BRCA1)-associated protein 1 (BAP1) is a deubiquitinase interacting with the DNA repair regulator BRCA1 and is frequently inactivated in many cancers. Here, we report that BAP1 mRNA and protein levels are downregulated in a BCR-ABL1-expressing hematopoietic cell line (UT-7/11). A decrease of BAP1 transcripts is also observed in newly diagnosed CML patients. Moreover, BAP1 protein levels are low or undetectable in CD34(+) cells from CML patients at diagnosis as compared with CD34(+) cells from normal donors. In addition, BRCA1 protein level is reduced in BCR-ABL1-expressing UT-7/11 cells. Finally, the enforced expression of BAP1 is associated with BRCA1 protein deubiquitination and restoration. These results demonstrate BAP1 as a major link with the BCR-ABL-induced downregulation of BRCA1 in CML

Protein O-mannosylation deficiency increases LprG-associated lipoarabinomannan release by Mycobacterium tuberculosis and enhances the TLR2-associated inflammatory response

International audienc