227 resultados para Sub-microscopic
em QUB Research Portal - Research Directory and Institutional Repository for Queen's University Belfast
Resumo:
The biased agonism of the G protein-coupled receptors (GPCRs), where in addition to a traditional G protein-signalling pathway a GPCR promotes intracellular signals though ß-arrestin, is a novel paradigm in pharmacology. Biochemical and biophysical studies have suggested that a GPCR forms a distinct ensemble of conformations signalling through the G protein and ß-arrestin. Here we report on the dynamics of the ß2 adrenergic receptor bound to the ß-arrestin and G protein biased agonists and the empty receptor to further characterize the receptor conformational changes caused by biased agonists. We use conventional and accelerated molecular dynamics (aMD) simulations to explore the conformational transitions of the GPCR from the active state to the inactive state. We found that aMD simulations enable monitoring the transition within the nanosecond timescale while capturing the known microscopic characteristics of the inactive states, such as the ionic lock, the inward position of F6.44, and water clusters. Distinct conformational states are shown to be stabilized by each biased agonist. In particular, in simulations of the receptor with the ß-arrestin biased agonist, N-cyclopentylbutanepherine we observe a different pattern of motions in helix 7 when compared to simulations with the G protein biased agonist, Salbutamol that involves perturbations of the network of interactions within the NPxxY motif. Understanding the network of interactions induced by biased ligands and the subsequent receptor conformational shifts will lead to development of more efficient drugs. © 2013 American Chemical Society
Resumo:
Using first principles calculations for O vacancy diffusion on CeO2(111), we locate a surface diffusion mechanism, the two-step O vacancy exchange one, which is more favored than the most common hopping mechanism. By analyzing the results, we identify quantitatively the physical origin of why the two-step exchange mechanism is preferred.
Resumo:
The European lobster is distributed throughout the south and western regions of the Norwegian coast. A previous lobster allozyme investigation (1993) in the Tysfjord region, north of the Arctic Circle demonstrated that the lobster population from this region was genetically different from lobster samples collected in other parts of Norway. More detailed investigation including supplementary extensive sampling and additional allozyme, microsatellite and mtDNA analyses are reported here. This investigation supports the genetic distinctness of the Tysfjord population and shows that this is mainly due to a reduction (60�70%) in gene diversity (observed heterozygosities and number of alleles) compared with lobsters from more southern regions. In addition to the Tysfjord region, the comprehensive sampling also included lobsters found in the adjacent Nordfolda fjord system. Genetic analyses provided evidence for significant differences between the lobster populations of Tysfjord and Nordfolda, even though they are separated by a coastal distance of only 142 km. The two populations were also different with regards to several biological characteristics such as body size. The genetic difference between these two geographically close populations is likely to be due to the local hydrological conditions, preventing larval dispersal between the fjord systems. Assessment of lobster abundance in the north-west region suggests that the sub-arctic lobster populations are geographically isolated.
Resumo:
The two major incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), are currently being considered as prospective drug candidates for treatment of type 2 diabetes. Interest in these gut hormones was initially spurred by their potent insulinotropic activities, but a number of other antihyperglycaemic actions are now established. One of the foremost barriers in progressing GLP-1 and GIP to the clinic concerns their rapid degradation and inactivation by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV). Here, we compare the DPP IV resistance and biological properties of Abu(8)/ Abu(2) (2-aminobutyric acid) substituted analogues of GLP-1 and GIP engineered to impart DPP IV resistance. Whereas (Abu(8))GLP-1 was completely stable to human plasma (half-life > 12h), GLP-1, GIP, and (Abu(2))GIP were rapidly degraded (half-lives: 6.2, 6.0, and 7.1 h, respectively). Native GIP, GLP-1, and particularly (Abu(8))GLP-1 elicited significant adenylate cyclase and insulinotropic activity, while (Abu(2))GIP was less effective. Similarly, in obese diabetic (ob/ob) mice, GIP, GLP-1, and (Abu(8))GLP-1 displayed substantial glucose-lowering and insulin -releasing activities, whereas (Abu(2))GIP was only weakly active. These studies illustrate divergent effects of penultimate amino acid Ala(8)/Ala(2) substitution with Abu on the biological properties of GLP-1 and GIP, suggesting that (Abu(8))GLP-1 represents a potential candidate for future therapeutic development. (C) 2004 Elsevier Inc. All rights reserved.
Resumo:
Two 17-mer oligodeoxynucleotide-5'-linked-(6,7-diphenylpterin) conjugates, 2 and 3, were prepared as photosensitisers for targeting photooxidative damage to a 34-mer DNA oligodeoxynucleotide (ODN) fragment 1 representing the chimeric bcr-abl gene that is implicated in the pathogenesis of chronic myeloid leukaemia (CML). The base sequence in the 17-mer was 3'G G T A G T T A T T C C T T C T T5'. In the first of these ODN conjugates (2) the pterin was attached at its N3 atom, via a -(CH2)3OPO(OH)- linker, to the 5'-OH group of the ODN. Conjugate 2 was prepared from 2-amino-3-(3-hydroxypropyl)-6,7-diphenyl-4(3H)-pteridinone 10, using phosphoramidite methodology. Starting material 10 was prepared from 5-amino-7-methylthiofurazano[3,4-d]pyrimidine 4 via an unusual highly resonance stabilised cation 8, incorporating the rare 2H,6H-pyrimido[6,1-b][1,3]oxazine ring system. In the characterisation of 10 two pteridine phosphazenes, 15 and 29, were obtained, as well as new products containing two uncommon tricyclic ring systems, namely pyrimido[2,1-b]pteridine (20 and 24) and pyrimido[1,2-c]pteridine (27). In the second ODN conjugate the linker was -(CH2)5CONH(CH2)6OPO(OH)- and was attached to the 2-amino group of the pterin. In the preparation of 3, the N-hydroxysuccinimide ester 37 of 2-(5-carboxypentylamino)-6,7-diphenyl-4(3H)-pteridinone was condensed with the hexylamino-modified 17-mer. Excitation of 36 with near UV light in the presence of the single-stranded target 34-mer, 5'T G A C C A T C A A T A A G14 G A A G18 A A G21 C C C T T C A G C G G C C3' 1 caused oxidative damage at guanine bases, leading to alkali-labile sites which were monitored by polyacrylamide gel electrophoresis. Cleavage was observed at all guanine sites with a marked preference for cleavage at G14. In contrast, excitation of ODN-pteridine conjugate 2 in the presence of 1 caused oxidation of the latter predominantly at G18, with a smaller extent of cleavage at G15 and G14 (in the double-stranded portion) and G21. These results contrast with our previous observation of specific cleavage at G21 with ruthenium polypyridyl sensitisers, and suggest that a different mechanism, probably one involving Type 1 photochemical electron transfer, is operative. Much lower yields were found with the ODN-pteridine conjugate 3, perhaps as a consequence of the longer linker between the ODN and the pteridine in this case.
Resumo:
In this paper we have conclusively proven that the "enhanced" optical transmission through a periodic array of sub-wavelength holes in metal films (Ebbessen's experiment) is the result of the array periodicity. This work has overturned the commonly accepted theory that the surface plasmons were responsible for the transmission enhancement. It was demonstrated that the reflectance, transmittance and frequency selectivity of the multilayered arrays can be efficiently modified by the aperture shapes.
Resumo:
In this paper, we show that a multilayer freestanding slot array can be designed to give an insertion loss which is significantly lower than the value obtainable from a conventional dielectric backed printed frequency selective surface (FSS). This increase in filter efficiency is highlighted by comparing the performance of two structures designed to provide frequency selective beamsplitting in the quasioptical feed train of a submillimeter wave space borne radiometer. A two layer substrateless FSS providing more than 20 dB of isolation between the bands 316.5â??325.5 GHz and 349.5â??358.5 GHz, gives an insertion loss of 0.6 dB when the filter is orientated at 45 incidence in the TM plane, whereas the loss exhibited by a conventional printed FSS is in excess of 2 dB. A similar frequency response can be obtained in the TE plane, but here a triple screen structure is required and the conductor loss is shown to be comparable to the absorption loss of a dielectric backed FSS. Experimental devices have been fabricated using a precision micromachining technique. Transmission measurements performed in the range 250â??360 GHz are in good agreement with the simulated spectral performance of the individual periodic screens and the two multilayer freestanding FSS structures.