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771.
Eline K. M. Lebbe Steve Peigneur Mohitosh Maiti Prabha Devi Samuthirapandian Ravichandran Eveline Lescrinier Chris Ulens Etienne Waelkens Lisette D'Souza Piet Herdewijn Jan Tytgat 《The Journal of biological chemistry》2014,289(14):9573-9583
α-Conotoxins are peptide toxins found in the venom of marine cone snails and potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). nAChRs are cholinergic receptors forming ligand-gated ion channels in the plasma membranes of certain neurons and the neuromuscular junction. Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies such as epilepsy, myasthenic syndromes, schizophrenia, Parkinson disease, and Alzheimer disease. To expand the knowledge concerning cone snail toxins, we examined the venom of Conus longurionis. We isolated an 18-amino acid peptide named α-conotoxin Lo1a, which is active on nAChRs. To the best of our knowledge, this is the first characterization of a conotoxin from this species. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs expressed in Xenopus laevis oocytes. The three-dimensional solution structure of the α-conotoxin Lo1a was determined by NMR spectroscopy. Lo1a, a member of the α4/7 family, blocks the response to acetylcholine in oocytes expressing α7 nAChRs with an IC50 of 3.24 ± 0.7 μm. Furthermore, Lo1a shows a high selectivity for neuronal versus muscle subtype nAChRs. Because Lo1a has an unusual C terminus, we designed two mutants, Lo1a-ΔD and Lo1a-RRR, to investigate the influence of the C-terminal residue. Lo1a-ΔD has a C-terminal Asp deletion, whereas in Lo1a-RRR, a triple-Arg tail replaces the Asp. They blocked the neuronal nAChR α7 with a lower IC50 value, but remarkably, both adopted affinity for the muscle subtype α1β1δϵ. 相似文献
772.
773.
SUMMARY 1. We studied the seasonal succession of phyto- and zooplankton and the potential impact of predation by salmonids on zooplankton population dynamics in a high-mountain Swiss lake.
2. A comparison of patterns in the abundance, body length, fecundity and age structure in the Daphnia galeata population strongly suggests that trout predation had little impact on the population and was not the cause for a decline in summer.
3. The dominance in the lake of adult trout that feed mainly on benthic prey may buffer the effect of predation on the larger zooplankton. Further, the relatively high amount of phytoplankton after spring thaw could be important for sustaining the Daphnia population under moderate fish predation.
4. Partial correlation analyses proved circumstantial evidence for both exploitative and interference competition between some zooplankton taxa. D. galeata depressed performance of other plankton species through exploitative competition.
5. Our study shows that the impact of fish on zooplankton in high-mountain lakes depends strongly on food web structure and trophic state of the lake. Where fish predation is weak, invertebrate predation combined with competition for food may be responsible for the dominance of large-bodied zooplankton species. 相似文献
2. A comparison of patterns in the abundance, body length, fecundity and age structure in the Daphnia galeata population strongly suggests that trout predation had little impact on the population and was not the cause for a decline in summer.
3. The dominance in the lake of adult trout that feed mainly on benthic prey may buffer the effect of predation on the larger zooplankton. Further, the relatively high amount of phytoplankton after spring thaw could be important for sustaining the Daphnia population under moderate fish predation.
4. Partial correlation analyses proved circumstantial evidence for both exploitative and interference competition between some zooplankton taxa. D. galeata depressed performance of other plankton species through exploitative competition.
5. Our study shows that the impact of fish on zooplankton in high-mountain lakes depends strongly on food web structure and trophic state of the lake. Where fish predation is weak, invertebrate predation combined with competition for food may be responsible for the dominance of large-bodied zooplankton species. 相似文献
774.
Mi-Yeon Jang Steven De Jonghe Kristien Van Belle Thierry Louat Mark Waer Piet Herdewijn 《Bioorganic & medicinal chemistry letters》2010,20(3):844-847
The synthesis of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidines is described. The synthetic route allows introducing structural variety at positions 2, 4 and 6 of the scaffold. Evaluation of their immunosuppressive activity in a Mixed Lymphocyte Reaction (MLR) assay revealed that the most potent compound has an IC50-value of 66 nM and therefore deserves attention for further medicinal chemistry optimization. 相似文献
775.
776.
Modeling studies were performed on HCV NS5B polymerase in an effort to design new inhibitors. The binding models of five different
scaffold inhibitors were investigated and compared by using molecular dynamics simulations, free energy calculation and decomposition.
Our results show Tyr448 plays the most critical role in the binding of most inhibitors. In addition, favorable contributions
of residues Pro197, Arg200, Cys366, Met414 and Tyr448 in a deep hydrophobic pocket prove to be important for the selectivity
of inhibitors. Furthermore, an optimized docking protocol was presented based on cross-docking the five inhibitors in the
palm binding site of this enzyme using the Autodock program. This protocol was used later to virtually screen NCI and Maybridge
diversity set libraries. The binding site was profiled via the statistics and analysis of the hydrogen bond networks formed between the receptor and the top-ranked diversity set compounds.
Based on our detailed binding site analysis two useful rules were proposed to guide the selection of promising hits. 相似文献
777.
An automated inhibitor affinity extraction method for the activity-based enrichment of matrix metallo-proteases (MMPs) is presented. Samples containing purified MMP-12 were first extracted at different flow rates in a syringe pump setup, using cartridges packed with an MMP inhibitor affinity sorbent based on an immobilized hydroxamic acid containing peptide (PLG-NHOH) with mumol/L MMP affinity. Faster extractions, a reduced number of manual manipulations, and higher extraction yields (98.9%-99.3%) were obtained over the whole flow rate range compared to batch extractions. Application of the method to synovial fluid from a rheumatoid arthritis patient followed by gelatin-zymography revealed a strong enrichment of distinct MMPs from this biological sample that were not clearly visible in the original sample. The use of an auto-sampler and a solid-phase extraction (SPE) workstation allowed full automation of the extraction procedure with the potential for on-line coupling to further sample preparation and analytical steps. MMP-12 extractions were optimized showing that ligand density is an important factor with a clear extraction yield optimum around 5 to 7.5 mmol/L. Conditioning of the stationary phase for 1 week prior to use resulted in a further slight increase in extraction yield. Under optimal conditions, an extraction yield of 99.5% was reached with a cartridge contact time of only 13 s for MMP-12. The efficacy of the extraction method for activity-based MMP profiling was further improved by the use of a broad-spectrum MMP inhibitor with nmol/L affinity (TAPI-2). This resulted in an increased extraction yield for all tested MMPs. For MMP-1, -7, -8, -10, -12, and -13 extraction yields of at least 98.8% were obtained, while for MMP-9 (full length and catalytic domain) an extraction yield of at least 96.1% was reached. 相似文献
778.
The STAR project: context, objectives and approaches 总被引:20,自引:20,他引:0
Mike Furse Daniel Hering Otto Moog Piet Verdonschot Richard K. Johnson Karel Brabec Kostas Gritzalis Andrea Buffagni Paulo Pinto Nikolai Friberg John Murray-Bligh Jiri Kokes Renate Alber Philippe Usseglio-Polatera Peter Haase Roger Sweeting Barbara Bis Krzysztof Szoszkiewicz Hanna Soszka Gunta Springe Ferdinand Sporka Il’ja Krno 《Hydrobiologia》2006,566(1):3-29
STAR is a European Commission Framework V project (EVK1-CT-2001-00089). The project aim is to provide practical advice and solutions with regard to many of the issues associated with the Water Framework Directive. This paper provides a context for the STAR research programme through a review of the requirements of the directive and the Common Implementation Strategy responsible for guiding its implementation. The scientific and strategic objectives of STAR are set out in the form of a series of research questions and the reader is referred to the papers in this volume that address those objectives, which include: (a) Which methods or biological quality elements are best able to indicate certain stressors? (b) Which method can be used on which scale? (c) Which method is suited for early and late warnings? (d) How are different assessment methods affected by errors and uncertainty? (e) How can data from different assessment methods be intercalibrated? (f) How can the cost-effectiveness of field and laboratory protocols be optimised? (g) How can boundaries of the five classes of Ecological Status be best set? (h) What contribution can STAR make to the development of European standards? The methodological approaches adopted to meet these objectives are described. These include the selection of the 22 stream-types and 263 sites sampled in 11 countries, the sampling protocols used to sample and survey phytobenthos, macrophytes, macroinvertebrates, fish and hydromorphology, the quality control and uncertainty analyses that were applied, including training, replicate sampling and audit of performance, the development of bespoke software and the project outputs. This paper provides the detailed background information to be referred to in conjunction with most of the other papers in this volume. These papers are divided into seven sections: (1) typology, (2) organism groups, (3) macrophytes and diatoms, (4) hydromorphology, (5) tools for assessing European streams with macroinvertebrates, (6) intercalibration and comparison and (7) errors and uncertainty. The principal findings of the papers in each section and their relevance to the Water Framework Directive are synthesised in short summary papers at the beginning of each section. Additional outputs, including all sampling and laboratory protocols and project deliverables, together with a range of freely downloadable software are available from the project website at www.eu_star.at. 相似文献
779.
van der Maas P van den Brink P Utomo S Klapwijk B Lens P 《Biotechnology and bioengineering》2006,94(3):575-584
BioDeNOx is a novel technique for NOx removal from industrial flue gases. In principle, BioDeNOx is based on NO absorption into an aqueous Fe(II)EDTA2- solution combined with biological regeneration of that scrubber liquor in a bioreactor. The technical and economical feasibility of the BioDeNOx concept is strongly determined by high rate biological regeneration of the aqueous Fe(II)EDTA2- scrubber liquor and by EDTA degradation. This investigation deals with the Fe(II)EDTA2- regeneration capacity and EDTA degradation in a lab-scale BioDeNOx reactor (10-20 mM Fe(II)EDTA2-, pH 7.2 +/- 0.2, 55 degrees C), treating an artificial flue gas (1.5 m3/h) containing 60-155 ppm NO and 3.5-3.9% O2. The results obtained show a contradiction between the optimal redox state of the aqueous FeEDTA solution for NO absorption and the biological regeneration. A low redox potential (below -150 mV vs. Ag/AgCl) is needed to obtain a maximal NO removal efficiency from the gas phase via Fe(II)EDTA2- absorption. Fe(III)EDTA- reduction was found to be too slow to keep all FeEDTA in the reduced state. Stimulation of Fe(III)EDTA- reduction via periodical sulfide additions (2 mM spikes twice a week for the conditions applied in this study) was found to be necessary to regenerate the Fe(II)EDTA2- scrubber liquor and to achieve stable operation at redox potentials below -150 mV (pH 7.2 +/- 0.2). However, redox potentials of below -200 mV should be avoided since sulfide accumulation is unwanted because it is toxic for NO reduction. Very low values for biomass growth rate and yield, respectively, 0.043/d and 0.009 mg protein per mg ethanol, were observed. This might be due to substrate limitations, that is the electron acceptors NO and presumably polysulfide, or to physiological stress conditions induced by the EDTA rich medium or by radicals formed in the scrubber upon the oxidation of Fe(II)EDTA2- by oxygen present in the flue gas. Radicals possibly also induce EDTA degradation, which occurs at a substantial rate: 2.1 (+/-0.1) mM/d under the conditions investigated. 相似文献
780.
This paper reports on the findings of the Biomedical Research Institute, as one of the participants in the pilot study of the HUPO Brain Proteome Project. A biopsy and autopsy study sample derived from human brain was distributed among the participants for proteomic analysis. In our laboratory, attention was focused on protein identification using the bottom-up shotgun approach. Protein extracts derived from both samples were trypsinized and analyzed separately by 2-D LC and MS. In a complementary approach, the tryptic digests were analyzed directly by LC-ESI-MS/MS and gas-phase fractionation in the mass spectrometer. Taken together, both proteomic approaches in combination with a stringent evaluation process, resulted in the confident identification of 209 proteins in the human brain samples under investigation. 相似文献