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71.
Islam I Brown G Bryant J Hrvatin P Kochanny MJ Phillips GB Yuan S Adler M Whitlow M Lentz D Polokoff MA Wu J Shen J Walters J Ho E Subramanyam B Zhu D Feldman RI Arnaiz DO 《Bioorganic & medicinal chemistry letters》2007,17(14):3819-3825
Based on the lead compound BX-517, a series of C-4' substituted indolinones have been synthesized and evaluated for PDK1 inhibition. Modification at C-4' of the pyrrole afforded potent compounds (7b and 7d) with improved solubility and ADME properties. In this letter, we describe the synthesis, selectivity profile, and pharmacokinetic data of selected compounds. 相似文献
72.
Islam I Bryant J Chou YL Kochanny MJ Lee W Phillips GB Yu H Adler M Whitlow M Ho E Lentz D Polokoff MA Subramanyam B Wu JM Zhu D Feldman RI Arnaiz DO 《Bioorganic & medicinal chemistry letters》2007,17(14):3814-3818
HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA. 相似文献
73.
Angela Deakin Graham Duddy Steve Wilson Steve Harrison Judi Latcham Mick Fulleylove Sylvia Fung Jason Smith Mike Pedrick Tom McKevitt Leigh Felton Joanne Morley Diana Quint Dilniya Fattah Brian Hayes Jade Gough Roberto Solari 《PloS one》2014,9(9)
Interleukin-2 inducible tyrosine kinase (ITK) is expressed in T cells and plays a critical role in signalling through the T cell receptor. Evidence, mainly from knockout mice, has suggested that ITK plays a particularly important function in Th2 cells and this has prompted significant efforts to discover ITK inhibitors for the treatment of allergic disease. However, ITK is known to have functions outside of its kinase domain and in general kinase knockouts are often not good models for the behaviour of small molecule inhibitors. Consequently we have developed a transgenic mouse where the wild type Itk allele has been replaced by a kinase dead Itk allele containing an inactivating K390R point mutation (Itk-KD mice). We have characterised the immune phenotype of these naive mice and their responses to airway inflammation. Unlike Itk knockout (Itk−/−) mice, T-cells from Itk-KD mice can polymerise actin in response to CD3 activation. The lymph nodes from Itk-KD mice showed more prominent germinal centres than wild type mice and serum antibody levels were significantly abnormal. Unlike the Itk−/−, γδ T cells in the spleens of the Itk-KD mice had an impaired ability to secrete Th2 cytokines in response to anti-CD3 stimulation whilst the expression of ICOS was not significantly different to wild type. However ICOS expression is markedly increased on αβCD3+ cells from the spleens of naïve Itk-KD compared to WT mice. The Itk-KD mice were largely protected from inflammatory symptoms in an Ovalbumin model of airway inflammation. Consequently, our studies have revealed many similarities but some differences between Itk−/−and Itk-KD transgenic mice. The abnormal antibody response and enhanced ICOS expression on CD3+ cells has implications for the consideration of ITK as a therapeutic target. 相似文献
74.
Cummings V Hewitt J Van Rooyen A Currie K Beard S Thrush S Norkko J Barr N Heath P Halliday NJ Sedcole R Gomez A McGraw C Metcalf V 《PloS one》2011,6(1):e16069
Ocean acidification is a well recognised threat to marine ecosystems. High
latitude regions are predicted to be particularly affected due to cold waters
and naturally low carbonate saturation levels. This is of concern for organisms
utilising calcium carbonate (CaCO3) to generate shells or skeletons.
Studies of potential effects of future levels of pCO2 on high latitude
calcifiers are at present limited, and there is little understanding of their
potential to acclimate to these changes. We describe a laboratory experiment
to compare physiological and metabolic responses of a key benthic bivalve, Laternula
elliptica, at pCO2 levels of their natural environment
(430 µatm, pH 7.99; based on field measurements) with those predicted
for 2100 (735 µatm, pH 7.78) and glacial levels (187 µatm, pH
8.32). Adult L. elliptica basal metabolism (oxygen consumption
rates) and heat shock protein HSP70 gene expression levels
increased in response both to lowering and elevation of pH. Expression of
chitin synthase (CHS), a key enzyme involved in synthesis
of bivalve shells, was significantly up-regulated in individuals at pH 7.78,
indicating L. elliptica were working harder to calcify in
seawater undersaturated in aragonite (ΩAr = 0.71),
the CaCO3 polymorph of which their shells are comprised. The different
response variables were influenced by pH in differing ways, highlighting the
importance of assessing a variety of factors to determine the likely impact
of pH change. In combination, the results indicate a negative effect of ocean
acidification on whole-organism functioning of L. elliptica
over relatively short terms (weeks-months) that may be energetically difficult
to maintain over longer time periods. Importantly, however, the observed changes
in L. elliptica CHS gene expression provides evidence for
biological control over the shell formation process, which may enable some
degree of adaptation or acclimation to future ocean acidification scenarios. 相似文献
75.
The p75 Neurotrophin Receptor Mediates Neuronal Apoptosis and Is Essential for Naturally Occurring Sympathetic Neuron Death 总被引:29,自引:1,他引:29 下载免费PDF全文
Shernaz X. Bamji Marta Majdan Christine D. Pozniak Daniel J. Belliveau Raquel Aloyz Judi Kohn Carrie G. Causing Freda D. Miller 《The Journal of cell biology》1998,140(4):911-923
Abstract. To determine whether the p75 neurotrophin receptor (p75NTR) plays a role in naturally occurring neuronal death, we examined neonatal sympathetic neurons that express both the TrkA tyrosine kinase receptor and p75NTR. When sympathetic neuron survival is maintained with low quantities of NGF or KCl, the neurotrophin brain-derived neurotrophic factor (BDNF), which does not activate Trk receptors on sympathetic neurons, causes neuronal apoptosis and increased phosphorylation of c-jun. Function-blocking antibody studies indicate that this apoptosis is due to BDNF-mediated activation of p75NTR. To determine the physiological relevance of these culture findings, we examined sympathetic neurons in BDNF−/− and p75NTR−/− mice. In BDNF−/− mice, sympathetic neuron number is increased relative to BDNF+/+ littermates, and in p75NTR−/− mice, the normal period of sympathetic neuron death does not occur, with neuronal attrition occurring later in life. This deficit in apoptosis is intrinsic to sympathetic neurons, since cultured p75NTR−/− neurons die more slowly than do their wild-type counterparts. Together, these data indicate that p75NTR can signal to mediate apoptosis, and that this mechanism is essential for naturally occurring sympathetic neuron death. 相似文献
76.
González F Rote NS Minium J O'leary VB Kirwan JP 《Obesity (Silver Spring, Md.)》2007,15(10):2436-2444
Objective: The objective was to determine if physiological hyperglycemia induces a proatherogenic inflammatory response in mononuclear cells (MNCs) in obese reproductive‐age women. Research Methods and Procedures: Seven obese and 6 age‐matched lean women (20 to 39 years of age) underwent a 2‐hour 75‐g oral glucose tolerance test. The release of interleukin‐6 (IL‐6) and interleukin‐1β (IL‐1β) from MNCs cultured in the presence of lipopolysaccharide (LPS) was measured after isolation from blood samples drawn fasting and 2 hours after glucose ingestion. Reactive oxygen species (ROS) generation and intra‐nuclear nuclear factor κB (NFκB) from MNCs were quantified from the same blood samples. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA‐IR). Total body fat and truncal fat were determined by DXA. Results: Obese women had a higher (p < 0.03) total body fat (42.2 ± 1.1 vs. 27.7 ± 2.0%), truncal fat (42.1 ± 1.2 vs. 22.3 ± 2.4%), and HOMA‐IR (3.3 ± 0.5 vs. 1.8 ± 0.2). LPS‐stimulated IL‐6 release from MNCs was suppressed during hyperglycemia in lean subjects (1884 ± 495 vs. 638 ± 435 pg/mL, p < 0.05) but not in obese women (1184 ± 387 vs. 1403 ± 498 pg/mL). There was a difference (p < 0.05) between groups in the hyperglycemia‐induced MNC‐mediated release of IL‐6 (?1196 ± 475 vs. 219 ± 175 pg/mL) and IL‐1β (?79 ± 43 vs. 17 ± 12 pg/mL). In addition, the obese group exhibited increased (p < 0.05) MNC‐derived ROS generation (39.3 ± 9.9 vs. ?1.0 ± 12.8%) and intra‐nuclear NFκB (9.4 ± 7.3 vs. ?23.5 ± 13.5%). Truncal fat was positively correlated with the MNC‐derived IL‐6 response (ρ = 0.58, p < 0.05) and intra‐nuclear NFκB (ρ = 0.64, p < 0.05). Discussion: These data suggest that obese reproductive‐age women are unable to suppress proatherogenic inflammation during physiological hyperglycemia. Increased adiposity may be a significant contributor to this pro‐inflammatory susceptibility. 相似文献
77.
The organization of the alpha- and beta-tubulin gene families in Physarum was investigated by Mendelian analysis. Restriction endonuclease-generated DNA fragments homologous to alpha- and beta-tubulin show length polymorphisms that can be used as markers for genetic mapping. Analysis of meiotic assortment among progeny of heterozygotes allowed alpha- and beta-tubulin sequence loci to be defined. There are four unlinked alpha-tubulin sequence loci (altA, altB, altC and altD) and at least three unlinked beta-tubulin sequence loci (betA, betB and betC). The alpha-tubulin loci are not linked to the beta-tubulin loci. --Segregation of tubulin sequence loci with respect to ben mutations that confer resistance to antitubulin benzimidazole drugs was used to investigate whether any members of the alpha- or beta-tubulin gene families are allelic to ben loci. The beta-tubulin sequence locus betB is allelic to the resistance locus benD, the betA locus is probably allelic to benA and the alpha-tubulin sequence locus altC may be allelic to benC. The molecular implications of benzimidazole resistance phenotypes when only one of the expressed beta-tubulin gene family members mutates to drug resistance are discussed in relation to tubulin function. 相似文献
78.
Does the chlorophyll a content of phytoplankton vary with trophic status in lakes on the New Zealand central volcanic plateau? 总被引:1,自引:0,他引:1
Recently, it has been shown that ratios of chlorophyll a toparticulate phosphorus (Chl a/PP) and chlorophyll a to particulatenitrogen (Chl a/PN) were significantly higher in eutrophic thanoligo/mesotrophic waters in 17 lakes on the central volcanicplateau, North Island, New Zealand. This difference was thoughtto be due to an increase in the chlorophyll a content of phytoplanktonin these eutrophic lakes. Corresponding measurements of chlorophylla and phytoplankton cell volume made during this study do notsupport this hypothesis. However, ratios of chlorophyll a toadenosine triphosphate and estimates of percentage phytoplanktonbiomass were significantly higher (P<0.05) in our eutrophicthan oligo/mesotrophic samples, suggesting that Chl a/PP andChl a/PN may be high in eutrophic waters simply because phytoplanktoncomprise more of the total microbial biomass. This hypothesisis supported by a strong linear relationship (r=0.88, P<0.001)between Chl a/PP and percentage phytoplankton biomass in sixof our study lakes where corresponding measurements were made. 相似文献
79.
80.
Site-specific gene modifications in cells are initiated by the introduction of exogenous DNA. We used a recently established cell assay to compare the ability of DNA donors to induce a single point mutation that converts a target gene encoding blue fluorescent protein (BFP) into expressing green fluorescent protein (GFP). In a chromosomal assay with cells stably expressing BFP, we showed that fluorescently labeled single-stranded oligonucleotides and a donor plasmid cotranscribing a red fluorescent protein provide similar efficiencies in triggering BFP–GFP conversions. In transient cotransfections, an isogenic donor plasmid comprising a nonfunctional GFP gene yielded a greater efficiency for the conversion of the BFP target gene than a nonisogenic donor, and all plasmid donors were superior to oligonucleotides. 相似文献