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111.
Adel Nefzi Jon Appel Sergey Arutyunyan Richard A. Houghten 《Bioorganic & medicinal chemistry letters》2009,19(17):5169-5175
Combinatorial chemistry offers a unique opportunity for the synthesis and screening of large numbers of compounds and significantly enhances the prospect of finding new drugs. Collaborative efforts with the Tuberculosis Antimicrobial Acquisition & Coordinating Facility (TAACF), have led to the identification of submicromolar novel antitubercular hits. Chiral pentaamines and bis-heterocyclic compounds with 90–100% inhibition against Mycobacterium tuberculosis strain H37Rv were identified. Some of the identified compounds are more active than the existing drug ethambutol. 相似文献
112.
Hugues Massimba Dibama Igor Clarot Stéphane Fontanay Adel Ben Salem Maxime Mourer Chantal Finance Raphaël E. Duval Jean-Bernard Regnouf-de-Vains 《Bioorganic & medicinal chemistry letters》2009,19(10):2679-2682
A water-soluble calixarene-based heterocyclic podand incorporating a quinolone antibiotic subunit, the nalidixic acid, was synthesised and fully characterised. Its prodrug behaviour was assessed in vitro by HPLC, demonstrating the release of the tethered quinolone in model biological conditions. Microbiological studies performed on various Gram-positive and Gram-negative reference strains showed very interesting antibacterial activities. 相似文献
113.
Quantification of Key Genes Steering the Microbial Nitrogen Cycle in the Rhizosphere of Sorghum Cultivars in Tropical Agroecosystems 总被引:2,自引:0,他引:2
Brigitte Hai Ndeye Hélène Diallo Saidou Sall Felix Haesler Kristina Schauss Moussa Bonzi Komi Assigbetse Jean-Luc Chotte Jean Charles Munch Michael Schloter 《Applied and environmental microbiology》2009,75(15):4993-5000
The effect of agricultural management practices on geochemical cycles in moderate ecosystems is by far better understood than in semiarid regions, where fertilizer availability and climatic conditions are less favorable. We studied the impact of different fertilizer regimens in an agricultural long-term observatory in Burkina Faso at three different plant development stages (early leaf development, flowering, and senescence) of sorghum cultivars. Using real-time PCR, we investigated functional microbial communities involved in key processes of the nitrogen cycle (nitrogen fixation, ammonia oxidation, and denitrification) in the rhizosphere. The results indicate that fertilizer treatments and plant development stages combined with environmental factors affected the abundance of the targeted functional genes in the rhizosphere. While nitrogen-fixing populations dominated the investigated communities when organic fertilizers (manure and straw) were applied, their numbers were comparatively reduced in urea-treated plots. In contrast, ammonia-oxidizing bacteria (AOB) increased not only in absolute numbers but also in relation to the other bacterial groups investigated in the urea-amended plots. Ammonia-oxidizing archaea exhibited higher numbers compared to AOB independent of fertilizer application. Similarly, denitrifiers were also more abundant in the urea-treated plots. Our data imply as well that, more than in moderate regions, water availability might shape microbial communities in the rhizosphere, since low gene abundance data were obtained for all tested genes at the flowering stage, when water availability was very limited.Land degradation is one of the most serious threats to food production on the African continent. Soil erosion, nutrient depletion, low organic matter content, and unfavorable pH values are some of the reasons for a deficient soil fertility (30), mainly in Central African countries. Combined with high variability and irregular distribution of rainfall, these factors contribute to negative nutrient balances. For example, 4.4 million tons of nitrogen (N) are lost per year in African soils, but only 0.8 million tons are reapplied by fertilization (12, 34). Since nitrogen is a key nutrient determining the productivity of agroecosystems (7, 11, 43), it is of central importance to optimize the nitrogen balance in these countries, mainly by steering the genetic resources of soil microbes in a way that losses of applied nitrogen are minimized and biological nitrogen fixation is increased. The aim should be to obtain a highly efficient nitrogen turnover, with leaching of nitrate and losses of gaseous products such as nitrous oxide (N2O) or dinitrogen (N2) as low as possible.Despite the importance of this issue, not much data are available on microbial community structure and function related to the nitrogen cycle in agroecosystems of Central Africa, and scenarios from moderate climatic regions cannot simply be transferred to tropical agroecosystems. Furthermore, the few studies published thus far only investigated effects of agricultural management on a single process of the nitrogen turnover (18, 20, 32) and ignore the fact that nitrogen turnover is a network of closely interlinked processes.Therefore, we sought to investigate the effects of different fertilizer regimens on multiple transformation processes within the nitrogen cycle in agroecosystems from semiarid areas in Central Africa. We investigated nitrogen dynamics on a full-cycle approach, including the most important steps in well-aerated agricultural soils (nitrification, denitrification, and nitrogen fixation). We hypothesized that each fertilizer regimen results in typical abundance pattern of the functional populations. While in moderate agroecosystems the plant (respectively, the plant development stage and the plant performance) plays an important role in shaping microbial community structure and function in the rhizosphere, we further postulated that nitrogen turnover and the corresponding populations are also influenced by the availability of water in semiarid soils. To test these hypotheses on a molecular basis, we quantified bacterial genes encoding the nitrogenase reductase (nifH), ammonia monooxygenase (amoA), and nitrite reductase (nirK and nirS), as well as archaeal amoA genes, by real-time PCR and linked the data to soil properties and grain yield. 相似文献
114.
115.
Mahendra Damarla Emile Hasan Adel Boueiz Anne Le Hyun Hae Pae Calypso Montouchet Todd Kolb Tiffany Simms Allen Myers Usamah S. Kayyali Matthias Gaestel Xinqi Peng Sekhar P. Reddy Rachel Damico Paul M. Hassoun 《PloS one》2009,4(2)
Mechanical ventilation, a fundamental therapy for acute lung injury, worsens pulmonary vascular permeability by exacting mechanical stress on various components of the respiratory system causing ventilator associated lung injury. We postulated that MK2 activation via p38 MAP kinase induced HSP25 phosphorylation, in response to mechanical stress, leading to actin stress fiber formation and endothelial barrier dysfunction. We sought to determine the role of p38 MAP kinase and its downstream effector MK2 on HSP25 phosphorylation and actin stress fiber formation in ventilator associated lung injury. Wild type and MK2−/− mice received mechanical ventilation with high (20 ml/kg) or low (7 ml/kg) tidal volumes up to 4 hrs, after which lungs were harvested for immunohistochemistry, immunoblotting and lung permeability assays. High tidal volume mechanical ventilation resulted in significant phosphorylation of p38 MAP kinase, MK2, HSP25, actin polymerization, and an increase in pulmonary vascular permeability in wild type mice as compared to spontaneous breathing or low tidal volume mechanical ventilation. However, pretreatment of wild type mice with specific p38 MAP kinase or MK2 inhibitors abrogated HSP25 phosphorylation and actin polymerization, and protected against increased lung permeability. Finally, MK2−/− mice were unable to phosphorylate HSP25 or increase actin polymerization from baseline, and were resistant to increases in lung permeability in response to HVT MV. Our results suggest that p38 MAP kinase and its downstream effector MK2 mediate lung permeability in ventilator associated lung injury by regulating HSP25 phosphorylation and actin cytoskeletal remodeling. 相似文献
116.
Steven T. Lott Nanyue Chen Dawn S. Chandler Qifeng Yang Luo Wang Marivonne Rodriguez Hongyan Xie Seetharaman Balasenthil Thomas A. Buchholz Aysegul A. Sahin Katrina Chaung Baili Zhang Shodimu-Emmanu Olufemi Jinyun Chen Henry Adams Vimla Band Adel K. El-Naggar Marsha L. Frazier Khandan Keyomarsi Kelly K. Hunt Subrata Sen Bruce Haffty Stephen M. Hewitt Ralf Krahe Ann McNeill Killary 《PLoS medicine》2009,6(5)
Background
Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.Methods and Findings
Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER−, PR−, HER-2−) of breast cancers with poor prognosis.Conclusions
Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease. 相似文献117.
Rose Y Ciblat S Reddy R Belley AC Dietrich E Lehoux D McKay GA Poirier H Far AR Delorme D 《Bioorganic & medicinal chemistry letters》2006,16(4):891-896
The preparation and biological evaluation of 5-substituted-6-hydroxy-2-(anilino)pyrimidinones as a new class of DNA polymerase IIIC inhibitors, required for the replication of chromosomal DNA in Gram-positive bacteria, are described. These new dGTP competitive inhibitors displayed good levels of in vitro inhibition and antibacterial activity against Staphylococcus aureus. A new class of dATP competitive inhibitors, 6-substituted-2-amino-5-alkyl-pyrimidin-4-ones, whose antibacterial activity was unaffected by serum, were identified. 相似文献
118.
McKay GA Reddy R Arhin F Belley A Lehoux D Moeck G Sarmiento I Parr TR Gros P Pelletier J Far AR 《Bioorganic & medicinal chemistry letters》2006,16(5):1286-1290
Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduction in cytotoxicity. The impact of serum and initial investigations toward a mode of action highlight several features of this class of compounds as antibacterials. 相似文献
119.
120.
Human crowd motion is mainly driven by self-organized processes based on local interactions among pedestrians. While most studies of crowd behaviour consider only interactions among isolated individuals, it turns out that up to 70% of people in a crowd are actually moving in groups, such as friends, couples, or families walking together. These groups constitute medium-scale aggregated structures and their impact on crowd dynamics is still largely unknown. In this work, we analyze the motion of approximately 1500 pedestrian groups under natural condition, and show that social interactions among group members generate typical group walking patterns that influence crowd dynamics. At low density, group members tend to walk side by side, forming a line perpendicular to the walking direction. As the density increases, however, the linear walking formation is bent forward, turning it into a V-like pattern. These spatial patterns can be well described by a model based on social communication between group members. We show that the V-like walking pattern facilitates social interactions within the group, but reduces the flow because of its “non-aerodynamic” shape. Therefore, when crowd density increases, the group organization results from a trade-off between walking faster and facilitating social exchange. These insights demonstrate that crowd dynamics is not only determined by physical constraints induced by other pedestrians and the environment, but also significantly by communicative, social interactions among individuals. 相似文献