Pungent general anesthetics activate transient receptor potential-A1 to produce hyperalgesia and neurogenic bronchoconstriction

BACKGROUND: Volatile anesthetics such as isoflurane and halothane have been in clinical use for many years and represent the group of drugs most commonly used to maintain general anesthesia. However, despite their widespread use, the molecular mechanisms by which these drugs exert their effects are not completely understood. Recently, a seemingly paradoxical effect of general anesthetics has been identified: the activation of peripheral nociceptors by irritant anesthetics. This mechanism may explain the hyperalgesic actions of inhaled anesthetics and their adverse effects in the airways. METHODS: To test the hypothesis that irritant inhaled anesthetics activate the excitatory ion-channel transient receptor potential (TRP)-A1 and thereby contribute to hyperalgesia and irritant airway effects, we used the measurement of intracellular calcium concentration in isolated cells in culture. For our functional experiments, we used models of isolated guinea pig bronchi to measure bronchoconstriction and withdrawal threshold to mechanical stimulation with von Frey filaments in mice. RESULTS: Irritant inhaled anesthetics activate TRPA1 expressed in human embryonic kidney cells and in nociceptive neurons. Isoflurane induces mechanical hyperalgesia in mice by a TRPA1-dependent mechanism. Isoflurane also induces TRPA1-dependent constriction of isolated bronchi. Nonirritant anesthetics do not activate TRPA1 and fail to produce hyperalgesia and bronchial constriction. CONCLUSIONS: General anesthetics induce a reversible loss of consciousness and render the patient unresponsive to painful stimuli. However, they also produce excitatory effects such as airway irritation and they contribute to postoperative pain. Activation of TRPA1 may contribute to these adverse effects, a hypothesis that remains to be tested in the clinical setting.

Carbon monoxide inhibits L-type Ca2+ channels via redox modulation of key cysteine residues by mitochondrial reactive oxygen species

Conditions of stress, such as myocardial infarction, stimulate up-regulation of heme oxygenase (HO-1) to provide cardioprotection. Here, we show that CO, a product of heme catabolism by HO-1, directly inhibits native rat cardiomyocyte L-type Ca2+ currents and the recombinant alpha1C subunit of the human cardiac L-type Ca2+ channel. CO (applied via a recognized CO donor molecule or as the dissolved gas) caused reversible, voltage-independent channel inhibition, which was dependent on the presence of a spliced insert in the cytoplasmic C-terminal region of the channel. Sequential molecular dissection and point mutagenesis identified three key cysteine residues within the proximal 31 amino acids of the splice insert required for CO sensitivity. CO-mediated inhibition was independent of nitric oxide and protein kinase G but was prevented by antioxidants and the reducing agent, dithiothreitol. Inhibition of NADPH oxidase and xanthine oxidase did not affect the inhibitory actions of CO. Instead, inhibitors of complex III (but not complex I) of the mitochondrial electron transport chain and a mitochondrially targeted antioxidant (Mito Q) fully prevented the effects of CO. Our data indicate that the cardioprotective effects of HO-1 activity may be attributable to an inhibitory action of CO on cardiac L-type Ca2+ channels. Inhibition arises from the ability of CO to promote generation of reactive oxygen species from complex III of mitochondria. This in turn leads to redox modulation of any or all of three critical cysteine residues in the channel's cytoplasmic C-terminal tail, resulting in channel inhibition.

Synthesis, characterization, crystal structure, and DNA-binding of ruthenium(II) complexes of heterocyclic nitrogen ligands resulting from a benzimidazole-based quinazoline derivative

The reaction of cis-[RuCl2(dmso)(4)] with [6-(2-pyridinyl)-5,6-dihydrobenzimidazo[1,2-c] quinazoline] (L) afforded in pure form a blue ruthenium(II) complex, [Ru(L-1)(2)] (1), where the original L changed to [2-(1H-benzoimidazol-2-yl)-phenyl]-pyridin-2-ylmethylene-amine (HL1). Treatment of RuCl3 center dot 3H(2)O with L in dry tetrahydrofuran in inert atmosphere led to a green ruthenium(II) complex, trans-[RuCl2(L-2)(2)] (2), where L was oxidized in situ to the neutral species 6-pyridin-yl-benzo[4,5]imidazo[1,2-c] quinazoline (L-2). Complex 2 was also obtained from the reaction of RuCl3 center dot 3H(2)O with L-2 in dry ethanol. Complexes 1 and 2 have been characterized by physico-chemical and spectroscopic tools, and 1 has been structurally characterized by single-crystal X-ray crystallography. The electrochemical behavior of the complexes shows the Ru(III)/Ru(II) couple at different potentials with quasi-reversible voltammograms. The interaction of these complexes with calf thymus DNA by using absorption and emission spectral studies allowed determination of the binding constant K-b and the linear Stern-Volmer quenching constant K-SV

A very rare self-assembled ribbon of fused cyclic water pentamers encapsulated in a Cu-II based metal-organic framework

A metal organic framework of Cu-II, tartarate (tar) and 2,2'-bipyridyl (2,2'-bipy)], {[Cu(tar)(2,2'-bipy)]center dot 5H(2)O}(n)} (1) has been synthesized at the mild ambient condition and characterized by single crystal X-ray crystallography. In the compound, the Cu(2,2'-bipy) entities are bridged by tartarate ions which are coordinated to Cu-II by both hydroxyl and monodentate carboxylate oxygen to form a one-dimensional chain. The non-coordinated water molecules form ID water chains by edge-sharing cyclic water pentamers along with dangling water dimers. It shows reversible water expulsion upon heating. The water chains join the ID coordination polymeric chains to a 31) network through hydrogen-bond interactions.

Two macrocyclic pentaaza compounds containing pyridine evaluated as novel chelating agents in copper(II) and nickel(II) overload

Two pentaaza macrocycles containing pyridine in the backbone, namely 3,6,9,12,18-pentaazabicyclo[12.3.1] octadeca-1(18),14,16-triene ([15]pyN(5)), and 3,6,10,13,19-pentaazabicyclo[13.3.1]nonadeca-1(19),15,17-triene ([16]pyN(5)), were synthesized in good yields. The acid-base behaviour of these compounds was studied by potentiometry at 298.2 K in aqueous solution and ionic strength 0.10 M in KNO3. The protonation sequence of [15]pyN(5) was investigated by H-1 NMR titration that also allowed the determination of protonation constants in D2O. Binding studies of the two ligands with Ca2+, Ni2+, Cu2+, Zn2+, Cd2+, and Pb2+ metal ions were performed under the same experimental conditions. The results showed that all the complexes formed with the 15-membered ligand, particularly those of Cu2+ and especially Ni2+, are thermodynamically more stable than with the larger macrocycle. Cyclic voltammetric data showed that the copper(II) complexes of the two macrocycles exhibited analogous behaviour, with a single quasi-reversible one-electron transfer reduction process assigned to the Cu(II)/Cu(I) couple. The UV-visible-near IR spectroscopic and magnetic moment data of the nickel(II) complexes in solution indicated a tetragonal distorted coordination geometry for the metal centre. X-band EPR spectra of the copper(II) complexes are consistent with distorted square pyramidal geometries. The crystal structure of [Cu([15]pyN(5))](2+) determined by X-ray diffraction showed the copper(II) centre coordinated to all five macrocyclic nitrogen donors in a distorted square pyramidal environment.

Spectral gap for Glauber type dynamics for a special class of potentials

We consider an equilibrium birth and death type process for a particle system in infinite volume, the latter is described by the space of all locally finite point configurations on Rd. These Glauber type dynamics are Markov processes constructed for pre-given reversible measures. A representation for the ``carré du champ'' and ``second carré du champ'' for the associate infinitesimal generators L are calculated in infinite volume and for a large class of functions in a generalized sense. The corresponding coercivity identity is derived and explicit sufficient conditions for the appearance and bounds for the size of the spectral gap of L are given. These techniques are applied to Glauber dynamics associated to Gibbs measure and conditions are derived extending all previous known results and, in particular, potentials with negative parts can now be treated. The high temperature regime is extended essentially and potentials with non-trivial negative part can be included. Furthermore, a special class of potentials is defined for which the size of the spectral gap is as least as large as for the free system and, surprisingly, the spectral gap is independent of the activity. This type of potentials should not show any phase transition for a given temperature at any activity.

Healable Polymer Systems

Polymers are used in many everyday technologies and their degradation due to environmental exposure has lead to great interest in materials which can heal and repair themselves. In order to design new self healing polymers it's important to understand the fundamental healing mechanisms behind the material.Healable Polymer Systems will outline the key concepts and mechanisms underpinning the design and processing of healable polymers, and indicate potential directions for progress in the future development and applications of these fascinating and potentially valuable materials. The book covers the different techniques developed successfully to date for both autonomous healable materials (those which do not require an external stimulus to promote healing) and rehealable or remendable materials (those which only recover their original physical properties if a specific stimulus is applied). These include the encapsulated-monomer approach, reversible covalent bond formation, irreversible covalent bond formation and supramolecular self-assembly providing detailed insights into their chemistry.Written by leading experts, the book provides polymer scientists with a compact and readily accessible source of reference for healable polymer systems.

Carbon monoxide inhibition of Cav3.2 T-type Ca2+ channels reveals tonic modulation by thioredoxin

T-type Ca2+ channels play diverse roles in tissues such as sensory neurons, vascular smooth muscle, and cancers, where increased expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1) is often found. Here, we report regulation of T-type Ca2+ channels by carbon monoxide (CO) a HO-1 by-product. CO (applied as CORM-2) caused a concentration-dependent, poorly reversible inhibition of all T-type channel isoforms (Cav3.1-3.3, IC50 ∼3 μM) expressed in HEK293 cells, and native T-type channels in NG108-15 cells and primary rat sensory neurons. No recognized CO-sensitive signaling pathway could account for the CO inhibition of Cav3.2. Instead, CO sensitivity was mediated by an extracellular redox-sensitive site, which was also highly sensitive to thioredoxin (Trx). Trx depletion (using auranofin, 2-5 μM) reduced Cav3.2 currents and their CO sensitivity by >50% but increased sensitivity to dithiothreitol ∼3-fold. By contrast, Cav3.1 and Cav3.3 channels, and their sensitivity to CO, were unaffected in identical experiments. Our data propose a novel signaling pathway in which Trx acts as a tonic, endogenous regulator of Cav3.2 channels, while HO-1-derived CO disrupts this regulation, causing channel inhibition. CO modulation of T-type channels has widespread implications for diverse physiological and pathophysiological mechanisms, such as excitability, contractility, and proliferation

Immobilisation of phenanthroline-bis triazine(c1-btphen) on magnetic nanoparticles for co-extraction of americium(III) and europium(III)

The present work reports a convenient route for the immobilisation of a phenanthroline-bis triazine (C1-BTPhen) group on the surface of zirconia-coated maghemite (γ-Fe2O3) magnetic nanoparticles. The magnetic nanoparticles functionalized with C1-BTPhen were able to co-extract Am(III) and Eu(III) from nitric acid (HNO3). The extraction efficiency of these C1-BTPhen-functionalized magnetic nanoparticles for both Am(III) and Eu(III) was 20% at 4M HNO3. The interaction between C1-BTPhen and metal cations is reversible. These functionalized magnetic nanoparticles can be used for the co-extraction of traces of Am(III) and Eu(III).

The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy.

Two major pathways contribute to Ras-proximate-1-mediated integrin activation in stimulated platelets. Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI, RasGRP2) mediates the rapid but reversible activation of integrin αIIbβ3, while the adenosine diphosphate receptor P2Y12, the target for antiplatelet drugs like clopidogrel, facilitates delayed but sustained integrin activation. To establish CalDAG-GEFI as a target for antiplatelet therapy, we compared how each pathway contributes to thrombosis and hemostasis in mice. Ex vivo, thrombus formation at arterial or venous shear rates was markedly reduced in CalDAG-GEFI(-/-) blood, even in the presence of exogenous adenosine diphosphate and thromboxane A(2). In vivo, thrombosis was virtually abolished in arterioles and arteries of CalDAG-GEFI(-/-) mice, while small, hemostatically active thrombi formed in venules. Specific deletion of the C1-like domain of CalDAG-GEFI in circulating platelets also led to protection from thrombus formation at arterial flow conditions, while it only marginally increased blood loss in mice. In comparison, thrombi in the micro- and macrovasculature of clopidogrel-treated wild-type mice grew rapidly and frequently embolized but were hemostatically inactive. Together, these data suggest that inhibition of the catalytic or the C1 regulatory domain in CalDAG-GEFI will provide strong protection from athero-thrombotic complications while maintaining a better safety profile than P2Y12 inhibitors like clopidogrel.

Healable supramolecular polymers

This mini-review details the recent development of self-healing and mendable polymeric materials which take advantage of the reversible characteristics of non-covalent interactions during their physical recovery process. Supramolecular polymer systems which undergo spontaneous (autonomous) healing, as well as those which require external stimuli to initiate the healing process (healable/mendable), are introduced and discussed. Supramolecular polymers offer key advantages over alternative approaches, as these materials can typically withstand multiple healing cycles without substantial loss of performance, as a consequence of the highly directional and fully reversible non-covalent interactions present within the polymer matrix.

The reversibility of sea level rise

During the last century, global climate has been warming, and projections indicate that such a warming is likely to continue over coming decades. Most of the extra heat is stored in the ocean, resulting in thermal expansion of seawater and global mean sea level rise. Previous studies have shown that after CO2 emissions cease or CO2 concentration is stabilized, global mean surface air temperature stabilizes or decreases slowly, but sea level continues to rise. Using idealized CO2 scenario simulations with a hierarchy of models including an AOGCM and a step-response model, the authors show how the evolution of thermal expansion can be interpreted in terms of the climate energy balance and the vertical profile of ocean warming. Whereas surface temperature depends on cumulative CO2 emissions, sea level rise due to thermal expansion depends on the time profile of emissions. Sea level rise is smaller for later emissions, implying that targets to limit sea level rise would need to refer to the rate of emissions, not only to the time integral. Thermal expansion is in principle reversible, but to halt or reverse it quickly requires the radiative forcing to be reduced substantially, which is possible on centennial time scales only by geoengineering. If it could be done, the results indicate that heat would leave the ocean more readily than it entered, but even if thermal expansion were returned to zero, the geographical pattern of sea level would be altered. Therefore, despite any aggressive CO2 mitigation, regional sea level change is inevitable.

Modelling the effects of gravity waves on stratocumulus clouds observed during VOCALS-UK

During the VOCALS campaign spaceborne satellite observations showed that travelling gravity wave packets, generated by geostrophic adjustment, resulted in perturbations to marine boundary layer (MBL) clouds over the south-east Pacific Ocean (SEP). Often, these perturbations were reversible in that passage of the wave resulted in the clouds becoming brighter (in the wave crest), then darker (in the wave trough) and subsequently recovering their properties after the passage of the wave. However, occasionally the wave packets triggered irreversible changes to the clouds, which transformed from closed mesoscale cellular convection to open form. In this paper we use large eddy simulation (LES) to examine the physical mechanisms that cause this transition. Specifically, we examine whether the clearing of the cloud is due to (i) the wave causing additional cloud-top entrainment of warm, dry air or (ii) whether the additional condensation of liquid water onto the existing drops and the subsequent formation of drizzle are the important mechanisms. We find that, although the wave does cause additional drizzle formation, this is not the reason for the persistent clearing of the cloud; rather it is the additional entrainment of warm, dry air into the cloud followed by a reduction in longwave cooling, although this only has a significant effect when the cloud is starting to decouple from the boundary layer. The result in this case is a change from a stratocumulus to a more patchy cloud regime. For the simulations presented here, cloud condensation nuclei (CCN) scavenging did not play an important role in the clearing of the cloud. The results have implications for understanding transitions between the different cellular regimes in marine boundary layer (MBL) clouds.

Irreversible compressible work and APE dissipation in turbulent stratified fluid

Although it plays a key role in the theory of stratified turbulence, the concept of available potential energy (APE) dissipation has remained until now a rather mysterious quantity, owing to the lack of rigorous result about its irreversible character or energy conversion type. Here, we show by using rigorous energetics considerations rooted in the analysis of the Navier-Stokes for a fully compressible fluid with a nonlinear equation of state that the APE dissipation is an irreversible energy conversion that dissipates kinetic energy into internal energy, exactly as viscous dissipation. These results are established by showing that APE dissipation contributes to the irreversible production of entropy, and by showing that it is a part of the work of expansion/contraction. Our results provide a new interpretation of the entropy budget, that leads to a new exact definition of turbulent effective diffusivity, which generalizes the Osborn-Cox model, as well as a rigorous decomposition of the work of expansion/contraction into reversible and irreversible components. In the context of turbulent mixing associated with parallel shear flow instability, our results suggests that there is no irreversible transfer of horizontal momentum into vertical momentum, as seems to be required when compressible effects are neglected, with potential consequences for the parameterisations of momentum dissipation in the coarse-grained Navier-Stokes equations.

The effects of retinoic acid on human corneal stromal keratocytes cultured in vitro under serum-free conditions

Purpose: Retinoic acid (RA) is a metabolite of vitamin A that plays a fundamental role in the development and function of the human eye. The purpose of this study was to investigate the effects of RA on the phenotype of corneal stromal keratocytes maintained in vitro for extended periods under serum-free conditions. Methods: Keratocytes isolated from human corneas were cultured up to 21 days in serum-free media supplemented with RA or DMSO vehicle. The effects of RA and of its removal after treatment on cell proliferation and morphology were evaluated. In addition, the expression of keratocyte markers was quantified at the transcriptional and protein levels by quantitative PCR and immunoblotting or ELISA, respectively. Furthermore, the effects of RA on keratocyte migration were tested using scratch assays. Results: Keratocytes cultured with RA up to 10×10-6 M showed enhanced proliferation and stratification, and reduced mobility. RA also promoted the expression of keratocyte-characteristic proteoglycans such as keratocan, lumican, and decorin, and increased the amounts of collagen type-I in culture while significantly reducing the expression of matrix metalloproteases 1, 3, and 9. RA effects were reversible, and cell phenotype reverted to that of control after removal of RA from media. Conclusions: RA was shown to control the phenotype of human corneal keratocytes cultured in vitro by regulating cell behaviour and extracellular matrix composition. These findings contribute to our understanding of corneal stromal biology in health and disease, and may prove useful in optimizing keratocyte cultures for applications in tissue engineering, cell biology, and medicine.