The importance of clinically relevant background therapy in cardioprotective studies

Treatment of acute myocardial infarct patients (AMI) includes rapid restoration of coronary blood flow and pharmacological therapy aimed to prevent pain and maintain vessel patency. Many interventions have been investigated to offer additional protection. One such intervention is remote ischaemic conditioning (RIC) involving short-episodes of ischaemia of the arm with a blood pressure cuff, followed by reperfusion to protect the heart organs from subsequent severe ischaemia. However, the recent CONDI2-ERIC-PPCI multicentre study of RIC in STEMI showed no benefit in clinical outcome in low risk patients. It could also be argued that these patients were already in a partially protected state, highlighting the disconnect between animal- and clinical-based outcome studies. To improve potential translatability, we developed an animal model using pharmacological agents similar to those given to patients presenting with an AMI, prior to PPCI. Rats underwent MI on a combined background of an opioid agonist, heparin and a platelet-inhibitor thereby allowing us to assess whether additional cardioprotective strategies had any effect over and above this “cocktail”. We demonstrated that the “background drugs” were protective in their own right, reducing MI from 57.5 ± 3.7% to 37.3 ± 2.9% (n = 11, p < 0.001). On this background of drugs, RIC did not add any further protection (38.0 ± 3.4%). However, using a caspase inhibitor, which acts via a different mechanistic pathway to RIC, we were able to demonstrate additional protection (20.6 ± 3.3%). This concept provides initial evidence to develop models which can be used to evaluate future animal-to-clinical translation in cardioprotective studies

SpBase: the sea urchin genome database and web site

SpBase is a system of databases focused on the genomic information from sea urchins and related echinoderms. It is exposed to the public through a web site served with open source software (http://spbase.org/). The enterprise was undertaken to provide an easily used collection of information to directly support experimental work on these useful research models in cell and developmental biology. The information served from the databases emerges from the draft genomic sequence of the purple sea urchin, Strongylocentrotus purpuratus and includes sequence data and genomic resource descriptions for other members of the echinoderm clade which in total span 540 million years of evolutionary time. This version of the system contains two assemblies of the purple sea urchin genome, associated expressed sequences, gene annotations and accessory resources. Search mechanisms for the sequences and the gene annotations are provided. Because the system is maintained along with the Sea Urchin Genome resource, a database of sequenced clones is also provided

Anomalous Gauge Interactions of the Higgs Boson: Precision Constraints and Weak Boson Scatterings

Interaction of Higgs scalar (H) with weak gauge bosons (V=W,Z) is the {\it key} to understand electroweak symmetry breaking (EWSB) mechanism. New physics effects in the HVV interactions, as predicted by models of compositeness, supersymmetry and extra dimensions, can be formulated as anomalous couplings via a generic effective Lagrangian. We first show that the existing electroweak precision data already impose nontrivial indirect constraints on the anomalous HVV couplings. Then, we systematically study VV --> VV scatterings in the TeV region, via Gold-plated pure leptonic decay modes of the weak bosons. We demonstrate that, even for a light Higgs boson in the mass range 115GeV < m_H < 300GeV, this process can directly probe the anomalous HVV interactions at the LHC with an integrated luminosity of 300fb^{-1}, which further supports the ``No-Lose'' theorem for the LHC to uncover the EWSB mechanism. Comparisons with the constraints from measuring the cross section of VH associate production and the Higgs boson decay width are also given.Comment: Version in Phys. Lett. B (v3: minor typos removed, v2,v4: fix Latex top-margin

Small extracellular vesicles secreted from human amniotic fluid mesenchymal stromal cells possess cardioprotective and promigratory potential

Mesenchymal stromal cells (MSCs) exhibit antiapoptotic and proangiogenic functions in models of myocardial infarction which may be mediated by secreted small extracellular vesicles (sEVs). However, MSCs have frequently been harvested from aged or diseased patients, while the isolated sEVs often contain high levels of impurities. Here, we studied the cardioprotective and proangiogenic activities of size-exclusion chromatography-purified sEVs secreted from human foetal amniotic fluid stem cells (SS-hAFSCs), possessing superior functional potential to that of adult MSCs. We demonstrated for the first time that highly pure (up to 1.7 × 1010 particles/µg protein) and thoroughly characterised SS-hAFSC sEVs protect rat hearts from ischaemia–reperfusion injury in vivo when administered intravenously prior to reperfusion (38 ± 9% infarct size reduction, p < 0.05). SS-hAFSC sEVs did not protect isolated primary cardiomyocytes in models of simulated ischaemia–reperfusion injury in vitro, indicative of indirect cardioprotective effects. SS-hAFSC sEVs were not proangiogenic in vitro, although they markedly stimulated endothelial cell migration. Additionally, sEVs were entirely responsible for the promigratory effects of the medium conditioned by SS-hAFSC. Mechanistically, sEV-induced chemotaxis involved phosphatidylinositol 3-kinase (PI3K) signalling, as its pharmacological inhibition in treated endothelial cells reduced migration by 54 ± 7% (p < 0.001). Together, these data indicate that SS-hAFSC sEVs have multifactorial beneficial effects in a myocardial infarction setting

CP Violation with Heavy Hadrons

I review several topics involving CP violation with heavy hadrons. In particular, I discuss (i) Hyperons: CP violation in the decay $\Lambda^0 \to p \pi^-$, (ii) Charm: indirect CP violation in the D^0 system, both within and beyond the SM, and (iii) Beauty: indirect CP violation in the neutral B-meson system beyond the SM. Talk presented at the 2nd International Conference on Hyperons, Charm and Beauty Hadrons, Montr\'eal, Canada, August 1996.Comment: 12 pages, latex, 1 figure (included

Global Strong solution with vacuum to the 2D nonhomogeneous incompressible MHD system

In this paper, we first prove the unique global strong solution with vacuum to the two dimensional nonhomogeneous incompressible MHD system, as long as the initial data satisfies some compatibility condition. As a corollary, the global existence of strong solution with vacuum to the 2D nonhomogeneous incompressible Navier-Stokes equations is also established. Our main result improves all the previous results where the initial density need to be strictly positive. The key idea is to use some critical Sobolev inequality of logarithmic type, which is originally due to Brezis-Wainger.Comment: 16 page

Experimental investigation of the intermediates of isooctane during ignition

Direct measurements of intermediates of ignition are challenging experimental objectives, yet such measurements are critical for understanding fuel decomposition and oxidation pathways. In the current work, a new gas-sampling system is used to provide quantitative discrete measurements of 30 hydrocarbon and oxygenate species during rapid compression facility studies of isooctane ignition. Two target conditions and equivalence ratios (based on molar fuel to oxygen ratio) were studied (P = 5.2 atm, T = 1000 K, φ = 0.4 and P = 4.8 atm, T = 975 K, φ = 1.2). The results are compared with model predictions that use the detailed reaction mechanism developed by Curran et al. ( Combust Flame 2002, 129, 253–280). In general, the model predictions are in excellent agreement with the experimental data, including several trace species. Isobutene (i-C 4 H 8 ) and propene (C 3 H 6 ) were the major olefin species identified in the experiments. The results are consistent with an intermediate temperature reaction path sequence, where isooctane is consumed by H-atom abstraction to yield isooctyl radicals that undergo Β-scission to form olefin and alkyl radical species. © 2007 Wiley Periodicals, Inc. Int J Chem Kinet 39: 498–517, 2007Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56133/1/20254_ftp.pd

Coherent addition of two dimensional array of fiber lasers

Configurations for efficient free space coherent addition of four separate fiber lasers arranged in two dimensional array are presented. They include compact and robust interferometric combiners that can be inserted either inside or outside the cavity of the combined lasers system. The results reveal that over 85% combining efficiency can be obtained.Comment: To be published in Optics Communicatio

Exosomes from neuronal stem cells may protect the heart from ischaemia/reperfusion injury via JAK1/2 and gp130

Myocardial infarction requires urgent reperfusion to salvage viable heart tissue. However, reperfusion increases infarct size further by promoting mitochondrial damage in cardiomyocytes. Exosomes from a wide range of different cell sources have been shown to activate cardioprotective pathways in cardiomyocytes, thereby reducing infarct size. Yet, it is currently challenging to obtain highly pure exosomes in quantities enough for clinical studies. To overcome this problem, we used exosomes isolated from CTX0E03 neuronal stem cells, which are genetically stable, conditionally inducible and can be produced on an industrial scale. However, it is unknown whether exosomes from neuronal stem cells may reduce cardiac ischaemia/reperfusion injury. In this study, we demonstrate that exosomes from differentiating CTX0E03 cells can reduce infarct size in mice. In an in vitro assay, these exosomes delayed cardiomyocyte mitochondrial permeability transition pore opening, which is responsible for cardiomyocyte death after reperfusion. The mechanism of MPTP inhibition was via gp130 signalling and the downstream JAK/STAT pathway. Our results support previous findings that exosomes from non-cardiomyocyte-related cells produce exosomes capable of protecting cardiomyocytes from myocardial infarction. We anticipate our findings may encourage scientists to use exosomes obtained from reproducible clinical-grade stocks of cells for their ischaemia/reperfusion studies

Dual Function of CD81 in Influenza Virus Uncoating and Budding

As an obligatory pathogen, influenza virus co-opts host cell machinery to harbor infection and to produce progeny viruses. In order to characterize the virus-host cell interactions, several genome-wide siRNA screens and proteomic analyses have been performed recently to identify host factors involved in influenza virus infection. CD81 has emerged as one of the top candidates in two siRNA screens and one proteomic study. The exact role played by CD81 in influenza infection, however, has not been elucidated thus far. In this work, we examined the effect of CD81 depletion on the major steps of the influenza infection. We found that CD81 primarily affected virus infection at two stages: viral uncoating during entry and virus budding. CD81 marked a specific endosomal population and about half of the fused influenza virus particles underwent fusion within the CD81-positive endosomes. Depletion of CD81 resulted in a substantial defect in viral fusion and infection. During virus assembly, CD81 was recruited to virus budding site on the plasma membrane, and in particular, to specific sub-viral locations. For spherical and slightly elongated influenza virus, CD81 was localized at both the growing tip and the budding neck of the progeny viruses. CD81 knockdown led to a budding defect and resulted in elongated budding virions with a higher propensity to remain attached to the plasma membrane. Progeny virus production was markedly reduced in CD81-knockdown cells even when the uncoating defect was compensated. In filamentous virus, CD81 was distributed at multiple sites along the viral filament. Taken together, these results demonstrate important roles of CD81 in both entry and budding stages of the influenza infection cycle