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71.
Sundari Chetty Elise N. Engquist Elie Mehanna Kathy O. Lui Alexander M. Tsankov Douglas A. Melton 《The Journal of cell biology》2015,210(7):1257-1268
Driving human pluripotent stem cells (hPSCs) into specific lineages is an inefficient and challenging process. We show that a potent Src inhibitor, PP1, regulates expression of genes involved in the G1 to S phase transition of the cell cycle, activates proteins in the retinoblastoma family, and subsequently increases the differentiation propensities of hPSCs into all three germ layers. We further demonstrate that genetic suppression of Src regulates the activity of the retinoblastoma protein and enhances the differentiation potential of hPSCs across all germ layers. These positive effects extend beyond the initial germ layer specification and enable efficient differentiation at subsequent stages of differentiation. 相似文献
72.
In restored grasslands of southern Europe, perennial plants remain highly underrepresented compared with the reference ecosystems. We tested various treatments to reintroduce common perennial plant species (Brachypodium retusum, Poaceae, and Thymus vulgaris, Lamiaceae), which are usually not or poorly reintroduced via soil and hay transfer. Treatments included microenvironmental manipulations (rock cover and plant interactions) and two grazing intensities. Target perennial species were transplanted in 2002 in the reference grassland ecosystem (intact grassland area used as a control) and in two abandoned fields. Survival was assessed in June 2003 and June 2004. Target species shoot and root biomass were measured in June 2004. Grazing greatly reduced the survival and biomass of both target species and its effects were reinforced by summer drought: plants that did not establish well enough during the autumn and spring did not survive summer. The restored rock cover had a mild positive effect, particularly on B. retusum. There were no negative or positive plant neighbor interactions in the steppe, while there was competition in both abandoned fields. Competition was particularly intense in the abandoned melon field, composed of a dense sward of annual grasses (Bromus sp.). In order to reintroduce perennial species to dry grasslands, the ideal combination of treatments is to exclude or reduce grazing during the first year to allow seedlings to establish and to recreate adequate microenvironmental conditions. Reducing competition from arable weeds may help but is not essential in such dry grasslands. 相似文献
73.
Steven M. Berry Erika L. Bladholm Elise J. Mostad Audrey R. Schenewerk 《Journal of biological inorganic chemistry》2011,16(3):473-480
Abstract
Loop-directed mutagenesis was applied to the blue copper protein azurin to replace its copper binding loop with that from the red copper protein nitrosocyanin. A ten amino acid long loop that provides three of the four copper ligands from nitrosocyanin was incorporated into azurin to make a variant called NC-azurin. The chimeric protein displayed a red color, and UV–vis absorption and EPR spectra that closely resembled those of the loop parent, nitrosocyanin. We added the fourth ligand from nitrosocyanin into NC-azurin, a carboxylate-containing amino acid, but the proteins had altered stability and spectroscopic properties that did not resemble those of either parent copper protein. The loop alone, however, was enough to impart red copper site characteristics to the NC-azurin protein. Finally, the reduction potential of the variant was found to be between the reduction potentials of the parent proteins and about 50 mV below that of wild-type azurin. 相似文献74.
The effect of organic loading rate on foam initiation during mesophilic anaerobic digestion of municipal wastewater sludge 总被引:3,自引:0,他引:3
The impact of increasing organic load on anaerobic digestion foaming was studied at both full and bench scale. Organic loadings of 1.25, 2.5 and 5 kg VS m−3 were applied to bench-scale digesters. Foaming was monitored at a full scale digester operated in a comparable organic loading range over 15 months. The bench scale batch studies identified 2.5 kg VS m−3 as a critical threshold for foam initiation while 5 kg VS m−3 resulted in persistent foaming. Investigation of a full scale foaming event corroborated the laboratory observation that foaming may be initiated at a loading rate of ?2.5 kg VS m−3. Experimental findings on foam composition and differences in the quality characteristics between foaming and non-foaming sludges indicated that foam initiation derived from the combined effect of the liquid and gas phases inside a digester and that the solids/biomass ultimately stabilized foaming. 相似文献
75.
Powell DA Black WC Bleasby K Chan CC Deschenes D Gagnon M Gordon R Guay J Guiral S Hafey MJ Huang Z Isabel E Leblanc Y Styhler A Xu LJ Zhang L Oballa RM 《Bioorganic & medicinal chemistry letters》2011,21(24):7281-7286
An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity. 相似文献
76.
Isabel E Powell DA Black WC Chan CC Crane S Gordon R Guay J Guiral S Huang Z Robichaud J Skorey K Tawa P Xu L Zhang L Oballa R 《Bioorganic & medicinal chemistry letters》2011,21(1):479-483
Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared. 相似文献
77.
Ramtohul YK Powell D Leclerc JP Leger S Oballa R Black C Isabel E Li CS Crane S Robichaud J Guay J Guiral S Zhang L Huang Z 《Bioorganic & medicinal chemistry letters》2011,21(19):5692-5696
Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors. 相似文献
78.
79.
Ciliopathies are pleiotropic and genetically heterogeneous disorders caused by defective development and function of the primary cilium. Bardet-Biedl syndrome (BBS) proteins localize to the base of cilia and undergo intraflagellar transport, and the loss of their functions leads to a multisystemic ciliopathy. Here we report the identification of mutations in guanylate cyclases (GCYs) as modifiers of Caenorhabditis elegans bbs endophenotypes. The loss of GCY-35 or GCY-36 results in suppression of the small body size, developmental delay, and exploration defects exhibited by multiple bbs mutants. Moreover, an effector of cGMP signalling, a cGMP-dependent protein kinase, EGL-4, also modifies bbs mutant defects. We propose that a misregulation of cGMP signalling, which underlies developmental and some behavioural defects of C. elegans bbs mutants, may also contribute to some BBS features in other organisms. 相似文献
80.
Tawa P Falgueyret JP Guiral S Isabel E Powell DA Zuck P Skorey K 《Journal of biomolecular screening》2011,16(5):506-517
Stearoyl-CoA desaturase (SCD) catalyzes the synthesis of monounsaturated fatty acids and has been implicated in a number of disease states, including obesity and diabetes. To find small-molecule inhibitor leads, a high-throughput scintillation proximity assay (SPA) was developed using the hydrophobic binding characteristics of a glass microsphere scintillant bead to capture SCD1 from a crude lysate of recombinant SCD1 in Sf9 lysate coupled with the strong binding characteristics of an azetidine compound ([(3)H]AZE). The SPA assay was stable over 24 h and could detect compounds with micromolar to nanomolar potencies. A robust 1536-well high-throughput screening assay was developed with good signal-to-noise ratio (10:1) and excellent Z' factor (0.8). A screening collection of 1.6 million compounds was screened at 11 μM, and approximately 7700 compounds were identified as initial hits, exhibiting at least 35% inhibition of [(3)H]AZE binding. Further screening and confirmation with an SCD enzyme activity assay led to a number of new structural leads for inhibition of the enzyme. The SPA assay complements the enzyme activity assay for SCD1 as a tool for the discovery of novel leads in drug discovery. 相似文献