Effect of Fluticasone propionate Aqueous Nasal Spray Treatment on Platelet Activating Factor and Eicosanoid Production By nasal Mucosa in Patients with A house Dust Mite Allergy

The relationship between the release of platelet activating factor (PAF), leukotriene C4/D4/EE (LTC4/D4/E4) and prostaglandin D2 (PGD2) from nasal mucosa in vivo was examined in 24 rhinitis patients allergic to the house dust mite (HDM). During a double blind placebo controlled cross-over study 200 μg fluticasone propionate aqueous nasal spray (FPANS) was administered twice daily for two weeks. In response to allergen provocation (100, 1 000, 10 000 Bu/ml) and during the 9.5 h after this challenge the nasal fluid was obtained by washing the nose with saline and the levels of PAF, LTC4/D4/E4 and PGD2, as indicators of mediator release, were measured at the following time-points: baseline (t = − 1/2), allergen provocation with 10 000 Bu/ml (t = 0), 3.5 and 7.5 h (late phase). After allergen provocation the levels of the mediators increased in the nasal fluids of placebo treated patients (x-fold increase to baseline: PAF, 15; LTC4/D4/E4, 12; PGD2, 1.5). In fluids of patients treated with FPANS these levels tended to decrease. At the time of provocation the levels of PAF, LTC4/D4/E4 and PGD2 showed a significant correlation. The results indicate that these mediators can be used as markers of allergic reactions against house dust mites and that fluticasone propionate aqueous nasal spray tended to reduce the release of mediators of inflammation correlated with beneficial effects on clinical symptoms in this type of allergic reactions

Interplay of erythropoietin, fibroblast growth factor 23, and erythroferrone in patients with hereditary hemolytic anemia

Recently, erythropoietin (EPO) was identified as regulator of fibroblast growth factor 23 (FGF23). Proteolytic cleavage of biologically active intact FGF23 (iFGF23) results in the formation of C-terminal fragments (cFGF23). An increase in cFGF23 relative to iFGF23 suppresses FGF receptor signaling by competitive inhibition. EPO lowers the i:cFGF23 ratio, thereby overcoming iFGF23-mediated suppression of erythropoiesis. We investigated EPO-FGF23 signaling and levels of erythroferrone (ERFE) in 90 patients with hereditary hemolytic anemia (www.trialregister.nl [NL5189]). We show, for the first time, the importance of EPO-FGF23 signaling in hereditary hemolytic anemia: there was a clear correlation between total FGF23 and EPO levels (r = +0.64; 95% confidence interval [CI], 0.09-0.89), which persisted after adjustment for iron load, inflammation, and kidney function. There was no correlation between iFGF23 and EPO. Data are consistent with a low i:cFGF23 ratio. Therefore, as expected, we report a correlation between EPO and ERFE in a diverse set of hereditary hemolytic anemias (r = +0.47; 95% CI, 0.14-0.69). There was no association between ERFE and total FGF23 or iFGF23, which suggests that ERFE does not contribute to the connection between FGF23 and EPO. These findings open a new area of research and might provide potentially new druggable targets with the opportunity to ameliorate ineffective erythropoiesis and the development of disease complications in hereditary hemolytic anemias

Effects of Metformin on the Regulation of Free Fatty Acids in Insulin Resistance: A Double-Blind, Placebo-Controlled Study

Introduction. Impaired free fatty acid (FFA) metabolism is closely linked to insulin resistance. Our aim was to evaluate plasma FFA changes in insulin resistance in a physiological situation after improvement of insulin sensitivity by metformin. Methods. A double-blind, placebo-controlled intervention with metformin was carried out in patients with insulin resistance. Nineteen patients were randomized to receive metformin 850 mg b.i.d. during 6 weeks or placebo. Participants underwent a mental stress test and an oral glucose tolerance test (OGTT) before and after treatment. Results. Fasting plasma glucose, FFA, and HOMA-IR tended to decrease after metformin, suggesting improved insulin sensitivity. FFA concentrations during the mental stress test showed a similar pattern after metformin, albeit lower at all time points, in contrast to the placebo group. The decrease in fasting plasma FFAs was positively associated to the decrease in HbA1c (; ) and in fasting glucose (; ). The suppression of plasma FFAs during OGTT did not change by metformin or placebo. Conclusion. Metformin in insulin resistance did not lead to improved FFA dynamics despite a trend of improved insulin sensitivity. Metformin most likely decreases plasma FFAs mainly by suppressing fasting FFA concentrations and not by suppression of acute stress-induced lipolysis

Анализ механических состояний силовых систем. Сообщение 1. Предельное состояние

Изложены основы теории предельных состояний силовых систем, которые работают в условиях сложного нагружения (механическая усталость, трение и изнашивание, температура, электрохимическая коррозия). Получен энергетический критерий предельного состояния и описаны методы определения его параметров. Записаны условия прочности с учетом как циклической, так и контактной нагрузок.Викладено основи теорії граничних станів силових систем, що працюють в умовах складного навантаження (механічна утома, тертя та спрацьовування, температура, електрохімічна корозія). Отримано енергетичний критерій граничного стану та описано методи визначення його параметрів. Записано рівняння міцності з урахуванням як циклічного, так і контактного навантажень.Fundamentals of the theory of ultimate states in force systems operating under complex loading (mechanical fatigue, friction and wear, temperature, and electrochemical corrosion) have been described. Energy criterion of an ultimate state has been obtained and methods for calculating its parameters are given. Strength conditions taking into account both cyclic and contact loads are described

A Tonnetz Model for pentachords

This article deals with the construction of surfaces that are suitable for representing pentachords or 5-pitch segments that are in the same $T/I$ class. It is a generalization of the well known \"Ottingen-Riemann torus for triads of neo-Riemannian theories. Two pentachords are near if they differ by a particular set of contextual inversions and the whole contextual group of inversions produces a Tiling (Tessellation) by pentagons on the surfaces. A description of the surfaces as coverings of a particular Tiling is given in the twelve-tone enharmonic scale case.Comment: 27 pages, 12 figure

WLM-1: A Non-Rotating, Gravitationally Unperturbed, Highly Elliptical Extragalactic Globular Cluster

Globular clusters have long been known for presenting (at times) significant deviations from spherical symmetry. While rotation has been the main proposed explanation, other complicating factors such as their constant interaction with the strong gravitational potential of their host galaxy have made it difficult for a consensus to be reached. To address this question we have obtained high-resolution spectra of WLM-1, the lone globular cluster associated with the isolated, low-mass dwarf irregular galaxy WLM. Using archival HST WFPC2 data, we measure the radial ellipticity profile of WLM-1, finding it to be highly elliptical, with a mean value of 0.17 in the region 0.5-5" -- which is comparable to what is found in our Galaxy for the most elliptical globular clusters. There is no evidence of isophote twisting, except for the innermost regions of the cluster (r < 0.5"). To investigate whether the observed flattening can be ascribed to rotation, we have obtained long-slit high-resolution VLT/UVES spectra of this cluster along and perpendicular to the axis of flattening. Using cross-correlation we find that the velocity profile of the cluster is consistent with zero rotation along either axis. Thus neither cluster rotation nor galactic tides can be responsible for the flattened morphology of WLM-1. We argue that the required velocity dispersion anisotropy between the semi-major and semi-minor axes that would be required to account for the observed flattening is relatively small, of order 1 km/s. Even though our errors preclude us from conclusively establishing that such a difference indeed exists, velocity anisotropy remains at present the most plausible explanation for the shape of this cluster.Comment: 11 pages, 10 figures, submitted to the A

Mapping carcass and meat quality QTL on Sus Scrofa chromosome 2 in commercial finishing pigs

Quantitative trait loci (QTL) affecting carcass and meat quality located on SSC2 were identified using variance component methods. A large number of traits involved in meat and carcass quality was detected in a commercial crossbred population: 1855 pigs sired by 17 boars from a synthetic line, which where homozygous (A/A) for IGF2. Using combined linkage and linkage disequilibrium mapping (LDLA), several QTL significantly affecting loin muscle mass, ham weight and ham muscles (outer ham and knuckle ham) and meat quality traits, such as Minolta-L* and -b*, ultimate pH and Japanese colour score were detected. These results agreed well with previous QTL-studies involving SSC2. Since our study is carried out on crossbreds, different QTL may be segregating in the parental lines. To address this question, we compared models with a single QTL-variance component with models allowing for separate sire and dam QTL-variance components. The same QTL were identified using a single QTL variance component model compared to a model allowing for separate variances with minor differences with respect to QTL location. However, the variance component method made it possible to detect QTL segregating in the paternal line (e.g. HAMB), the maternal lines (e.g. Ham) or in both (e.g. pHu). Combining association and linkage information among haplotypes improved slightly the significance of the QTL compared to an analysis using linkage information only

Comprehensive Gene-Expression Survey Identifies Wif1 as a Modulator of Cardiomyocyte Differentiation

During chicken cardiac development the proepicardium (PE) forms the epicardium (Epi), which contributes to several non-myocardial lineages within the heart. In contrast to Epi-explant cultures, PE explants can differentiate into a cardiomyocyte phenotype. By temporal microarray expression profiles of PE-explant cultures and maturing Epi cells, we identified genes specifically associated with differentiation towards either of these lineages and genes that are associated with the Epi-lineage restriction. We found a central role for Wnt signaling in the determination of the different cell lineages. Immunofluorescent staining after recombinant-protein incubation in PE-explant cultures indicated that the early upregulated Wnt inhibitory factor-1 (Wif1), stimulates cardiomyocyte differentiation in a similar manner as Wnt stimulation. Concordingly, in the mouse pluripotent embryogenic carcinoma cell line p19cl6, early and late Wif1 exposure enhances and attenuates differentiation, respectively. In ovo exposure of the HH12 chicken embryonic heart to Wif1 increases the Tbx18-positive cardiac progenitor pool. These data indicate that Wif1 enhances cardiomyogenesis

Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway

The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al

Cellular Communication through Light

Information transfer is a fundamental of life. A few studies have reported that cells use photons (from an endogenous source) as information carriers. This study finds that cells can have an influence on other cells even when separated with a glass barrier, thereby disabling molecule diffusion through the cell-containing medium. As there is still very little known about the potential of photons for intercellular communication this study is designed to test for non-molecule-based triggering of two fundamental properties of life: cell division and energy uptake. The study was performed with a cellular organism, the ciliate Paramecium caudatum. Mutual exposure of cell populations occurred under conditions of darkness and separation with cuvettes (vials) allowing photon but not molecule transfer. The cell populations were separated either with glass allowing photon transmission from 340 nm to longer waves, or quartz being transmittable from 150 nm, i.e. from UV-light to longer waves. Even through glass, the cells affected cell division and energy uptake in neighboring cell populations. Depending on the cuvette material and the number of cells involved, these effects were positive or negative. Also, while paired populations with lower growth rates grew uncorrelated, growth of the better growing populations was correlated. As there were significant differences when separating the populations with glass or quartz, it is suggested that the cell populations use two (or more) frequencies for cellular information transfer, which influences at least energy uptake, cell division rate and growth correlation. Altogether the study strongly supports a cellular communication system, which is different from a molecule-receptor-based system and hints that photon-triggering is a fine tuning principle in cell chemistry