Mechanism of gas permeation in processed HNBR/nanoclay composites

The influence of the layered silicate clay platelets on the nitrogen permeation properties of hydrogenated nitrile butadiene rubber (HNBR)/nanoclay nanocomposites has been investigated. Nanocomposites of HNBR modified with different percentages of the organoclay are processed through various routes. Commercially available organoclay (CLOISITE 15A) and various silane-coupling agents are used to improve the dispersion of the nanoclay in HNBR. A total of 10 different formulations of nanocomposites are manufactured. The addition of the organoclay has resulted in a significant enhancement of the nitrogen barrier properties of the manufactured nanocomposite. The mechanism of the reduction in the permeability is explained through the changes in the morphology and its bond to the filler. These changes are confirmed through examination of the morphology using x-ray diffraction, transmission electron microscope, and dynamic mechanical thermal analysis. There has been a drastic reduction up to 55.7% in nitrogen permeability. The reduction in gas permeation in HNBR is attributed to uniformly exfoliated clay platelets. Finally, three different permeability models, namely, the Nielsen model, modified Nielsen model, and Cussler model, have also been considered to predict the permeability behavior of nanocomposites with different volume filler fractions. The experimental values of gas permeability have been compared with theoretical models. It is observed that the modified Nielsen model closely matches with the measured permeation behavior. © 2011 Wiley Periodicals, Inc.

An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): Protocol for a randomized controlled trial

Background

Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.

This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 μg.kg^-1.min^-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients will be recruited from approximately 25 ICUs in the United Kingdom.

This trial will test the efficacy of levosimendan to reduce acute organ dysfunction in adult patients who have septic shock and evaluate its biological mechanisms of action.

Targeting Trypsin-Like Proteases: A Mechanism to Restore Mucociliary Function in Cystic Fibrosis Airways

Dehydration of the airway surface liquid (ASL) and the resultant decline in function of the mucociliary escalator in cystic fibrosis airways is largely underpinned by the excessive flux of Na+ and water though ENaC. Proteolysis of the endogenous  and  subunits of epithelial sodium channels (ENaC) by channel activating proteases (CAPS) is the key regulatory mechanism for channel activation. Recent reports highlight that (1) CFTR (cystic fibrosis transmembrane conductance regulator) normally protects ENaC from the action of proteases and (2) a stark imbalance in proteases/protease inhibitor levels in CF airway cultures favour activation of normally inactive ENaC. The current study examines the potential therapeutic benefit of CAPS/ENaC inhibition in CF airways.
Our group has developed a panel of active-site directed affinity-based probes which target and inhibit trypsin-like proteases (potential CAPS); including the broad-spectrum inhibitor QUB-TL1. We have utilised this compound to interrogate the impact of trypsin-like protease inhibition on ENaC activity in differentiated primary airway epithelial cell cultures.
Electrophysiological data demonstrate QUB-TL1 selectively and irreversibly binds to extracellularly located trypsin-like proteases resulting in impaired ENaC-mediated Na+ transport. Visualisation of ENaC at the apical surface compartment of primary airway epithelial cells shows a large reduction in a low molecular weight (processed and active) form of ENaC, which was found to be abundant in untreated CF cultures. Consistent with the reduction in ENaC activity observed, QUB-TL1 treatment was subsequently shown to increase ASL height (performed in collaboration with Royal College of Surgeons in Ireland).
Our results are consistent with the hypothesis that targeting the CAPS-ENaC signalling axis may restore the depleted ASL seen in CF airways.

Fast Byzantine Leader Election in Dynamic Networks

We study the fundamental Byzantine leader election problem in dynamic networks where the topology can change from round to round and nodes can also experience heavy {\em churn} (i.e., nodes can join and leave the network continuously over time). We assume the full information model where the Byzantine nodes have complete knowledge about the entire state of the network at every round (including random choices made by all the nodes), have unbounded computational power and can deviate arbitrarily from the protocol. The churn is controlled by an adversary that has complete knowledge and control over which nodes join and leave and at what times and also may rewire the topology in every round and has unlimited computational power, but is oblivious to the random choices made by the algorithm. Our main contribution is an $O(\log^3 n)$ round algorithm that achieves Byzantine leader election under the presence of up to $O({n}^{1/2 - \epsilon})$ Byzantine nodes (for a small constant $\epsilon > 0$) and a churn of up to \\$O(\sqrt{n}/\poly\log(n))$ nodes per round (where $n$ is the stable network size).The algorithm elects a leader with probability at least $1-n^{-\Omega(1)}$ and guarantees that it is an honest node with probability at least $1-n^{-\Omega(1)}$; assuming the algorithm succeeds, the leader's identity will be known to a $1-o(1)$ fraction of the honest nodes. Our algorithm is fully-distributed, lightweight, and is simple to implement. It is also scalable, as it runs in polylogarithmic (in $n$) time and requires nodes to send and receive messages of only polylogarithmic size per round.To the best of our knowledge, our algorithm is the first scalable solution for Byzantine leader election in a dynamic network with a high rate of churn; our protocol can also be used to solve Byzantine agreement in a straightforward way.We also show how to implement an (almost-everywhere) public coin with constant bias in a dynamic network with Byzantine nodes and provide a mechanism for enabling honest nodes to store information reliably in the network, which might be of independent interest.

Strength reduction of till under dynamic pore pressure condition

Cuttings in heavily overconsolidated clays are known to be susceptible to progressive deformation caused by creep and fatigue that usually begins at the toe of the slope. The progressive deformation leads to strength reduction with time at constant stress (or called softening) and could be accelerated by fluctuation of groundwater level associated with more extreme rainfall events predicted through climate change. The purpose of this paper is to assess the mechanism of progressive deformation due to creep and fatigue using element testing on samples of till. The samples were subjected to fully drained loading and the deviator stresses were held constant at various percentages of peak failure stress, while the pore water pressure was kept static or dynamic (fluctuating ±5 kPa) over a period of time. The results have shown that the samples experienced significant deformation even at a higher factor of safety (i.e. the failure deviator stress/deviator stress at which the pore water pressure was fluctuated) under pore water pressure dynamics.

A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.

XFEL resonant photo-pumping of dense plasmas and dynamic evolution of autoionizing core hole states

Similarly to the case of LIF (Laser-Induced Fluorescence), an equally revolutionary impact to science is expected from resonant X-ray photo-pumping. It will particularly contribute to a progress in high energy density science: pumped core hole states create X-ray transitions that can escape dense matter on a 10 fs-time scale without essential photoabsorption, thus providing a unique possibility to study matter under extreme conditions. In the first proof of principle experiment at the X-ray Free Electron Laser LCLS at SCLAC [Seely, J., Rosmej, F.B., Shepherd, R., Riley, D., Lee, R.W. Proposal to Perform the 1^st High Energy Density Plasma Spectroscopic Pump/Probe Experiment", approved LCLS proposal L332 (2010)] we have successfully pumped inner-shell X-ray transitions in dense plasmas. The plasma was generated with a YAG laser irradiating solid Al and Mg targets attached to a rotating cylinder. In parallel to the optical laser beam, the XFEL was focused into the plasma plume at different delay times and pump energies. Pumped X-ray transitions have been observed with a spherically bent crystal spectrometer coupled to a Princeton CCD. By using this experimental configuration, we have simultaneously achieved extremely high spectral (λ/δλ ≈ 5000) and spatial resolution (δx≈70 μm) while maintaining high luminosity and a large spectral range covered (6.90 - 8.35 Å). By precisely measuring the variations in spectra emitted from plasma under action of XFEL radiation, we have successfully demonstrated transient X- ray pumping in a dense plasma.