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91.
Discovery of Inhibitors of Trypanosoma brucei by Phenotypic Screening of a Focused Protein Kinase Library
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Dr. Andrew Woodland Dr. Stephen Thompson Dr. Laura A. T. Cleghorn Dr. Neil Norcross Dr. Manu De Rycker Dr. Raffaella Grimaldi Irene Hallyburton Dr. Bhavya Rao Suzanne Norval Laste Stojanovski Prof. Reto Brun Dr. Marcel Kaiser Prof. Julie A. Frearson Dr. David W. Gray Prof. Paul G. Wyatt Dr. Kevin D. Read Prof. Ian H. Gilbert 《ChemMedChem》2015,10(11):1809-1820
A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μm . Screening of these hits in a T. b. brucei proliferation assay highlighted three compounds with a 1H‐imidazo[4,5‐b]pyrazin‐2(3H)‐one scaffold that showed sub‐micromolar activity and excellent selectivity against the MRC5 cell line. Subsequent rounds of optimisation led to the identification of compounds that exhibited good in vitro drug metabolism and pharmacokinetics (DMPK) properties, although in general this series suffered from poor solubility. A scaffold‐hopping exercise led to the identification of a 1H‐pyrazolo[3,4‐b]pyridine scaffold, which retained potency. A number of examples were assessed in a T. b. brucei growth assay, which could differentiate static and cidal action. Compounds from the 1H‐imidazo[4,5‐b]pyrazin‐2(3H)‐one series were found to be either static or growth‐slowing and not cidal. Compounds with the 1H‐pyrazolo[3,4‐b]pyridine scaffold were found to be cidal and showed an unusual biphasic nature in this assay, suggesting they act by at least two mechanisms. 相似文献
92.
Annamma?JohnEmail author Shyla?Joseph K.?M.?Manu J.?K.?Thomas Sam?Solomon 《Journal of Materials Science: Materials in Electronics》2011,22(7):776-780
The Ln2/3Gd1/3TiNbO6 ceramic compositions are prepared through the solid state ceramic route. The compositions are calcined at 1250 °C and sintered
in the range 1350–1435 °C. Structural analysis of the materials is done using X-ray diffraction analysis and vibrational spectroscopy.
Surface morphology is examined by Scanning Electron Microscopy. Microwave dielectric properties such as dielectric constant
(εr), quality factor (Q) and temperature coefficient of resonant frequency (Tf) are measured using cavity resonator method. The compositions have εr in between 46 and 41.8 and Tf in between +52 and +25 ppm/°C. By the substitution of Gd, the Tf is reduced considerably with a slight decrease in dielectric constant. Cerium based composition had additional reflections
other than that of aeschynite structure. For Pr, Nd and Sm based systems, solid solutions were formed. UV visible spectrum
of the representative composition is recorded and the band gap energy is estimated. Photoluminescence spectra of the samples
are recorded and the transitions causing emissions are identified. The materials are suitable for microwave and optoelectronic
applications. 相似文献
93.
N Simonsen P van''t Veer JJ Strain JM Martin-Moreno JK Huttunen JF Navajas BC Martin M Thamm AF Kardinaal FJ Kok L Kohlmeier 《Canadian Metallurgical Quarterly》1998,147(4):342-352
Three experiments examined the effect of either withdrawal from diazepam, or repeated treatment with the convulsant, pentylenetetrazol (PTZ), on behaviour and seizure threshold. The behaviours measured were on the elevated plus maze and in the four-plate test; seizure threshold was measured as dose of PTZ infused via the tail vein to the first clonic twitch. In experiment 1, we examined the effect of either single or repeated withdrawal from diazepam using a procedure in which the drug was administered SC in a slow release depot. Three cycles of withdrawal from diazepam were compared to a single withdrawal experience. A single withdrawal from diazepam following chronic treatment gave rise, 72 h following the last dosing, to behavioural changes, suggestive of anxiety, in both tests, but did not result in a reduced convulsant threshold. In contrast, repeated withdrawal resulted in a reduction in sensitivity in several measures of anxiety, but sensitised the mice to the convulsive effects of the PTZ. The unexpected failure to find an increased sensitivity to a convulsive agent following a single withdrawal from SC diazepam was examined in experiment 2. The seizure threshold following a single withdrawal of mice which had received diazepam chronically IP in aqueous vehicle was significantly reduced relative to vehicle-treated controls, whereas that of animals receiving the same dose SC in oil, was not. It is argued that the difference may arise from the animals treated repeatedly with IP diazepam unintentionally experiencing repeated withdrawal, since the half-life of the drug by this route is short. In experiment 3, repeated sub-convulsant PTZ treatment reduced the convulsant threshold (the dose of PTZ required to give rise to the first clonic twitch), but had no significant effect on the behavioural measures of anxiety compared to a single dose of PTZ or vehicle controls. The results suggest that repeated withdrawal from chronic treatments with diazepam sensitises mice to convulsant stimuli in a manner resembling the effects of repeated administration of sub-convulsant doses of PTZ, but that neither repeated PTZ nor repeated diazepam withdrawal results in increased sensitivity to anxiogenic stimuli; rather, repeated withdrawal from diazepam may reduce the susceptibility of mice to behavioural measures of anxiety. 相似文献
94.
95.
Induction of immediate-early genes c-jun, junB, and c-fos was demonstrated during echovirus 1 infection in a human osteogenic sarcoma (HOS) cell line. Tenfold induction was seen at 10 h postinfection, corresponding approximately to the end of the first replication cycle of the virus. Echovirus 1 uses VLA-2 integrin as its cellular receptor, and ligand binding by integrin is known to trigger signal transduction pathways ultimately activating immediate-early genes. In the present study, however, VLA-2 binding alone was not sufficient to induce their expression; viral replication was needed. This conclusion was based on the observations that no stimulation of the immediate-early genes occurred in the MG-63 cell line where the virus attached only to VLA-2 but was not able to replicate and that induction of these genes was observed when the HOS cells were infected with echovirus type 7, known to use a different cellular receptor. Induction was not seen in the presence of the antiviral compound WIN 54954, which evidently inhibits the uncoating but not receptor binding of echovirus 1, suggesting that viral replication triggers the activation of the immediate-early genes. The induction of these genes may have a role in viral replication and in the pathogenesis of infection. 相似文献
96.
A magnetic mesoporous chitosan based core‐shells biopolymer for anionic dye adsorption: Kinetic and isothermal study and application of ANN
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Bahareh Tanhaei Ali Ayati Manu Lahtinen Behrooz Mahmoodzadeh Vaziri Mika Sillanpää 《应用聚合物科学杂志》2016,133(22)
In this study, Chitosan/Al2O3/Fe3O4 core‐shell composite microsphere (CAMF) was used as an effective sorbent with high adsorption capacity for the removal of anionic azo dye model from aqueous solution. The obtained composite was characterized by XRD, SEM, EDX, and BET analysis. The results showed the high methyl orange (MO) adsorption in a wide pH range of 4–10 and the optimum adsorbent dosage was obtained 0.6 g L?1. It is indicated that the equilibrium data followed the Langmuir isotherm model and the adsorption kinetic was well fitted with pseudo‐second‐order kinetic model. Also, the adsorption kinetic was controlled by the film diffusion and intra‐particle diffusion, simultaneously. It is revealed that by increasing the particle size from <0.1 μm to ~0.4 μm, the adsorption capacity did not change, significantly. The adsorption capacity of MO on CAMF was predicted by multilayer perceptron (MLP) neural network at different initial MO concentration, in which the predictions of MLP model had very good agreement with experimental data. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43466. 相似文献
97.
Kurusaroor Mana Manu Chinnathambi Karthik Lii‐Cherng Leu Kokken Anlin Lazar Rick Ubic Mailadil Thomas Sebastian 《Journal of the American Ceramic Society》2013,96(5):1504-1511
The crystal structure and microwave dielectric properties of apatite‐type LiRE9(SiO4)6O2 ceramics (RE = La, Pr, Nd, Sm, Eu, Gd, and Er) have been investigated. The densification of lithium apatites has been greatly improved with the addition of 1 wt% LiF. Selected area electron diffraction and X‐ray diffraction (XRD) Rietveld analysis confirm that these compounds belong to the P63/m (No. 176) space group with hexagonal crystal symmetry. The porosity‐corrected relative permittivity was found to decrease with decreasing ionic polarizability of RE3+ ions. Relationships between the structural parameters and microwave dielectric properties have been examined. The observed variation in the quality factor of LiRE9(SiO4)6O2 + 1 wt% LiF ceramics (RE = La, Pr, and Nd) was correlated with average cation covalency (%). The temperature coefficient of resonant frequency was found to depend on the bond valence sum of cations. LiEr9(SiO4)6O2 + 1 wt% LiF ceramics showed good microwave dielectric properties with εr = 12.8, Qu × f = 13000 GHz and τf = +17 ppm/°C. All the compositions showed low coefficient of thermal expansion with thermal conductivity in the range 1.3–2.8 W (m K)?1. 相似文献
98.
Mahipal Singh Kesawat Bhagwat Singh Kherawat Anupama Singh Prajjal Dey Mandakini Kabi Debanjana Debnath Debanjana Saha Ansuman Khandual Sandeep Rout Manorama Asjad Ali Ramasubba Reddy Palem Ravi Gupta Avinash Ashok Kadam Hyun-Uk Kim Sang-Min Chung Manu Kumar 《International journal of molecular sciences》2021,22(16)
Brassinosteroids (BRs) play crucial roles in various biological processes, including plant developmental processes and response to diverse biotic and abiotic stresses. However, no information is currently available about this gene family in wheat (Triticum aestivum L.). In the present investigation, we identified the BZR gene family in wheat to understand the evolution and their role in diverse developmental processes and under different stress conditions. In this study, we performed the genome-wide analysis of the BZR gene family in the bread wheat and identified 20 TaBZR genes through a homology search and further characterized them to understand their structure, function, and distribution across various tissues. Phylogenetic analyses lead to the classification of TaBZR genes into five different groups or subfamilies, providing evidence of evolutionary relationship with Arabidopsis thaliana, Zea mays, Glycine max, and Oryza sativa. A gene exon/intron structure analysis showed a distinct evolutionary path and predicted the possible gene duplication events. Further, the physical and biochemical properties, conserved motifs, chromosomal, subcellular localization, and cis-acting regulatory elements were also examined using various computational approaches. In addition, an analysis of public RNA-seq data also shows that TaBZR genes may be involved in diverse developmental processes and stress tolerance mechanisms. Moreover, qRT-PCR results also showed similar expression with slight variation. Collectively, these results suggest that TaBZR genes might play an important role in plant developmental processes and various stress conditions. Therefore, this work provides valuable information for further elucidate the precise role of BZR family members in wheat. 相似文献
99.
100.
Laymon C.A. Crosson W.L. Jackson T.J. Manu A. Tsegaye T.D. 《Geoscience and Remote Sensing, IEEE Transactions on》2001,39(9):1844-1858
A ground-based experiment in passive microwave remote sensing of soil moisture was conducted in Huntsville, AL, from July 1-14, 1996. The goal of the experiment was to evaluate the overall performance of an empirically-based retrieval algorithm at S-band and L-band under a different set of conditions and to characterize the site-specific accuracy inherent within the technique. With high temporal frequency observations at S-band and L-band, the authors were able to observe large scale moisture changes following irrigation and rainfall events, as well as diurnal behavior of surface moisture among three plots, one bare, one covered with short grass and another covered with alfalfa. The L-band emitting depth was determined to be on the order of 0-3 or 0-5 cm below 0.30 cm3/cm3 with an indication that it is less at higher moisture values. The S-band emitting depth was not readily distinguishable from L-band. The uncertainty in remotely sensed soil moisture observations due to surface heterogeneity and temporal variability in variables and parameters was characterized by imposing random errors on the most sensitive variables and parameters and computing the confidence limits on the observations. Discrepancies between remotely sensed and gravimetric soil moisture estimates appear to be larger than those expected from errors in variable and parameter estimation. This would suggest that a vegetation correction procedure based on more dynamic modeling may be required to improve the accuracy of remotely sensed soil moisture 相似文献