Atmospheric histories and growth trends of C4F10, C5F12, C6F14, C7F16 and C8F18

Atmospheric observations and trends are presented for the high molecular weight perfluorocarbons (PFCs): decafluorobutane (C4F10), dodecafluoropentane (C5F12), tetradecafluorohexane (C6F14), hexadecafluoroheptane (C7F16) and octadecafluorooctane (C8F18). Their atmospheric histories are based on measurements of 36 Northern Hemisphere and 46 Southern Hemisphere archived air samples collected between 1973 to 2011 using the Advanced Global Atmospheric Gases Experiment (AGAGE) 'Medusa' preconcentration gas chromatography-mass spectrometry systems. A new calibration scale was prepared for each PFC, with estimated accuracies of 6.8% for C4F10, 7.8% for C5F12, 4.0% for C6F14, 6.6% for C7F16 and 7.9% for C8F18. Based on our observations the 2011 globally averaged dry air mole fractions of these heavy PFCs are: 0.17 parts-per-trillion (ppt, i.e., parts per 10(12)) for C4F10, 0.12 ppt for C5F12, 0.27 ppt for C6F14, 0.12 ppt for C7F16 and 0.09 ppt for C8F18. These atmospheric mole fractions combine to contribute to a global average radiative forcing of 0.35 mW m(-2), which is 6% of the total anthropogenic PFC radiative forcing (Montzka and Reimann, 2011; Oram et al., 2012). The growth rates of the heavy perfluorocarbons were largest in the late 1990s peaking at 6.2 parts per quadrillion (ppq, i.e., parts per 10(15)) per year (yr) for C4F10, at 5.0 ppq yr(-1) for C5F12 and 16.6 ppq yr(-1) for C6F14 and in the early 1990s for C7F16 at 4.7 ppq yr(-1) and in the mid 1990s for C8F18 at 4.8 ppq yr(-1). The 2011 globally averaged mean atmospheric growth rates of these PFCs are subsequently lower at 2.2 ppq yr(-1) for C4F10, 1.4 ppq yr(-1) for C5F12, 5.0 ppq yr(-1) for C6F14, 3.4 ppq yr(-1) for C7F16 and 0.9 ppq yr(-1) for C8F18. The more recent slowdown in the growth rates suggests that emissions are declining as compared to the 1980s and 1990s.</p

Domain switching energies: Mechanical versus electrical loading in La-doped bismuth ferrite-lead titanate

The mechanical stress-induced domain switching and energy dissipation in morphotropic phase boundary (1 - x)(Bi(1-y)La(y))FeO(3)-xPbTiO(3) during uniaxial compressive loading have been investigated at three different temperatures. The strain obtained was found to decrease with increasing lanthanum content, although a sharp increase in strain was observed for compositions doped with 7.5 and 10 at. % La. Increased domain switching was found in compositions with decreased tetragonality. This is discussed in terms of the competing influences of the amount of domain switching and the spontaneous strain on the macroscopic behavior under external fields. Comparison of the mechanically and electrically dissipated energy showed significant differences, discussed in terms of the different microscopic interactions of electric field and stress.open10

Shear induced instabilities in layered liquids

Motivated by the experimentally observed shear-induced destabilization and reorientation of smectic A like systems, we consider an extended formulation of smectic A hydrodynamics. We include both, the smectic layering (via the layer displacement u and the layer normal p) and the director n of the underlying nematic order in our macroscopic hydrodynamic description and allow both directions to differ in non equilibrium situations. In an homeotropically aligned sample the nematic director does couple to an applied simple shear, whereas the smectic layering stays unchanged. This difference leads to a finite (but usually small) angle between n and p, which we find to be equivalent to an effective dilatation of the layers. This effective dilatation leads, above a certain threshold, to an undulation instability of the layers. We generalize our earlier approach [Rheol. Acta, vol.39(3), 15] and include the cross couplings with the velocity field and the order parameters for orientational and positional order and show how the order parameters interact with the undulation instability. We explore the influence of various material parameters on the instability. Comparing our results to recent experiments and molecular dynamic simulations, we find a good qualitative agreement.Comment: 15 pages, 12 figures, accepted for publication in PR

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.

Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing

Current approaches and future role of high content imaging in safety sciences and drug discovery

High content imaging combines automated microscopy with image analysis approaches to simultaneously quantify multiple phenotypic and/or functional parameters in biological systems. The technology has become an important tool in the fields of safety sciences and drug discovery, because it can be used for mode-of-action identification, determination of hazard potency and the discovery of toxicity targets and biomarkers. In contrast to conventional biochemical endpoints, high content imaging provides insight into the spatial distribution and dynamics of responses in biological systems. This allows the identification of signaling pathways underlying cell defense, adaptation, toxicity and death. Therefore high content imaging is considered a promising technology to address the challenges for the Toxicity testing in the 21st century approach. Currently high content imaging technologies are frequently applied in academia for mechanistic toxicity studies and in pharmaceutical industry for the ranking and selection of lead drug compounds or to identify/confirm mechanisms underlying effects observed in vivo. A recent workshop gathered scientists working on high content imaging in academia, pharmaceutical industry and regulatory bodies with the objective to compile the state-of-the-art of the technology in the different institutions. They defined technical and methodological gaps, addressed the need for quality control, suggested control compounds and acceptance criteria, highlighted cell sources and new readouts and discussed future requirements for regulatory implementation. This review summarizes the discussion, proposed solutions and recommendations of the specialists contributing to the workshop.JRC.I.5-Systems Toxicolog

Low oxygen tension primes aortic endothelial cells to the reparative effect of tissue-protective cytokines

Erythropoietin (EPO) has both erythropoietic and tissue-protective properties. The EPO analogues carbamylated EPO (CEPO) and pyroglutamate helix B surface peptide (pHBSP) lack the erythropoietic activity of EPO but retain the tissue-protective properties that are mediated by a heterocomplex of EPO receptor (EPOR) and the β common receptor (βCR). We studied the action of EPO and its analogues in a model of wound healing where a bovine aortic endothelial cells (BAECs) monolayer was scratched and the scratch closure was assessed over 24 h under different oxygen concentrations. We related the effects of EPO and its analogues on repair to their effect on BAECs proliferation and migration (evaluated using a micro-Boyden chamber). EPO, CEPO and pHBSP enhanced scratch closure only at lower oxygen (5%), while their effect at atmospheric oxygen (21%) was not significant. The mRNA expression of EPOR was doubled in 5% compared to 21% oxygen, and this was associated with increased EPOR assessed by immunofluorescence and Western blot. By contrast βCR mRNA levels were similar in 5% and 21% oxygen. EPO and its analogues increased both BAECs proliferation and migration, suggesting that both may be involved in the reparative process. The priming effect of low oxygen tension on the action of tissue-protective cytokines may be of relevance to vascular disease, including atherogenesis and restenosis

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B

Amanita phalloides is responsible for more than 90 % of mushroom-related fatalities, and no effective antidote is available. a-Amanitin, the main toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and kidney failure. In silico studies included docking and molecular dynamics simulation coupled to molecular mechanics with generalized Born and surface area method energy decomposition on RNAP II. They were performed with a clinical drug that shares chemical similarities to a-amanitin, polymyxin B. The results show that polymyxin B potentially binds to RNAP II in the same interface of a-amanitin, preventing the toxin from binding to RNAP II. In vivo, the inhibition of the mRNA transcripts elicited by a-amanitin was efficiently reverted by polymyxin B in the kidneys. Moreover, polymyxin B significantly decreased the hepatic and renal a-amanitin-induced injury as seen by the histology and hepatic aminotransferases plasma data. In the survival assay, all animals exposed to a-amanitin died within 5 days, whereas 50 % survived up to 30 days when polymyxin B was administered 4, 8, and 12 h post-a-amanitin. Moreover, a single dose of polymyxin B administered concomitantly with a-amanitin was able to guarantee 100 % survival. Polymyxin B protects RNAP II from inactivation leading to an effective prevention of organ damage and increasing survival in a-amanitin-treated animals. The present use of clinically relevant concentrations of an already human-use-approved drug prompts the use of polymyxin B as an antidote for A. phalloides poisoning in humans.Juliana Garcia, Vera Marisa Costa, Ricardo Dinis-Oliveira and Ricardo Silvestre thank FCT-Foundation for Science and Technology-for their PhD grant (SFRH/BD/74979/2010), Post-doc grants (SFRH/BPD/63746/2009 and SFRH/BPD/110001/2015) and Investigator grants (IF/01147/2013) and (IF/00021/2014), respectively. This work was supported by the Fundacao para a Ciencia e Tecnologia (FCT) - project PTDC/DTPFTO/4973/2014 - and the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundacao para a Ciencia e Tecnologia) through project Pest-C/EQB/LA0006/2013

Imaging an unsupported metal–metal bond in dirhenium molecules at the atomic scale

Metallic bonds remain one of the most important and least understood of the chemical bonds. In this study, we generated Re2 molecules in which the Re–Re core is unsupported by ligands. Real-time imaging of the atomic-scale dynamics of Re2 adsorbed on a graphitic lattice allows direct measurement of Re–Re bond lengths for individual molecules that changes in discrete steps correlating with bond order from one to four. Direct imaging of the Re–Re bond breaking process reveals a new bonding state with the bond order less than one and a high-amplitude vibrational stretch, preceding the bond dissociation. The methodology, based on aberration-corrected transmission electron microscopy imaging, is shown to be a powerful analytical tool for the investigation of dynamics of metallic bonding at the atomic level