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81.
Quan-Xiang Wei Rainer Claus Thomas Hielscher Daniel Mertens Aparna Raval Christopher C. Oakes Stephan M. Tanner Albert de la Chapelle John C. Byrd Stephan Stilgenbauer Christoph Plass 《PloS one》2013,8(1)
We previously reported a rare germline variant (c.1-6531) that resulted in allele–specific expression (ASE) of death-associated protein kinase 1 (DAPK1) and predisposition to chronic lymphocytic leukemia (CLL). We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of DAPK1. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE) with MALDI-TOF mass spectrometry, and detected germline DAPK1 ASE in 17 out of 120 (14.2%) CLL patients associated with a trend towards younger age at diagnosis. ASE was absent in 63 healthy controls. Germline cells of CLL patients with ASE showed increased levels of DNA methylation in the promoter region, however, neither genetic nor further epigenetic aberrations could be identified in the DAPK1 5′ upstream regulatory region, within distinct exons or in the 3′-UTR. We identified B-lymphoid malignancy related cell line models harboring allelic imbalance and found that allele-specific methylation in DAPK1 is associated with ASE. Our data indicate that ASE at the DAPK1 gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL. 相似文献
82.
Sascha Venturelli Alexander Berger Alexander B?cker Christian Busch Timo Weiland Seema Noor Christian Leischner Sabine Schleicher Mascha Mayer Thomas S. Weiss Stephan C. Bischoff Ulrich M. Lauer Michael Bitzer 《PloS one》2013,8(8)
The polyphenolic alcohol resveratrol has demonstrated promising activities for the prevention and treatment of cancer. Different modes of action have been described for resveratrol including the activation of sirtuins, which represent the class III histone deacetylases (HDACs). However, little is known about the activity of resveratrol on the classical HDACs of class I, II and IV, although these classes are involved in cancer development or progression and inhibitors of HDACs (HDACi) are currently under investigation as promising novel anticancer drugs. We could show by in silico docking studies that resveratrol has the chemical structure to inhibit the activity of different human HDAC enzymes. In vitro analyses of overall HDAC inhibition and a detailed HDAC profiling showed that resveratrol inhibited all eleven human HDACs of class I, II and IV in a dose-dependent manner. Transferring this molecular mechanism into cancer therapy strategies, resveratrol treatment was analyzed on solid tumor cell lines. Despite the fact that hepatocellular carcinoma (HCC) is known to be particularly resistant against conventional chemotherapeutics, treatment of HCC with established HDACi already has shown promising results. Testing of resveratrol on hepatoma cell lines HepG2, Hep3B and HuH7 revealed a dose-dependent antiproliferative effect on all cell lines. Interestingly, only for HepG2 cells a specific inhibition of HDACs and in turn a histone hyperacetylation caused by resveratrol was detected. Additional testing of human blood samples demonstrated a HDACi activity by resveratrol ex vivo. Concluding toxicity studies showed that primary human hepatocytes tolerated resveratrol, whereas in vivo chicken embryotoxicity assays demonstrated severe toxicity at high concentrations. Taken together, this novel pan-HDACi activity opens up a new perspective of resveratrol for cancer therapy alone or in combination with other chemotherapeutics. Moreover, resveratrol may serve as a lead structure for chemical optimization of bioavailability, pharmacology or HDAC inhibition. 相似文献
83.
Yara Koréissi-Dembélé Nadia Fanou-Fogny Diego Moretti Stephan Schuth Romain A. M. Dossa Ines Egli Michael B. Zimmermann Inge D. Brouwer 《PloS one》2013,8(10)
Low iron and high phytic acid content make fonio based meals a poor source of bioavailable iron. Phytic acid degradation in fonio porridge using whole grain cereals as phytase source and effect on iron bioavailability when added to iron fortified fonio meals were investigated. Grains, nuts and seeds collected in Mali markets were screened for phytic acid and phytase activity. We performed an iron absorption study in Beninese women (n = 16), using non-dephytinised fonio porridge (FFP) and dephytinised fonio porridge (FWFP; 75% fonio-25% wheat), each fortified with 57Fe or 58Fe labeled FeSO4. Iron absorption was quantified by measuring the erythrocyte incorporation of stable iron isotopes. Phytic acid varied from 0.39 (bambara nut) to 4.26 g/100 g DM (pumpkin seed), with oilseeds values higher than grains and nuts. Phytase activity ranged from 0.17±1.61 (fonio) to 2.9±1.3 phytase unit (PU) per g (whole wheat). Phytic acid was almost completely degraded in FWFP after 60 min of incubation (pH≈5.0, 50°C). Phytate∶iron molar ratios decreased from 23.7∶1 in FFP to 2.7∶1 in FWFP. Iron fortification further reduced phytate∶iron molar ratio to 1.9∶1 in FFP and 0.3∶1 in FWFP, respectively. Geometric mean (95% CI) iron absorption significantly increased from 2.6% (0.8–7.8) in FFP to 8.3% (3.8–17.9) in FWFP (P<0.0001). Dephytinisation of fonio porridge with intrinsic wheat phytase increased fractional iron absorption 3.2 times, suggesting it could be a possible strategy to decrease PA in cereal-based porridges. 相似文献
84.
Reconstructing the function and behaviour of extinct groups of echinoderms is problematic because there are no modern analogues for their aberrant body plans. Cinctans, an enigmatic group of Cambrian echinoderms, exemplify this problem: their asymmetrical body plan differentiates them from all living species. Here, we used computational fluid dynamics to analyse the functional performance of cinctans without assuming an extant comparative model. Three-dimensional models of six species from across cinctan phylogeny were used in computer simulations of water flow. The results demonstrate that cinctans with strongly flattened bodies produced much less drag than species characterized by dorsal protuberances or swellings, suggesting the former were more stable on the seafloor. However, unlike the flattened forms, cinctans with high-relief bodies were able to passively direct flow towards the mouth and associated food grooves, indicating that they were capable of more efficient feeding on particles suspended in the water. This study provides evidence of a previously unknown evolutionary trade-off between feeding and stability in Cambrian cinctan echinoderms. 相似文献
85.
86.
Palanivel Mathangi Mac Aogáin Micheál Purbojati Rikky W. Uchida Akira Aung Ngu War Lim Serene B. Y. Putra Alexander Drautz-Moses Daniela I. Seaton Shila Rogers Thomas R. Schuster Stephan C. Chotirmall Sanjay H. 《Mycopathologia》2020,185(2):405-408
Mycopathologia - Aspergillus terreus species complex is an opportunistic fungal pathogen increasingly implicated in invasive infection, as well as chronic respiratory disease. Currently, an... 相似文献
87.
88.
Elaine T. Lim Soumya Raychaudhuri Stephan J. Sanders Christine Stevens Aniko Sabo Daniel G. MacArthur Benjamin M. Neale Andrew Kirby Douglas M. Ruderfer Menachem Fromer Monkol Lek Li Liu Jason Flannick Stephan Ripke Uma Nagaswamy Donna Muzny Jeffrey G. Reid Alicia Hawes Mark J. Daly 《Neuron》2013,77(2):235-242
89.
Steffen Willwacher Katina Mira Fischer Rita Benker Stephan Dill Gert–Peter Brüggemann 《Journal of biomechanics》2013
The purpose of the present study was to identify kinetic responses to running on mediolaterally elevated (cross-sloped) running surfaces. Ground reaction forces (GRFs), GRF lever arms and joint moment characteristics of 19 male runners were analyzed when running at 3.5 m/s on a custom-made, tiltable runway. Tilt angles of 3° and 6° for medial and lateral elevation were analyzed using a 10 camera Vicon Nexus system and a force platform. The point of force application of the GRF showed a systematic shift in the order of 1–1.5 cm to either the lateral or medial aspect of the foot for lateral or medial inclinations, respectively. Consequently, the strongest significant effects of tilt orientation and level on joint kinetics and ground reaction force lever arms were identified at the ankle, knee and hip joint in the frontal plane of movement. External eversion moments at the ankle were significantly increased by 35% for 6° of lateral elevation and decreased by 16% for 6° of medial elevation. Altering the cross-slope of the running surface changed the pattern of ankle joint moments in the transversal plane. Effect sizes were on average larger for laterally elevated conditions, indicating a higher sensitivity of kinetic parameters to this kind of surface tilt. These alterations in joint kinetics should be considered in the choice of the running environment, especially for specific risk groups, like runners in rehabilitation processes. 相似文献
90.
Kerstin Vocke Kristin Dauner Anne Hahn Anne Ulbrich Jana Broecker Sandro Keller Stephan Frings Frank M?hrlen 《The Journal of general physiology》2013,142(4):381-404
Calcium-dependent chloride channels serve critical functions in diverse biological systems. Driven by cellular calcium signals, the channels codetermine excitatory processes and promote solute transport. The anoctamin (ANO) family of membrane proteins encodes three calcium-activated chloride channels, named ANO 1 (also TMEM16A), ANO 2 (also TMEM16B), and ANO 6 (also TMEM16F). Here we examined how ANO 1 and ANO 2 interact with Ca2+/calmodulin using nonstationary current analysis during channel activation. We identified a putative calmodulin-binding domain in the N-terminal region of the channel proteins that is involved in channel activation. Binding studies with peptides indicated that this domain, a regulatory calmodulin-binding motif (RCBM), provides two distinct modes of interaction with Ca2+/calmodulin, one at submicromolar Ca2+ concentrations and one in the micromolar Ca2+ range. Functional, structural, and pharmacological data support the concept that calmodulin serves as a calcium sensor that is stably associated with the RCBM domain and regulates the activation of ANO 1 and ANO 2 channels. Moreover, the predominant splice variant of ANO 2 in the brain exhibits Ca2+/calmodulin-dependent inactivation, a loss of channel activity within 30 s. This property may curtail ANO 2 activity during persistent Ca2+ signals in neurons. Mutagenesis data indicated that the RCBM domain is also involved in ANO 2 inactivation, and that inactivation is suppressed in the retinal ANO 2 splice variant. These results advance the understanding of Ca2+ regulation in anoctamin Cl− channels and its significance for the physiological function that anoctamin channels subserve in neurons and other cell types. 相似文献