Pyridine-3-carboxamide-6-yl-ureas as novel inhibitors of bacterial DNA gyrase: Structure based design, synthesis, SAR and antimicrobial activity

The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy

Narrow band resonant grating of 100% reflection under normal incidence

9 pagesInternational audienceA resonant grating mirror comprising a multilayer submirror and a grating slab waveguide submirror exhibiting constructive mutual reflection is shown experimentally to provide zero transmission. Its reflection line width of less than 1 nm, its polarization selectivity and low overall loss make the device usable as a longitudinal mode filter in a disk laser in the 1000-1100 nm wavelength range

Transcription profiling suggests that mitochondrial topoisomerase IB acts as a topological barrier and regulator of mitochondrial DNA transcription

Mitochondrial DNA (mtDNA) is essential for cell viability because it encodes subunits of the respiratory chain complexes. Mitochondrial topoisomerase IB (TOP1MT) facilitates mtDNA replication by removing DNA topological tensions produced during mtDNA transcription, but it appears to be dispensable. To test whether cells lacking TOP1MT have aberrant mtDNA transcription, we performed mitochondrial transcriptome profiling. To that end, we designed and implemented a customized tiling array, which enabled genome-wide, strand-specific, and simultaneous detection of all mitochondrial transcripts. Our technique revealed that KO mouse cells process the mitochondrial transcripts normally but that protein-coding mitochondrial transcripts are elevated. Moreover, we found discrete long noncoding RNAs produced by H-strand transcription and encompassing the noncoding regulatory region of mtDNA in human and murine cells and tissues. Of note, these noncoding RNAs were strongly up-regulated in the absence of TOP1MT. In contrast, 7S DNA, produced by mtDNA replication, was reduced in the KO cells. We propose that the long noncoding RNA species in the D-loop region are generated by the extension of H-strand transcripts beyond their canonical stop site and that TOP1MT acts as a topological barrier and regulator for mtDNA transcription and D-loop formation

Detection of phloem restricted bacteria responsible for strawberry marginal chlorosis (SMC) by real-time PCR in a single assay

Two uncultured phloem restricted plant pathogens, the γ3 proteobacterium «Candidatus Phlomobacter fragariae » and the stolbur phytoplasma (group 16SrXII-A) are associated with strawberry marginal chlorosis (SMC) in France. As “Ca. P. fragariae” and stolbur phytoplasma induce identical symptoms, the only way to identify the pathogen infecting a given diseased plant is to perform conventional PCR assays. Because using two PCR techniques for detecting separately each of the two bacteria is time consuming and because specificity and sensitivity of the detection test needed to be improved, a new approach using triplex real time PCR was developed for the routine detection of “Ca. P. fragariae “ and stolbur phytoplasma. The real time PCR has the advantage of being faster reduces the risks of producing false positives. Furthermore, real-time PCR techniques provide the possibility of multiplexing by using probes with different compatible fluorescent dyes. Here, we present a new sensitive Taqman® method which permits the simultaneous amplification of three DNA targets in one test: the map gene of stolbur phytoplasma, the spoT gene of “Ca. P. fragariae” and the cox gene of strawberry chloroplast taken as an internal control. The specificity and the efficiency of this method were determined.Keywords: Strawberry Marginal Chlorosis, Triplex taqman® PCR ,Candidatus Phlomobacter fragariae, stolbur phytoplasma

Flying phase mask for the printing of long submicron-period stitchingless gratings

International audienceLong and stitchingless gratings are printed by means of a read/write head comprising a phase mask illuminated by an intensity modulated laser beam and a reference grating displacement sensor which dictates the modulation period real time. A nearly perfect grating copying is achieved by fixing the sensor grating scale and the written grating substrate on a long platform sliding under the read/write hea

Low-frequency radio emission in the massive galaxy cluster MACS J0717.5 + 3745

International audienceTo investigate the nonthermal emission mechanism and their interaction during cluster mergers, we analyze multiple low-frequency radio data for the X-ray luminous massive galaxy cluster MACS J0717.5 + 3745, located at z = 0.5548. Large-scale structure-formation models in the Universe suggest that galaxy clusters grow via constant accretion of gas and the merger of galaxy groups and smaller clusters. Low-frequency radio observations trace these mergers in the form of relics and halos. The dual frequency observations were performed on MACS J0717.5 + 3745 to investigate the spectral index pattern of the nonthermal emission and its interaction within the intracluster medium (ICM), during merger process. Methods: Continuum observations were carried out using GMRT at 0.235 and 0.61 GHz on MACS J0717.5 + 3745 and archival data from the VLA (0.074 and 1.42 GHz) and WSRT (0.325 GHz) was used to complement the results. Furthermore, to explore the thermal and nonthermal interactions within the ICM and the morphological distribution, Chandra X-ray and HST data were used. Results: A highly complex nonthermal radio emission distribution is seen in the cluster at very low frequencies, with a global spectral index α0.2350.61˜-1.17±0.37. We have detected a giant radio halo within the cluster system with a linear size of 1.58 Mpc and a "Chair-shaped" filament structure between the merging subclusters of linear size 853 kpc at 0.235 GHz. This is the most powerful halo ever observed with P1.4 = 9.88 × 1025 WHz-1 and an equipartition magnetic field estimate of ~6.49 μG. The bright filament structure is well located in the central merging region of subclusters with enhanced temperature, as shown by Chandra and HST data analysis, further indicating the formation of this structure due to shock waves encountered within the ICM during the merger events

Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis

Survivin is a member of the inhibitor of apoptosis gene family that is expressed in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Here, exposure of breast carcinoma MCF-7 or cervical carcinoma HeLa cells to anticancer agents, including Adriamycin, Taxol, or UVB resulted in a 4-5-fold increased survivin expression. Changes in survivin levels after anticancer treatment did not involve modulation of survivin mRNA expression and were independent of de novo gene transcription. Conversely, inhibition of survivin phosphorylation on Thr(34) by the cyclin-dependent kinase inhibitor flavopiridol resulted in loss of survivin expression, and nonphosphorylatable survivin Thr(34)--\u3eAla exhibited accelerated clearance as compared with wild-type survivin. Sequential ablation of survivin phosphorylation on Thr(34) enhanced tumor cell apoptosis induced by anticancer agents independently of p53 and suppressed tumor growth without toxicity in a breast cancer xenograft model in vivo. These data suggest that Thr(34) phosphorylation critically regulates survivin levels in tumor cells and that sequential ablation of p34(cdc2) kinase activity may remove the survivin viability checkpoint and enhance apoptosis in tumor cells