Haemorrhage control of the pre-hospital trauma patient.

. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

PCB-Related Alteration of Thyroid Hormones and Thyroid Hormone Receptor Gene Expression in Free-Ranging Harbor Seals (Phoca vitulina)

Persistent organic pollutants are environmental contaminants that, because of their lipophilic properties and long half-lives, bioaccumulate within aquatic food webs and often reach high concentrations in marine mammals, such as harbor seals (Phoca vitulina). Exposure to these contaminants has been associated with developmental abnormalities, immunotoxicity, and reproductive impairment in marine mammals and other high-trophic-level wildlife, mediated via a disruption of endocrine processes. The highly conserved thyroid hormones (THs) represent one vulnerable endocrine end point that is critical for metabolism, growth, and development in vertebrates. We characterized the relationship between contaminants and specific TH receptor (TR ) gene expression in skin/blubber biopsy samples, as well as serum THs, from free-ranging harbor seal pups (n = 39) in British Columbia, Canada, and Washington State, USA. We observed a contaminant-related increase in blubber TR-α gene expression [total polychlorinated biphenyls (∑PCBs); r = 0.679; p < 0.001] and a concomitant decrease in circulating total thyroxine concentrations (∑PCBs; r = −0.711; p < 0.001). Consistent with results observed in carefully controlled laboratory and captive feeding studies, our findings suggest that the TH system in harbor seals is highly sensitive to disruption by environmental contaminants. Such a disruption not only may lead to adverse effects on growth and development but also could have important ramifications for lipid metabolism and energetics in marine mammals

Downregulation of Vascular Hemeoxygenase-1 Leads to Vasculopathy in Systemic Sclerosis

Systemic sclerosis (SSc) is a terminal disease characterized by vasculopathy, tissue fibrosis, and autoimmunity. Although the exact etiology of SSc remains unknown, endothelial dysfunction, oxidative stress, and calcium handling dysregulation have been associated with a large number of SSc-related complications such as neointima formation, vasculogenesis, pulmonary arterial hypertension, impaired angiogenesis, and cardiac arrhythmias. Hemeoxygenase-1 (HO-1) is an antioxidant enzyme involved in multiple biological actions in the cardiovascular system including vascular tone, angiogenesis, cellular proliferation, apoptosis, and oxidative stress. The aim of this work was to investigate the physiological role of HO-1 and its relevance in the cardiovascular complications occurring in SSc. We found that, in early phases of SSc, the expression of HO-1 in dermal fibroblast is lower compared to those isolated from healthy control individuals. This is particularly relevant as reduction of the HO-1/CO signaling pathway is associated with endothelial dysfunction and vasculopathy. We show evidence of the role of HO-1/carbon monoxide (CO) signaling pathway in calcium handling. Using an in vitro model of pulmonary arterial hypertension (PAH) we investigated the role of HO-1 in Ca2+ mobilization from intracellular stores. Our results indicate that HO-1 regulates calcium release from intracellular stores of human pulmonary arterial endothelial cells. We interrogated the activity of HO-1 in angiogenesis using an organotypic co-culture of fibroblast-endothelial cell. Inhibition of HO-1 significantly reduced the ability of endothelial cells to form tubules. We further investigated if this could be associated with cell motility or migration of endothelial cells into the extracellular matrix synthesized by fibroblasts. By mean of holographic imaging, we studied the morphological and functional features of endothelial cells in the presence of an HO-1 activator and selective inhibitors. Our results demonstrate that inhibition of HO-1 significantly reduces cell proliferation and cell motility (migration) of cultured endothelial cells, whilst activation of HO-1 does not modify either morphology, proliferation or motility. In addition, we investigated the actions of CO on the Kv7.1 (KCQN1) channel current, an important component of the cardiac action potential repolarization. Using electrophysiology (whole-cell patch-clamp in a recombinant system overexpressing the KCQN1 channel), we assessed the regulation of KCQN1 by CO. CORM-2, a CO donor, significantly reduced the Kv7.1 current, suggesting that HO-1/CO signaling may play a role in the modulation of the cardiac action potential via regulation of this ion channel. In summary, our results indicate a clear link between: 1) downregulation of HO-1/CO signaling; and 2) pathophysiological processes occurring in early phases of SSc, such as calcium homeostasis dysregulation, impaired angiogenesis and cardiac arrhythmias. A better understanding of the canonical actions (mainly due to the biological actions of CO), and non-canonical actions of HO-1, as well as the interaction of HO-1/CO signaling with other gasotransmitters in SSc will contribute to the development of novel therapeutic approaches

A Quantitative Method to Analyze Drosophila Pupal Eye Patterning

BACKGROUND:The Drosophila pupal eye has become a popular paradigm for understanding morphogenesis and tissue patterning. Correct rearrangement of cells between ommatidia is required to organize the ommatidial array across the eye field. This requires cell movement, cell death, changes to cell-cell adhesion, signaling and fate specification. METHODOLOGY:We describe a method to quantitatively assess mis-patterning of the Drosophila pupal eye and objectively calculate a 'mis-patterning score' characteristic of a specific genotype. This entails step-by-step scoring of specific traits observed in pupal eyes dissected 40-42 hours after puparium formation and subsequent statistical analysis of this data. SIGNIFICANCE:This method provides an unbiased quantitative score of mis-patterning severity that can be used to compare the impact of different genetic mutations on tissue patterning

Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH

Background Systemic sclerosis (SSc) is characterised by autoimmune activation, tissue and vascular fibrosis in the skin and internal organs. Tissue fibrosis is driven by myofibroblasts, that are known to maintain their phenotype in vitro, which is associated with epigenetically driven trimethylation of lysine 27 of histone 3 (H3K27me3). Methods- Full-thickness skin biopsies were surgically obtained from the forearms of 12 adult patients with SSc of recent onset. Fibroblasts were isolated and cultured in monolayers and protein and RNA extracted. HOX transcript antisense RNA (HOTAIR) was expressed in healthy dermal fibroblasts by lentiviral induction employing a vector containing the specific sequence. Gamma secretase inhibitors were employed to block Notch signalling. Enhancer of zeste 2 (EZH2) was blocked with GSK126 inhibitor. Results- SSc myofibroblasts in vitro and SSc skin biopsies in vivo display high levels of HOTAIR, a scaffold long non-coding RNA known to direct the histone methyltransferase EZH2 to induce H3K27me3 in specific target genes. Overexpression of HOTAIR in dermal fibroblasts induced EZH2-dependent increase in collagen and α-SMA expression in vitro, as well as repression of miRNA-34A expression and consequent NOTCH pathway activation. Consistent with these findings, we show that SSc dermal fibroblast display decreased levels of miRNA-34a in vitro. Further, EZH2 inhibition rescued miRNA-34a levels and mitigated the profibrotic phenotype of both SSc and HOTAIR overexpressing fibroblasts in vitro. Conclusions- Our data indicate that the EZH2-dependent epigenetic phenotype of myofibroblasts is driven by HOTAIR and is linked to miRNA-34a repression-dependent activation of NOTCH signalling

TGFβ activation primes canonical Wnt signaling through the downregulation of AXIN2

OBJECTIVES: Aberrant activation of Wnt signaling has been observed in systemic sclerosis (SSc) affected tissues. This study aimed to determine the role of transforming growth factor (TGF)β in driving the increased Wnt signaling, through modulation of AXIN2, a critical regulator of Wnt canonical pathway. METHODS: Canonical Wnt signaling activation was analyzed by TOPFlash TCF/LEF promoter assays. AXIN2 was evaluated in vitro by analysis of AXIN2 primary/mature transcripts expression and decay, TβRI blockade, siRNA-mediated TTP-1 depletion and through XAV-939-mediated AXIN2 stabilisation. In vivo, Axin2 mRNA and protein expression was determined in skin and lung biopsies from TβRIIΔk-fib transgenic mice and littermate controls. RESULTS: SSc fibroblasts display increased response to canonical Wnt ligands despite basal levels of Wnt signaling comparable to healthy control (HC) fibroblasts in vitro. Notably, we show that SSc fibroblasts express reduced basal expression of AXIN2, which is caused by endogenous TGFβ-dependent increase of AXIN2 mRNA decay. Accordingly, we observed that TGFβ decreased AXIN2 expression both in vitro in HC fibroblasts and in vivo, employing TβRIIΔk-fib transgenic mice. Additionally, we demonstrate by AXIN2 loss and gain of function experiments, that the TGFβ-induced increased response to Wnt activation characteristic of SSc fibroblasts is dependent on reduced AXIN2 bioavailability. CONCLUSIONS: This study highlights the importance of reduced AXIN2 bioavailability in mediating the increased canonical Wnt response observed in SSc fibroblasts. This novel mechanism extends our understanding of the processes involved in Wnt/β-catenin-driven pathology and supports the rationale for targeting the TGFβ pathway to regulate the aberrant Wnt signaling observed during fibrosis. This article is protected by copyright. All rights reserved

Oxy-fuel combustion of coal and biomass blends

The ignition temperature, burnout and NO emissions of blends of a semi-anthracite and a high-volatile bituminous coal with 10 and 20 wt.% of olive waste were studied under oxy-fuel combustion conditions in an entrained flow reactor (EFR). The results obtained under several oxy-fuel atmospheres (21%O2–79%CO2, 30%O2–70%CO2 and 35%O2–65%CO2) were compared with those attained in air. The results indicated that replacing N2 by CO2 in the combustion atmosphere with 21% of O2 caused an increase in the temperature of ignition and a decrease in the burnout value. When the O2 concentration was increased to 30 and 35%, the temperature of ignition was lower and the burnout value was higher than in air conditions. A significant reduction in ignition temperature and a slight increase in the burnout value was observed after the addition of biomass, this trend becoming more noticeable as the biomass concentration was increased. The emissions of NO during oxy-fuel combustion were lower than under air-firing. However, they remained similar under all the oxy-fuel atmospheres with increasing O2 concentrations. Emissions of NO were significantly reduced by the addition of biomass to the bituminous coal, although this effect was less noticeable in the case of the semi-anthracite.This work was carried out with financial support from the Spanish MICINN (Project PS-120000-2005-2) co-financed by the European Regional Development Fund. M.V.G. and L.A. acknowledge funding from the CSIC JAE-Doc and CSIC JAE-Pre programs, respectively, co-financed by the European Social Fund. J.R. acknowledges funding from the Government of the Principado de Asturias (Severo Ochoa program).Peer reviewe

The nonlinear anomalous lattice elasticity associated with the high-pressure phase transition in spodumene: A high precission static compression study

The high-pressure behavior of the lattice elasticity of spodumene, LiAlSi2O6, was studied by static compression in a diamond-anvil cell up to 9.3 GPa. Investigations by means of single-crystal XRD and Raman spectroscopy within the hydrostatic limits of the pressure medium focus on the pressure ranges around similar to 3.2 and similar to 7.7 GPa, which have been reported previously to comprise two independent structural phase transitions. While our measurements confirm the well-established first-order C2/c-P2(1)/c transformation at 3.19 GPa (with 1.2% volume discontinuity and a hysteresis between 0.02 and 0.06 GPa), both unit-cell dimensions and the spectral changes observed in high-pressure Raman spectra give no evidence for structural changes related to a second phase transition. Monoclinic lattice parameters and unit-cell volumes at in total 59 different pressure points have been used to re-calculate the lattice-related properties of spontaneous strain, volume strain, and the bulk moduli as a function of pressure across the transition. A modified Landau free energy expansion in terms of a one component order parameter has been developed and tested against these experimentally determined data. The Landau solution provides a much better reproduction of the observed anomalies than any equation-of-state fit to data sets truncated below and above P (tr), thus giving Landau parameters of K (0) = 138.3(2) GPa, K' = 7.46(5), lambda (V) = 33.6(2) GPa, a = 0.486(3), b = -29.4(6) GPa and c = 551(11) GPa

Towards the Formalization of Fractional Calculus in Higher-Order Logic

Fractional calculus is a generalization of classical theories of integration and differentiation to arbitrary order (i.e., real or complex numbers). In the last two decades, this new mathematical modeling approach has been widely used to analyze a wide class of physical systems in various fields of science and engineering. In this paper, we describe an ongoing project which aims at formalizing the basic theories of fractional calculus in the HOL Light theorem prover. Mainly, we present the motivation and application of such formalization efforts, a roadmap to achieve our goals, current status of the project and future milestones.Comment: 9 page

Reduced haemodynamic response in the ageing visual cortex measured by absolute fNIRS

The effect of healthy ageing on visual cortical activation is still to be fully explored. This study aimed to elucidate whether the haemodynamic response (HDR) of the visual cortex altered as a result of ageing. Visually normal (healthy) participants were presented with a simple visual stimulus (reversing checkerboard). Full optometric screening was implemented to identify two age groups: younger adults (n = 12, mean age 21) and older adults (n = 13, mean age 71). Frequency-domain Multi-distance (FD-MD) functional Near-Infrared Spectroscopy (fNIRS) was used to measure absolute changes in oxygenated [HbO] and deoxygenated [HbR] haemoglobin concentrations in the occipital cortices. Utilising a slow event-related design, subjects viewed a full field reversing checkerboard with contrast and check size manipulations (15 and 30 minutes of arc, 50% and 100% contrast). Both groups showed the characteristic response of increased [HbO] and decreased [HbR] during stimulus presentation. However, older adults produced a more varied HDR and often had comparable levels of [HbO] and [HbR] during both stimulus presentation and baseline resting state. Younger adults had significantly greater concentrations of both [HbO] and [HbR] in every investigation regardless of the type of stimulus displayed (p<0.05). The average variance associated with this age-related effect for [HbO] was 88% and [HbR] 91%. Passive viewing of a visual stimulus, without any cognitive input, showed a marked age-related decline in the cortical HDR. Moreover, regardless of stimulus parameters such as check size, the HDR was characterised by age. In concurrence with present neuroimaging literature, we conclude that the visual HDR decreases as healthy ageing proceeds