Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension

<p>Aims: Pulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH.</p> <p>Methods and results: Dfen (5 mg kg−1 day−1 PO for 28 days) increased right ventricular pressure and pulmonary vascular remodelling in female mice only. Mice dosed with Dfen showed increased whole lung expression of CYP1B1 and Dfen-induced PAH was ablated in CYP1B1−/− mice. In line with this, Dfen up-regulated expression of CYP1B1 in PASMCs from PAH patients (PAH-PASMCs) and Dfen-mediated proliferation of PAH-PASMCs was ablated by pharmacological inhibition of CYP1B1. Dfen increased expression of tryptophan hydroxylase 1 (Tph1; the rate-limiting enzyme in the synthesis of serotonin) in PAH-PASMCs and both Dfen-induced proliferation and Dfen-induced up-regulation of CYP1B1 were ablated by inhibition of Tph1. 17β-Oestradiol increased expression of both Tph1 and CYP1B1 in PAH-PASMCs, and Dfen and 17β-oestradiol had synergistic effects on proliferation of PAH-PASMCs. Finally, ovariectomy protected against Dfen-induced PAH in female mice.</p> <p>Conclusion: CYP1B1 is critical in the development of Dfen-induced PAH in mice in vivo and proliferation of PAH-PASMCs in vitro. CYP1B1 may provide a novel therapeutic target for PAH.</p&gt

Influence of supramolecular forces on the linear viscoelasticity of gluten

Stress relaxation behavior of hydrated gluten networks was investigated by means of rheometry combined with μ-computed tomography (μ-CT) imaging. Stress relaxation behavior was followed over a wide temperature range (0–70 °C). Modulation of intermolecular bonds was achieved with urea or ascorbic acid in an effort to elucidate the presiding intermolecular interactions over gluten network relaxation. Master curves of viscoelasticity were constructed, and relaxation spectra were computed revealing three relaxation regimes for all samples. Relaxation commences with a well-defined short-time regime where Rouse-like modes dominate, followed by a power law region displaying continuous relaxation concluding in a terminal zone. In the latter zone, poroelastic relaxation due to water migration in the nanoporous structure of the network also contributes to the stress relief in the material. Hydrogen bonding between adjacent protein chains was identified as the determinant force that influences the relaxation of the networks. Changes in intermolecular interactions also resulted in changes in microstructure of the material that was also linked to the relaxation behavior of the networks

Distribution of lipids in the grain of wheat (cv Hereward) determined by lipidomic analysis of milling and pearling fractions

Lipidomic analyses of milling and pearling fractions from wheat grain were carried out to determine differences in composition which could relate to the spatial distribution of lipids in the grain. Free fatty acids and triacylglycerols were major components in all fractions, but the relative contents of polar lipids varied, particularly lysophosphatidyl choline and digalactosyldiglyceride, which were enriched in flour fractions. By contrast, minor phospholipids were enriched in bran and offal fractions. The most abundant fatty acids in the analysed acyl lipids were C16:0 and C18:2 and their combinations, including C36:4 and C34:2. Phospholipids and galactolipids have been reported to have beneficial properties for bread making, while free fatty acids and triacylglycerols are considered detrimental. The subtle differences in the compositions of fractions determined in the present study could therefore underpin the production of flour fractions with optimised compositions for different end uses

New Insights into the Organization, Recombination, Expression and Functional Mechanism of Low Molecular Weight Glutenin Subunit Genes in Bread Wheat

The bread-making quality of wheat is strongly influenced by multiple low molecular weight glutenin subunit (LMW-GS) proteins expressed in the seeds. However, the organization, recombination and expression of LMW-GS genes and their functional mechanism in bread-making are not well understood. Here we report a systematic molecular analysis of LMW-GS genes located at the orthologous Glu-3 loci (Glu-A3, B3 and D3) of bread wheat using complementary approaches (genome wide characterization of gene members, expression profiling, proteomic analysis). Fourteen unique LMW-GS genes were identified for Xiaoyan 54 (with superior bread-making quality). Molecular mapping and recombination analyses revealed that the three Glu-3 loci of Xiaoyan 54 harbored dissimilar numbers of LMW-GS genes and covered different genetic distances. The number of expressed LMW-GS in the seeds was higher in Xiaoyan 54 than in Jing 411 (with relatively poor bread-making quality). This correlated with the finding of higher numbers of active LMW-GS genes at the A3 and D3 loci in Xiaoyan 54. Association analysis using recombinant inbred lines suggested that positive interactions, conferred by genetic combinations of the Glu-3 locus alleles with more numerous active LMW-GS genes, were generally important for the recombinant progenies to attain high Zeleny sedimentation value (ZSV), an important indicator of bread-making quality. A higher number of active LMW-GS genes tended to lead to a more elevated ZSV, although this tendency was influenced by genetic background. This work provides substantial new insights into the genomic organization and expression of LMW-GS genes, and molecular genetic evidence suggesting that these genes contribute quantitatively to bread-making quality in hexaploid wheat. Our analysis also indicates that selection for high numbers of active LMW-GS genes can be used for improvement of bread-making quality in wheat breeding

The Role of Haptic Cues in Musical Instrument Quality Perception

We draw from recent research in violin quality evaluation and piano performance to examine whether the vibrotactile sensation felt when playing a musical instrument can have a perceptual effect on its judged quality from the perspective of the musician. Because of their respective sound production mechanisms, the violin and the piano offer unique example cases and diverse scenarios to study tactile aspects of musical interaction. Both violinists and pianists experience rich haptic feedback, but the former experience vibrations at more bodily parts than the latter. We observe that the vibrotactile component of the haptic feedback during playing, both for the violin and the piano, provides an important part of the integrated sensory information that the musician experiences when interacting with the instrument. In particular, the most recent studies illustrate that vibrations felt at the fingertips (left hand only for the violinist) can lead to an increase in perceived sound loudness and richness, suggesting the potential for more research in this direction

Influence of native lipids on the rheological properties of wheat flour dough and gluten

We report on the viscoelastic properties of dough and gluten (prepared by ultracentrifugation) after the flour lipids had been removed by solvents differing in polarity (chloroform, ethanol and diethylether). The extracted lipids were fractionated by thin layer chromatography. The flours differed in lipid composition after the extraction. Ethanol removed more polar lipids than the other solvents. Removal of lipids (0.6-0.9% on flour weight) altered the viscoelastic properties of dough significantly, whereas those of gluten were only marginally affected. The storage modulus (G') of dough increased with used solvent polarity. The highest value of G' was observed for the dough made with the flour where the lipids were removed by ethanol. This was consistent with a marked decrease in the frequency dependence of G' of dough when the lipids were removed

Developmental and environmental effects on the assembly of glutenin polymers and the impact on grain quality of wheat

Wheat kernel development can be divided into three phases i.e. cell division, cell enlargement and dehydration. Accumulation of gluten proteins continues till the end of the cell enlargement phase. During the dehydration phase, post-translational polymerization of the glutenin subunits occurs to form very large glutenin polymers. Assembly of the glutenin polymers has been monitored by increase in the unextractable polymeric protein. Lines possessing HMW-GS related to dough strength (e.g. 5. +. 10) started accumulating large polymers several days earlier than lines with HMW-GS related to dough weakness (e.g. 2. +. 12) and maintained their higher amounts till maturity. This may be explained by faster polymerization resulting from a higher concentration of cysteine residues in the x-type HMW-GS.Sulphur deficiency leads to an increase in the ratio of HMW- to LMW-GS, causing a shift in the MWD to higher MWs, resulting in bucky dough properties. High temperature during grain development appears to shift the MWD to lower MWs with corresponding lowering of dough strength but the presence of strength-associated HMW-GS appears to confer greater tolerance to heat stress. Since sulphur deficiency and higher global temperatures may be expected to increase in the future, some suggestions how breeders may use strategies to counter these effects are put forward. © 2012 Elsevier Ltd