Isopimaric acid - a multi-targeting ion channel modulator reducing excitability and arrhythmicity in a spontaneously beating mouse atrial cell line.

AIM: Atrial fibrillation is the most common persistent cardiac arrhythmia, and it is not well controlled by present drugs. Because some resin acids open voltage-gated potassium channels and reduce neuronal excitability, we explored the effects of the resin acid isopimaric acid (IPA) on action potentials and ion currents in cardiomyocytes. METHODS: Spontaneously beating mouse atrial HL-1 cells were investigated with the whole-cell patch-clamp technique. RESULTS: 1-25 µmol L-1 IPA reduced the action potential frequency by up to 50%. The effect of IPA on six different voltage-gated ion channels was investigated; most voltage-dependent parameters of ion channel gating were shifted in the negative direction along the voltage axis, consistent with a hypothesis that a lipophilic and negatively charged compound binds to the lipid membrane close to the positively charged voltage sensor of the ion channels. The major finding was that IPA inactivated sodium channels and L- and T-type calcium channels and activated the rapidly activating potassium channel and the transient outward potassium channel. Computer simulations of IPA effects on all of the ion currents were consistent with a reduced excitability, and they also showed that effects on the Na channel played the largest role to reduce the action potential frequency. Finally, induced arrhythmia in the HL-1 cells was reversed by IPA. CONCLUSION: Low concentrations of IPA reduced the action potential frequency and restored regular firing by altering the voltage dependencies of several voltage-gated ion channels. These findings can form the basis for a new pharmacological strategy to treat atrial fibrillation.

Demonstration of Einstein-Podolsky-Rosen Steering Using Single-Photon Path Entanglement and Displacement-Based Detection.

We demonstrate the violation of an Einstein-Podolsky-Rosen steering inequality developed for single-photon path entanglement with displacement-based detection. We use a high-rate source of heralded single-photon path-entangled states, combined with high-efficiency superconducting-based detectors, in a scheme that is free of any postselection and thus immune to the detection loophole. This result conclusively demonstrates single-photon entanglement in a one-sided device-independent scenario, and opens the way towards implementations of device-independent quantum technologies within the paradigm of path entanglement.

Unifying framework for relaxations of the causal assumptions in Bell's theorem.

Bell's theorem shows that quantum mechanical correlations can violate the constraints that the causal structure of certain experiments impose on any classical explanation. It is thus natural to ask to which degree the causal assumptions-e.g., locality or measurement independence-have to be relaxed in order to allow for a classical description of such experiments. Here we develop a conceptual and computational framework for treating this problem. We employ the language of Bayesian networks to systematically construct alternative causal structures and bound the degree of relaxation using quantitative measures that originate from the mathematical theory of causality. The main technical insight is that the resulting problems can often be expressed as computationally tractable linear programs. We demonstrate the versatility of the framework by applying it to a variety of scenarios, ranging from relaxations of the measurement independence, locality, and bilocality assumptions, to a novel causal interpretation of Clauser-Horne-Shimony-Holt inequality violations.

Noisy metrology beyond the standard quantum limit.

Parameter estimation is of fundamental importance in areas from atomic spectroscopy and atomic clocks to gravitational wave detection. Entangled probes provide a significant precision gain over classical strategies in the absence of noise. However, recent results seem to indicate that any small amount of realistic noise restricts the advantage of quantum strategies to an improvement by at most a multiplicative constant. Here, we identify a relevant scenario in which one can overcome this restriction and attain superclassical precision scaling even in the presence of uncorrelated noise. We show that precision can be significantly enhanced when the noise is concentrated along some spatial direction, while the Hamiltonian governing the evolution which depends on the parameter to be estimated can be engineered to point along a different direction. In the case of perpendicular orientation, we find superclassical scaling and identify a state which achieves the optimum.

Local orthogonality as a multipartite principle for quantum correlations.

In recent years, the use of information principles to understand quantum correlations has been very successful. Unfortunately, all principles considered so far have a bipartite formulation, but intrinsically multipartite principles, yet to be discovered, are necessary for reproducing quantum correlations. Here we introduce local orthogonality, an intrinsically multipartite principle stating that events involving different outcomes of the same local measurement must be exclusive or orthogonal. We prove that it is equivalent to no-signalling in the bipartite scenario but more restrictive for more than two parties. By exploiting this non-equivalence, it is then demonstrated that some bipartite supra-quantum correlations do violate the local orthogonality when distributed among several parties. Finally, we show how its multipartite character allows revealing the non-quantumness of correlations for which any bipartite principle fails. We believe that local orthogonality is a crucial ingredient for understanding no-signalling and quantum correlations.

Blending of heritable recognition cues among ant nestmates creates distinct colony gestalt odours but prevents within-colony nepotism.

The evolution of sociality is facilitated by the recognition of close kin, but if kin recognition is too accurate, nepotistic behaviour within societies can dissolve social cohesion. In social insects, cuticular hydrocarbons act as nestmate recognition cues and are usually mixed among colony members to create a Gestalt odour. Although earlier studies have established that hydrocarbon profiles are influenced by heritable factors, transfer among nestmates and additional environmental factors, no studies have quantified these relative contributions for separate compounds. Here, we use the ant Formica rufibarbis in a cross-fostering design to test the degree to which hydrocarbons are heritably synthesized by young workers and transferred by their foster workers. Bioassays show that nestmate recognition has a significant heritable component. Multivariate quantitative analyses based on 38 hydrocarbons reveal that a subset of branched alkanes are heritably synthesized, but that these are also extensively transferred among nestmates. In contrast, especially linear alkanes are less heritable and little transferred; these are therefore unlikely to act as cues that allow within-colony nepotistic discrimination or as nestmate recognition cues. These results indicate that heritable compounds are suitable for establishing a genetic Gestalt for efficient nestmate recognition, but that recognition cues within colonies are insufficiently distinct to allow nepotistic kin discrimination.

Hybrid long-distance entanglement distribution protocol.

We propose a hybrid (continuous-discrete variable) quantum repeater protocol for long-distance entanglement distribution. Starting from states created by single-photon detection, we show how entangled coherent state superpositions can be generated by means of homodyne detection. We show that near-deterministic entanglement swapping with such states is possible using only linear optics and homodyne detectors, and we evaluate the performance of our protocol combining these elements.

Carbohydrates as templates for control of distance-geometry in de novo-designed proteins.

An understanding of very complex natural systems can often only be achieved through detailed studies of systems with a reduced complexity. Thus, de novo design of proteins allows the study of fundamental forces determining protein folding and stability, as well as protein-protein interactions, by analyses of protein models of structural motifs. In addition, de novo design may lead to new biomimetic molecules with novel properties. In a synthetic approach to achieve structural economy, rigid templates, sometimes called topological scaffolds, have been used to connect secondary-structure elements, most notably alpha-helices. By positioning the helices on the template, the unfavorable entropy of protein folding is reduced. In a novel class of chimeric molecules called carboproteins, carbohydrates are used as templates for de novo design of protein models. Recently, a strategy relying on chemoselective ligation of C-terminal peptide aldehydes to tetra-aminooxy functionalized monosaccharides has provided 7-kDa 4-alpha-helix bundle carboproteins.

Changes in calcium currents and GABAergic spontaneous activity in cultured rat hippocampal neurons after a neurotropic influenza A virus infection.

In order to study mechanisms by which a neurotropic strain of influenza A virus (A/WSN/33) may affect neuronal function or cause nerve cell death, hippocampal cultures from embryonic rats were infected with this virus. Approximately 70% of the neurons in the infected cultures became immunopositive for viral antigens and showed reduced voltage-dependent Ca(2+) currents in whole-cell patch clamp recordings, but no changes in other membrane properties or in cytosolic Ca(2+) concentration were seen. These immunopositive neurons underwent apoptosis 3-4 days after infection. Ca(2+) channel inhibitors had no significant effect on neuronal survival. The immunonegative population of neurons survived, but displayed increased frequency of miniature inhibitory postsynaptic currents of gamma-amino-butyric acid origin compared with controls. The frequency of alpha-amino-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) receptor-mediated miniature excitatory postsynaptic currents was not altered. Viral nucleoproteins, overexpressed using the Semliki Forest virus system, were localized to the dendritic spines as shown by double immunolabeling with actinin, but did not by themselves cause neuronal death or changes in synaptic transmission as measured by AMPA-mediated excitatory postsynaptic currents. Our results show that an influenza A virus infection can cause selective neurophysiological changes in hippocampal neurons and that these can persist even after the viral antigens have been cleared.

Carboproteins: a 4-alpha-helix bundle protein model assembled on a D-galactopyranoside template.

We have recently introduced the concept of monosaccharides as templates for de novo design of protein models and described the synthesis of a model 'carbopeptide'. Here, we report the synthesis of a 64 amino acid (AA) 'carboprotein' by chemoselective ligation of a C-terminal hexadecapeptide aldehyde to a tetra-aminooxy functionalized methyl alpha-D-galactopyranoside (D-Galp) template. Biophysical characterizations by CD spectroscopy and NMR amide H-D exchange experiments indicated that the four-stranded carboprotein forms a 4-alpha-helix bundle structure.

Interferon-gamma-induced changes in synaptic activity and AMPA receptor clustering in hippocampal cultures.

Extended release of interferon-gamma (IFN-gamma) in the nervous system during immunological and infectious conditions may trigger demyelinating disorders and cause disturbances in brain function. The aim of this study was to examine the effects of IFN-gamma on neuronal function in rat hippocampal cell cultures by using whole cell patch clamp analysis together with quantitative immunocytochemistry. Acute application of IFN-gamma to differentiated neurons in culture caused no immediate neurophysiological responses, but recordings after 48 h of incubation displayed an increase in frequency of AMPA receptor (AMPAR)-mediated spontaneous excitatory postsynaptic currents (EPSCs). Quantitative immunocytochemistry for the AMPAR subunit GluR1 showed no alteration in receptor clustering at this time point. However, prolonged treatment with IFN-gamma for 2 weeks resulted in a significant reduction in AMPAR clustering on dendrites but no marked differences in EPSC frequency between treated neurons and controls could be observed. On the other hand, treatment of hippocampal neurons for 4 weeks, instituted at an immature stage (1 day in culture), caused a significant reduction in spontaneous EPSC frequency. These neurons developed with no overt alterations in dendritic arborization or in the appearance of dendritic spines as visualized by alpha-actinin immunocytochemistry. Nonetheless, there was a marked reduction in AMPAR clustering on dendrites. These observations show that a key immunomodulatory molecule, IFN-gamma, can cause long-term modifications of synaptic activity and perturb glutamate receptor clustering.

Tetraaza analogues of lithium and sodium alums: synthesis and X-ray structures of the single strand polymer [Li(THF)2(Al[SO2(NtBu)2]2)] infinity and the contact ion pairs [Na(15-crown-5)][Al(SO2(NtBu)2)2] and ([Na(15-crown-5)][O2S(mu-NBn)2Al(mu-NBnSO2NBn)])2.

The reaction of an alkali metal aluminohydride MAlH4 (M = Li, Na) with N,N'-bis-(tert-butyl)sulfamide or N,N'-bis-(benzyl)sulfamide in THF produces the complex ions (Al[SO2(NR)2]2)- (R = tBu, Bn). The X-ray structures of [Li(THF)2(Al[SO2(NtBu)2]2)] infinity (1), [Na(15-crown-5)][Al(SO2(NtBu)2)2], (2) and ([Na(15-crown-5)][O2S(mu-NBn)2Al(mu-NBnSO2NBn)])2 (3.3THF) are reported. The two diazasulfate ligands [SO2(NtBu)2]2- are N,N' chelated to Al3+ in both 1 and 2. In the lithium derivative 1 the spirocyclic (Al[SO2(NtBu)2]2)- anions are bridged by the bis-solvated cations Li(THF)2+ to give a polymeric strand. In the sodium salt 2 the complex anion is O,O' chelated to Na+, which is further encapsulated by a 15-crown-5 ligand to give a monomeric ion-pair complex. By contrast, the benzyl derivative 3 forms a dimer in which the terminal [SO2(NBn)2]2- ligands are (N,N'),(O,O') bis-chelated to Al3+ and Na+, respectively, and the bridging ligands adopt a novel N,O-chelate, N'-monodentate bonding mode. The central core of 3 consists of two four-membered AlOSN rings bridged by two NtBu groups. Crystal data: 1, orthorhombic, Pna2(1), a = 20.159(5) degrees, b = 10.354(3) degrees, c = 15.833(4) degrees, alpha = beta = gamma = 90 degrees, V = 3304.7(15) A3, Z = 4; 2, monoclinic, P2(1)/n, a = 16.031(2) A, b = 9.907(2) A, c = 23.963(4) A, beta = 103.326(2) degrees, Z = 4; 3, triclinic, P1, a = 12.7237(11) A, b = 14.0108(13) A, c = 16.2050(14) A, alpha = 110.351(2) degrees, beta = 111.538(2) degrees, gamma = 97.350(2) degrees, Z = 1.

Niobium and vanadium iminophosphinimide complexes.

The iminophosphinimide complexes [Ar(R)N]3M(NPNBut) (M = V, Nb) were prepared from the corresponding anionic nitride species ([Ar(R)N]3M identical to NNa)2 by way of a four-step synthetic strategy.

Carbopeptides: chemoselective ligation of peptide aldehydes to an aminooxy-functionalized D-galactose template.

Multifunctional, topological template molecules such as linear and cyclic peptides have been used for the attachment of peptide strands to form novel protein models of, for example, 4-alpha-helix bundles. The concept of carbohydrates as templates for de novo design of potential protein models has been previously described and these novel chimeric compounds were termed carbopeptides. Here, a second generation strategy in which carbopeptides are synthesized by chemoselective ligation of a peptide aldehyde to an aminooxy-functionalized alpha-D-galactopyranoside is described. This template was prepared by per-O-acylation of methyl alpha-D-galactopyranoside with N,N-Boc2-aminooxyacetic acid to form a tetra-functionalized template, followed by treatment with TFA-CH2Cl2 to release the aminooxy functionality. The peptide aldehydes Fmoc-Ser-Gly-Gly-H and H-Ala-Leu-Ala-Lys-Leu-Gly-Gly-H were synthesized by a BAL strategy. Four identical copies of peptide aldehyde were smoothly attached to the template by chemoselective ligation to form a 2.1 and a 2.9 kDa carbopeptide, respectively.

Polylithiated tetraaminosilanes: synthesis and characterization of (Et2O.Li)4[Si(Nnaph)4] and X-ray structure of (THF.Li3[Si(NiPr)3(NHiPr)])2.

The treatment of SiCl4 with 4 equiv of Li2(Nnaph) (naph = 1-naphthyl) in diethyl ether gives (Et2O.Li)4[Si(Nnaph)4] (4), which, upon reaction with excess tBuNH3Cl or MeO3SCF3, generates Si[N(H)naph]4 (5) or Si[N(Me)naph]4 (6), respectively. The centrosymmetric dimer (THF.Li3[Si(NiPr)3(NHiPr)])2 (7), formed via trilithiation of Si[N(H)iPr]4 with n-butyllithium, consists of a bis-THF-solvated Li6(NiPr)6 cyclic ladder bicapped by two SiN(H)iPr units. Crystal data for 7: C32H74Li6N8O2Si2, monoclinic, P2(1)/n, a = 10.661(7) A, b = 16.964(5) A, c = 12.405(4) A, beta = 93.22(4) degrees, V = 2239.9(15) A3, and Z = 2.