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101.
Massimo Ghizzoni André Boltjes Chris de Graaf Hidde J. Haisma Frank J. Dekker 《Bioorganic & medicinal chemistry》2010,18(16):5826-5834
Several lines of evidence indicate that histone acetyltransferases (HATs) are novel drug targets for treatment of diseases like, for example, cancer and inflammation. The natural product anacardic acid is a starting point for development of small molecule inhibitors of the histone acetyltransferase (HAT) p300/CBP associated factor (PCAF). In order to optimize the inhibitory potency, a binding model for PCAF inhibition by anacardic acid was proposed and new anacardic acid derivatives were designed. Ten new derivatives were synthesized using a novel synthetic route. One compound showed a twofold improved inhibitory potency for the PCAF HAT activity and a twofold improved inhibition of histone acetylation in HEP G2 cells. 相似文献
102.
Seyede Ghazal Mohades Peter Van Schuerbeek Yves Rosseel Piet Van De Craen Robert Luypaert Chris Baeken 《PloS one》2015,10(2)
Although numerous people grow up speaking more than one language, the impact of bilingualism on brain developing neuroanatomy is still poorly understood. This study aimed to determine whether the changes in the mean fractional-anisotropy (MFA) of language pathways are different between bilingual and monolingual children. Simultaneous-bilinguals, sequential-bilinguals and monolingual, male and female 10–13 years old children participated in this longitudinal study over a period of two years. We used diffusion tensor tractography to obtain mean fractional-anisotropy values of four language related pathways and one control bundle: 1-left-inferior-occipitofrontal fasciculus/lIFOF, 2-left-arcuate fasciculus/lAF/lSLF, 3-bundle arising from the anterior part of corpus-callosum and projecting to orbital lobe/AC-OL, 4-fibres emerging from anterior-midbody of corpus-callosum (CC) to motor cortices/AMB-PMC, 5- right-inferior-occipitofrontal fasciculus rIFOF as the control pathway unrelated to language. These values and their rate of change were compared between 3 groups. FA-values did not change significantly over two years for lAF/lSLF and AC-OL. Sequential-bilinguals had the highest degree of change in the MFA value of lIFOF, and AMB-PMC did not present significant group differences. The comparison of MFA of lIFOF yielded a significantly higher FA-value in simultaneous bilinguals compared to monolinguals. These findings acknowledge the existing difference of the development of the semantic processing specific pathway between children with different semantic processing procedure. These also support the hypothesis that age of second language acquisition affects the maturation and myelination of some language specific white-matter pathways. 相似文献
103.
104.
Ian Ford Vladimir Bezlyak David J Stott Naveed Sattar Chris J Packard Ivan Perry Brendan M Buckley J. Wouter Jukema Anton J. M de Craen Rudi G. J Westendorp James Shepherd 《PLoS medicine》2009,6(1)
Background
Reduced glomerular filtration rate (GFR) is associated with increased cardiovascular risk in young and middle aged individuals. Associations with cardiovascular disease and mortality in older people are less clearly established. We aimed to determine the predictive value of the GFR for mortality and morbidity using data from the 5,804 participants randomized in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).Methods and Findings
Glomerular filtration rate was estimated (eGFR) using the Modification of Diet in Renal Disease equation and was categorized in the ranges ([20–40], [40–50], [50–60]) ≥ 60 ml/min/1.73 m2. Baseline risk factors were analysed by category of eGFR, with and without adjustment for other risk factors. The associations between baseline eGFR and morbidity and mortality outcomes, accrued after an average of 3.2 y, were investigated using Cox proportional hazard models adjusting for traditional risk factors. We tested for evidence of an interaction between the benefit of statin treatment and baseline eGFR status. Age, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index, fasting glucose, female sex, histories of hypertension and vascular disease were associated with eGFR (p = 0.001 or less) after adjustment for other risk factors. Low eGFR was independently associated with risk of all cause mortality, vascular mortality, and other noncancer mortality and with fatal and nonfatal coronary and heart failure events (hazard ratios adjusted for CRP and other risk factors (95% confidence intervals [CIs]) for eGFR < 40 ml/min/1.73m2 relative to eGFR ≥ 60 ml/min/1.73m2 respectively 2.04 (1.48–2.80), 2.37 (1.53–3.67), 3.52 (1.78–6.96), 1.64 (1.18–2.27), 3.31 (2.03–5.41). There were no nominally statistically significant interactions (p < 0.05) between randomized treatment allocation and eGFR for clinical outcomes, with the exception of the outcome of coronary heart disease death or nonfatal myocardial infarction (p = 0.021), with the interaction suggesting increased benefit of statin treatment in subjects with impaired GFRs.Conclusions
We have established that, in an elderly population over the age of 70 y, impaired GFR is associated with female sex, with presence of vascular disease, and with levels of other risk factors that would be associated with increased risk of vascular disease. Further, impaired GFR is independently associated with significant levels of increased risk of all cause mortality and fatal vascular events and with composite fatal and nonfatal coronary and heart failure outcomes. Our analyses of the benefits of statin treatment in relation to baseline GFR suggest that there is no reason to exclude elderly patients with impaired renal function from treatment with a statin. 相似文献105.
Background
The deposition of aggregated β-amyloid peptide senile plaques and the accumulation of arginine within the astrocytes in the brain of an Alzheimer's patient are classic observations in the neuropathology of the disease. It would be logical, in the aetiology and pathogenesis, to investigate arginine-metabolising enzymes and their intimate association with amyloid peptides.Methods
Neuronal nitric oxide synthase (nNOS) was isolated, purified and shown, through fluorescence quenching spectroscopy and fluorescence resonance energy transfer (FRET), to interact with structural fragments of Aβ1–40 and be catalytic towards amyloid fibril formation.Results
Only one binding site on the enzyme was available for binding. Two amyloid peptide fragments of Aβ1–40 (Aβ17–28 and Aβ25–35) had Stern–Volmer values (KSV) of 0.111 μM−1 and 0.135 μM−1 indicating tight binding affinity to nNOS and easier accessibility to fluor molecules during binding. The polarity of this active site precludes binding of the predominantly hydrophobic amyloid peptide fragments contained within Aβ17–28 and within two glycine zipper motifs [G-X-X-X-G-X-X-X-G] [Aβ29–37] and bind to the enzyme at a site remote to the active region.Conclusions
The interaction and binding of Aβ17–28 and Aβ25–35 to nNOS causes the movement of two critical tryptophan residues of 0.77 nm and 0.57 nm respectively towards the surface of the enzyme.General significance
The binding of Aβ-peptide fragments with nNOS has been studied by spectrofluorimetry. The information and data presented should contribute towards understanding the mechanism for deposition of aggregated Aβ-peptides and fibrillogenesis in senile plaques in an AD brain. 相似文献106.
Hanson MA Brooun A Baker KA Jaakola VP Roth C Chien EY Alexandrov A Velasquez J Davis L Griffith M Moy K Ganser-Pornillos BK Hua Y Kuhn P Ellis S Yeager M Stevens RC 《Protein expression and purification》2007,56(1):85-92
Production of structure-grade mammalian membrane proteins in substantial quantities has been hindered by a lack of methods for effectively profiling multiple constructs expression in higher eukaryotic systems such as insect or mammalian cells. To address this problem, a specialized small-scale eukaryotic expression platform by Thomson Instrument Company (Vertiga-IM) was developed and used in tandem with a Guava EasyCyte microcapillary 96-well cytometer to monitor cell density and health and evaluate membrane protein expression. Two proof of concept experiments were conducted using the human beta(2)-adrenergic receptor (beta(2)AR) and the gap junction protein connexin26 (Cx26) in a baculovirus expression system. First, cell surface expression was used to assess the expression levels of 14 beta(2)AR truncation variants expressed using the Vertiga-IM shaker. Three of these variants were then compared to wild-type beta(2)AR using three metrics: cell surface expression, saturation ligand binding and protein immunoblot analysis of dodecylmaltoside extracted material. Second, a series of systematic Cx26 truncation variants were evaluated for expression by protein immunoblot analysis. The cumulative results for these two systems show that the Vertiga-IM instrument can be used effectively in the parallel insect cell microexpression of membrane protein variants, and that the expression of cell surface molecules as monitored with the Guava EasyCyte instrument can be used to rapidly assess the production of properly folded proteins in the baculovirus expression system. This approach expedites the in vitro evaluation of a large number of mammalian membrane protein variants. 相似文献
107.
Elevated oxidative stress plays a key role in diabetes-associated vascular disease. In this study, we tested the hypothesis that high glucose-induced oxidative stress was associated with changes in the expression of NADPH oxidase, superoxide dismutase (SOD) and endothelial nitric oxide synthase (eNOS). Oxidative stress was assessed in cell cultures of mouse microvessel endothelial cells (MMECs) by fluorescence labelling with dihydroethidium, lucigenin-enhanced chemiluminescence and determining NADPH oxidase subunit and eNOS expression with real-time polymerase chain reaction protocol and Western blotting. Oxidative stress and expression of the NADPH oxidase subunit, p22phox, were both increased, SOD1 and 3 expression lowered and eNOS significantly elevated in MMECs treated with 40 mM glucose for 72 h compared to low glucose medium. Oxidative stress, p22phox mRNA, eNOS mRNA, and protein were lowered by concurrent incubation with sepiapterin. When eNOS protein expression in endothelial cells was significantly decreased by eNOS siRNA treatment, superoxide generation was significantly higher in the MMECs grown in low glucose, but reduced in those grown in high glucose for 72 h. Thus, exposure of MMECs to high glucose results in increased oxidative stress that is associated with increased eNOS and NADPH oxidase subunit expression, notably p22phox, and decreased expression of SOD1 and 3. 相似文献
108.
The structural diversity of polypeptides in amphibian skin secretion probably reflects different roles in dermal regulation or in defense against predators. Here we report the structures of two novel trypsin inhibitor analogs, BOTI and BVTI, from the dermal venom of the toads, Bombina orientalis and Bombina variegata. Cloning of their respective precursors was achieved from lyophilized venom cDNA libraries for the first time. Amino acid alignment revealed that both deduced peptides, consisting of 60 amino acid residues, including 10 cysteines and the reactive center motif, -CDKKC-, can be affirmed as structural homologs of the trypsin inhibitor from Bombina bombina skin. 相似文献
109.
Frederique Ponchel Carmel Toomes Kieran Bransfield Fong T Leong Susan H Douglas Sarah L Field Sandra M Bell Valerie Combaret Alain Puisieux Alan J Mighell Philip A Robinson Chris F Inglehearn John D Isaacs Alex F Markham 《BMC biotechnology》2003,3(1):1-13
Background
Real-time PCR is increasingly being adopted for RNA quantification and genetic analysis. At present the most popular real-time PCR assay is based on the hybridisation of a dual-labelled probe to the PCR product, and the development of a signal by loss of fluorescence quenching as PCR degrades the probe. Though this so-called 'TaqMan' approach has proved easy to optimise in practice, the dual-labelled probes are relatively expensive.Results
We have designed a new assay based on SYBR-Green I binding that is quick, reliable, easily optimised and compares well with the published assay. Here we demonstrate its general applicability by measuring copy number in three different genetic contexts; the quantification of a gene rearrangement (T-cell receptor excision circles (TREC) in peripheral blood mononuclear cells); the detection and quantification of GLI, MYC-C and MYC-N gene amplification in cell lines and cancer biopsies; and detection of deletions in the OPA1 gene in dominant optic atrophy.Conclusion
Our assay has important clinical applications, providing accurate diagnostic results in less time, from less biopsy material and at less cost than assays currently employed such as FISH or Southern blotting. 相似文献110.
Engelhardt OG Boutell C Orr A Ullrich E Haller O Everett RD 《Experimental cell research》2003,283(1):36-50