The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury

Quadratic electroweak corrections for polarized Moller scattering

The paper discusses the two-loop (NNLO) electroweak radiative corrections to the parity violating electron-electron scattering asymmetry induced by squaring one-loop diagrams. The calculations are relevant for the ultra-precise 11 GeV MOLLER experiment planned at Jefferson Laboratory and experiments at high-energy future electron colliders. The imaginary parts of the amplitudes are taken into consideration consistently in both the infrared-finite and divergent terms. The size of the obtained partial correction is significant, which indicates a need for a complete study of the two-loop electroweak radiative corrections in order to meet the precision goals of future experiments

On the quest for unification - simplicity and antisimplicity

The road towards unification of elementary interactions is thought to start on the solid ground of a universal local gauge principle. I discuss the different types of bosonic gauge symmetries in gravitational and nongravitational (standard model) interactions and their extensions both fermionic, bosonic and with respect to space-time dimensions. The apparently paradoxical size and nature of the cosmological constant is sketched, which at first sight does not readily yield a clue as to the envelopping symmetry structure of a unified theory. Nevertheless a tentative outlook is given encouraging to proceed on this road.Comment: 29 pages, 4 figure

The Noncommutative Standard Model and Forbidden Decays

In this contribution we discuss the Noncommutative Standard Model and the associated Standard Model-forbidden decays that can possibly serve as an experimental signature of space-time noncommutativity.Comment: 15 pages, 1 figure, Invited talk at 9th Adriatic Meeting and Central European Symposia on Particle Physics and The Universe, Dubrovnik, Croatia, 4-14 Sep 200

ESC Working Group Cellular Biology of the Heart: Position Paper: Improving the pre-clinical assessment of novel cardioprotective therapies

Ischemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischemia-reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed pre-clinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the pre-clinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes

Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion

The signal transducer and activator of transcription 3 (STAT3) contributes to cardioprotection by ischemic pre- and postconditioning. Mitochondria are central elements of cardioprotective signaling, most likely by delaying mitochondrial permeability transition pore (MPTP) opening, and STAT3 has recently been identified in mitochondria. We now characterized the mitochondrial localization of STAT3 and its impact on respiration and MPTP opening. STAT3 was mainly present in the matrix of subsarcolemmal and interfibrillar cardiomyocyte mitochondria. STAT1, but not STAT5 was also detected in mitochondria under physiological conditions. ADP-stimulated respiration was reduced in mitochondria from mice with a cardiomyocyte-specific deletion of STAT3 (STAT3-KO) versus wildtypes and in rat mitochondria treated with the STAT3 inhibitor Stattic (STAT3 inhibitory compound, 6-Nitrobenzo[b]thiophene 1,1-dioxide). Mitochondria from STAT3-KO mice and Stattic-treated rat mitochondria tolerated less calcium until MPTP opening occurred. STAT3 co-immunoprecipitated with cyclophilin D, the target of the cardioprotective agent and MPTP inhibitor cyclosporine A (CsA). However, CsA reduced infarct size to a similar extent in wildtype and STAT3-KO mice in vivo. Thus, STAT3 possibly contributes to cardioprotection by stimulation of respiration and inhibition of MPTP opening

Microenvironment temperature prediction between body and seat interface using autoregressive data-driven model

There is a need to develop a greater understanding of temperature at the skin–seat interface during prolonged seating from the perspectives of both industrial design (comfort/discomfort) and medical care (skin ulcer formation). Here we test the concept of predicting temperature at the seat surface and skin interface during prolonged sitting (such as required from wheelchair users). As caregivers are usually busy, such a method would give them warning ahead of a problem. This paper describes a data-driven model capable of predicting thermal changes and thus having the potential to provide an early warning (15- to 25-min ahead prediction) of an impending temperature that may increase the risk for potential skin damages for those subject to enforced sitting and who have little or no sensory feedback from this area. Initially, the oscillations of the original signal are suppressed using the reconstruction strategy of empirical mode decomposition (EMD). Consequentially, the autoregressive data-driven model can be used to predict future thermal trends based on a shorter period of acquisition, which reduces the possibility of introducing human errors and artefacts associated with longer duration “enforced” sitting by volunteers. In this study, the method had a maximum predictive error of <0.4 °C when used to predict the temperature at the seat and skin interface 15 min ahead, but required 45 min data prior to give this accuracy. Although the 45 min front loading of data appears large (in proportion to the 15 min prediction), a relative strength derives from the fact that the same algorithm could be used on the other 4 sitting datasets created by the same individual, suggesting that the period of 45 min required to train the algorithm is transferable to other data from the same individual. This approach might be developed (along with incorporation of other measures such as movement and humidity) into a system that can give caregivers prior warning to help avoid exacerbating the skin disorders of patients who suffer from low body insensitivity and disability requiring them to be immobile in seats for prolonged periods

Distinct cardioprotective mechanisms of immediate, early and delayed ischaemic postconditioning

Cardioprotection against ischaemia/reperfusion injury in mice can be achieved by delayed ischaemic postconditioning (IPost) applied as late as 30 min after the onset of reperfusion. We determined the efficacy of delayed IPost in a rat model of myocardial infarction (MI) and investigated potential underlying mechanisms of this phenomenon. Rats were subjected to 20, 30 or 45 min of coronary artery occlusion followed by 120 min of reperfusion (I/R). Immediate and early IPost included six cycles of I/R (10/10 s) applied 10 s or 10 min after reperfusion onset. In the second series of experiments, the rats were subjected to 30 min of coronary occlusion followed by IPost applied 10 s, 10, 30, 45 or 60 min after the onset of reperfusion. Immediate and early IPost (applied 10 s or 10 min of reperfusion) established cardioprotection only when applied after a period of myocardial ischaemia lasting 30 min. Delayed IPost applied after 30 or 45 min of reperfusion reduced infarct sizes by 36 and 41 %, respectively (both P < 0.01). IPost applied 60 min after reperfusion onset was ineffective. Inhibition of RISK pathway (administration of ERK1/2 inhibitor PD-98059 or PI3K inhibitor LY-294002) abolished cardioprotection established by immediate IPost but had no effect on cardioprotection conferred by early IPost. Blockade of SAFE pathway using JAK/STAT inhibitor AG490 had no effect on the immediate or early IPost cardioprotection. Blockade of mitochondrial KATP (mitoKATP) channels (with 5-Hydroxydecanoate) abolished cardioprotection achieved by immediate and early IPost, but had no effect on cardioprotection when IPost was applied 30 or 45 min into the reperfusion period. Immediate IPost increased phosphorylation of PI3K-AKT and ERK1/2. Early or delayed IPost had no effect on phosphorylation of PI3K-AKT, ERK1/2 or STAT3. These data show that in the rat model, delayed IPost confers significant cardioprotection even if applied 45 min after onset of reperfusion. Cardioprotection induced by immediate and early postconditioning involves recruitment of RISK pathway and/or mitoKATP channels, while delayed postconditioning appears to rely on a different mechanism

Three-body correlations in Borromean halo nuclei

Three-body correlations in the dissociation of two-neutron halo nuclei are explored using a technique based on intensity interferometry and Dalitz plots. This provides for the combined treatment of both the n-n and core-n interactions in the exit channel. As an example, the breakup of 14Be into 12Be+n+n by Pb and C targets has been analysed and the halo n-n separation extracted. A finite delay between the emission of the neutrons in the reaction on the C target was observed and is attributed to 13Be resonances populated in sequential breakup.Comment: 5 pages, 4 figures, submitted to PR