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51.
Moorjani M Luo Z Lin E Vong BG Chen Y Zhang X Rueter JK Gross RS Lanier MC Tellew JE Williams JP Lechner SM Malany S Santos M Crespo MI Díaz JL Saunders J Slee DH 《Bioorganic & medicinal chemistry letters》2008,18(20):5402-5405
In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model. 相似文献
52.
Here, the class I polyhydroxyalkanoate synthase (PhaC) from Ralstonia eutropha was investigated regarding the functionality of its conserved C-terminal region and its ability to tolerate translational fusions to its C terminus. MalE, the maltose binding protein, and green fluorescent protein (GFP) were considered reporter proteins to be translationally fused to the C terminus. Interestingly, PhaC remained active only when a linker was inserted between PhaC and MalE, whereas MalE was not functional. However, the extension of the PhaC N terminus by 458 amino acid residues was required to achieve a functionality of MalE. These data suggested a positive interaction of the extended N terminus with the C terminus. To assess whether a linker and/or N-terminal extension is generally required for a functional C-terminal fusion, GFP was fused to the C terminus of PhaC. Both fusion partners were active without the requirement of a linker and/or N-terminal extension. A further reporter protein, the immunoglobulin G binding ZZ domain of protein A, was translationally fused to the N terminus of the fusion protein PhaC-GFP and resulted in a tripartite fusion protein mediating the production of polyester granules displaying two functional protein domains.Polyhydroxyalkanoates (PHAs) are biopolyesters synthesized by many bacteria and some archaea in times of unbalanced nutrient availability (7, 14-16, 22). These polyesters are stored as water-insoluble inclusions inside the cells and serve as energy and carbon storage (11, 29, 30). PHA synthases catalyze the stereoselective conversion of (R)-3-hydroxyacyl-coenzyme A (CoA) to PHAs while CoA is released and intracellular PHA granules are formed (32). The PHA synthase remains covalently attached to the PHA granule surface and has been targeted by protein engineering, i.e., translational fusion to the dispensable and variable N terminus, to enable the display of various protein functions without affecting the synthase activity (8, 26). PHA granules displaying certain functionalities have been considered as biobeads for biotechnological and medical applications (11).PHA synthases can be divided into four classes. Class I and class II enzymes consist of only one subunit (PhaC) (28) and produce short-chain-length PHAs (class I) or medium-chain-length PHAs (class II), respectively (30, 33). Polyester synthases belonging to class III consist of two subunits, PhaC and PhaE, and produce short-chain-length PHAs (20, 21). Class IV PHA synthases are similar to enzymes belonging to class III. The synthases of this class comprise the two subunits PhaC and PhaR (23, 24).It was previously shown that the N terminus of PhaC is a highly variable region and not essential for PHA synthase activity (30, 35). In contrast, the C terminus is a rather conserved region among class I and class II PHA synthases and is essential for enzyme activity (31). Alignments of the amino acid sequences of different PHA synthases revealed that the C terminus of these enzymes is hydrophobic and was therefore suggested to interact with the hydrophobic core of PHA granules (30). The PhaC subunits of class III and class IV PHA synthases do not show a high hydrophobicity for their C- terminal regions. Previous studies showed that the PhaC subunit of the class IV PHA synthase from Bacillus megaterium tolerates fusions to its C terminus without a loss in activity as long as the hydrophobic second subunit, PhaR, is present as well (23).The aim of this study was to assess the effect of the conserved hydrophobic C terminus of PhaC on enzyme activity with regard to the possibility of translationally fusing protein functions for display at the PHA granule surface. This will be of interest for the display of proteins that require their free C terminus for activity. 相似文献
53.
Robert Hoehndorf Anika Oellrich Michel Dumontier Janet Kelso Dietrich Rebholz-Schuhmann Heinrich Herre 《BMC bioinformatics》2010,11(1):441
Background
Most biomedical ontologies are represented in the OBO Flatfile Format, which is an easy-to-use graph-based ontology language. The semantics of the OBO Flatfile Format 1.2 enforces a strict predetermined interpretation of relationship statements between classes. It does not allow flexible specifications that provide better approximations of the intuitive understanding of the considered relations. If relations cannot be accurately expressed then ontologies built upon them may contain false assertions and hence lead to false inferences. Ontologies in the OBO Foundry must formalize the semantics of relations according to the OBO Relationship Ontology (RO). Therefore, being able to accurately express the intended meaning of relations is of crucial importance. Since the Web Ontology Language (OWL) is an expressive language with a formal semantics, it is suitable to de ne the meaning of relations accurately. 相似文献54.
Integrins link the extracellular matrix to the actin cytoskeleton by triggering the assembly of different types of adhesion complex. One of their major components is filamentous actin (F-actin), and they are important signaling hubs for actin cytoskeleton reorganization in response to chemical and mechanical signals. In an exciting publication, Butler et al. have demonstrated for the first time that purified adhesion complexes possess the entire machinery necessary to actively assemble F-actin as a function of integrin activity and clustering. 相似文献
55.
Multiple factors influence the role of arbuscular mycorrhizal fungi in soil aggregation—a meta-analysis 总被引:1,自引:0,他引:1
Eva F. Leifheit Stavros D. Veresoglou Anika Lehmann E. Kathryn Morris Matthias C. Rillig 《Plant and Soil》2014,374(1-2):523-537
Background and aims
Soil aggregation is a crucial aspect of ecosystem functioning in terrestrial ecosystems. Arbuscular mycorrhizal fungi (AMF) play a key role in soil aggregate formation and stabilization. Here we quantitatively analyzed the importance of experimental settings as well as biotic and abiotic factors for the effectiveness of AMF to stabilize soil macroaggregates.Methods
We gathered 35 studies on AMF and soil aggregation and tested 13 predictor variables for their relevance with a boosted regression tree analysis and performed a meta-analysis, fitting individual random effects models for each variable.Results and conclusions
The overall mean effect of inoculation with AMF on soil aggregation was positive and predictor variable means were all in the range of beneficial effects. Pot studies and studies with sterilized sandy soil, near neutral soil pH, a pot size smaller than 2.5 kg and a duration between 2.2 and 5 months were more likely to result in stronger effects of AMF on soil aggregation than experiments in the field, with non-sterilized or fine textured soil or an acidic pH. This is the first study to quantitatively show that the effect of AMF inoculation on soil aggregation is positive and context dependent. Our findings can help to improve the use of this important ecosystem process, e.g. for inoculum application in restoration sites. 相似文献56.
57.
58.
Manuel Hiss Rasa M. Meskauskiene Muhammad A. Arif Eva L. Decker Anika Erxleben Wolfgang Frank Sebastian T. Hanke Daniel Lang Anja Martin Christina Neu Ralf Reski Sandra Richardt Mareike Schallenberg‐Rüdinger Peter Szövényi Theodhor Tiko Gertrud Wiedemann Luise Wolf Philip Zimmermann Stefan A. Rensing 《The Plant journal : for cell and molecular biology》2014,79(3):530-539
59.
Sonja A. Kotz Anika Stockert Michael Schwartze 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2014,369(1658)
We live in a dynamic and changing environment, which necessitates that we adapt to and efficiently respond to changes of stimulus form (‘what’) and stimulus occurrence (‘when’). Consequently, behaviour is optimal when we can anticipate both the ‘what’ and ‘when’ dimensions of a stimulus. For example, to perceive a temporally expected stimulus, a listener needs to establish a fairly precise internal representation of its external temporal structure, a function ascribed to classical sensorimotor areas such as the cerebellum. Here we investigated how patients with cerebellar lesions and healthy matched controls exploit temporal regularity during auditory deviance processing. We expected modulations of the N2b and P3b components of the event-related potential in response to deviant tones, and also a stronger P3b response when deviant tones are embedded in temporally regular compared to irregular tone sequences. We further tested to what degree structural damage to the cerebellar temporal processing system affects the N2b and P3b responses associated with voluntary attention to change detection and the predictive adaptation of a mental model of the environment, respectively. Results revealed that healthy controls and cerebellar patients display an increased N2b response to deviant tones independent of temporal context. However, while healthy controls showed the expected enhanced P3b response to deviant tones in temporally regular sequences, the P3b response in cerebellar patients was significantly smaller in these sequences. The current data provide evidence that structural damage to the cerebellum affects the predictive adaptation to the temporal structure of events and the updating of a mental model of the environment under voluntary attention. 相似文献
60.
Anika I Tsuchida Michiel Beekhuizen Marieke C ‘t Hart Timothy RDJ Radstake Wouter JA Dhert Daniel BF Saris Gerjo JVM van Osch Laura B Creemers 《Arthritis research & therapy》2014,16(5)