Gap junction-mediated spontaneous Ca(2+) waves in differentiated cholinergic SN56 cells

Neuronal gap junctions are receiving increasing attention as a physiological means of intercellular communication, yet our understanding of them is poorly developed when compared to synaptic communication. Using microfluorimetry, we demonstrate that differentiation of SN56 cells (hybridoma cells derived from murine septal neurones) leads to the spontaneous generation of Ca(2+) waves. These waves were unaffected by tetrodotoxin (1microM), but blocked by removal of extracellular Ca(2+), or addition of non-specific Ca(2+) channel inhibitors (Cd(2+) (0.1mM) or Ni(2+) (1mM)). Combined application of antagonists of NMDA receptors (AP5; 100microM), AMPA/kainate receptors (NBQX; 20microM), nicotinic AChR receptors (hexamethonium; 100microM) or inotropic purinoceptors (brilliant blue; 100nM) was also without effect. However, Ca(2+) waves were fully prevented by carbenoxolone (200microM), halothane (3mM) or niflumic acid (100microM), three structurally diverse inhibitors of gap junctions, and mRNA for connexin 36 was detected by PCR. Whole-cell patch-clamp recordings revealed spontaneous inward currents in voltage-clamped cells which we inhibited by Cd(2+), Ni(2+) or niflumic acid. Our data suggest that differentiated SN56 cells generated spontaneous Ca(2+) waves which are propagated by intercellular gap junctions. We propose that this system can be exploited conveniently for the development of neuronal gap junction modulators.

Effect of a methyl group on the spontaneous resolution of a square-pyramidal coordination compound: crystal packing and conglomerate formation

Reaction of [Cu(pic)2]·2H2O (where pic stands for 2-picolinato) with 2-({[2-(dimethylamino)ethyl]amino}methyl)phenol (HL1) produces the square-pyramidal complex [CuL1(pic)] (1), which crystallizes as a conglomerate (namely a mixture of optically pure crystals) in the Sohncke space group P212121. The use of the methylated ligand at the benzylic position, i.e. (±)-2-(1-{[2-(dimethylamino)ethyl]amino}ethyl)phenol (HL2), yields the analogous five-coordinate complex [CuL2(pic)] (2) that crystallizes as a true racemate (namely the crystals contain both enantiomers) in the centrosymmetric space group P21/c. Density functional theory (DFT) calculations indicate that the presence of the methyl group indeed leads to a distinct crystallization behaviour, not only by intramolecular steric effects, but also because its involvement in non-covalent C–H···π and hydrophobic intermolecular contacts appears to be an important factor contributing to the crystal-lattice (stabilizing) energy of 2

Associating spontaneous with evoked activity in a neural mass model of cat visual cortex

Spontaneous activity of the brain at rest frequently has been considered a mere backdrop to the salient activity evoked by external stimuli or tasks. However, the resting state of the brain consumes most of its energy budget, which suggests a far more important role. An intriguing hint comes from experimental observations of spontaneous activity patterns, which closely resemble those evoked by visual stimulation with oriented gratings, except that cortex appeared to cycle between different orientation maps. Moreover, patterns similar to those evoked by the behaviorally most relevant horizontal and vertical orientations occurred more often than those corresponding to oblique angles. We hypothesize that this kind of spontaneous activity develops at least to some degree autonomously, providing a dynamical reservoir of cortical states, which are then associated with visual stimuli through learning. To test this hypothesis, we use a biologically inspired neural mass model to simulate a patch of cat visual cortex. Spontaneous transitions between orientation states were induced by modest modifications of the neural connectivity, establishing a stable heteroclinic channel. Significantly, the experimentally observed greater frequency of states representing the behaviorally important horizontal and vertical orientations emerged spontaneously from these simulations. We then applied bar-shaped inputs to the model cortex and used Hebbian learning rules to modify the corresponding synaptic strengths. After unsupervised learning, different bar inputs reliably and exclusively evoked their associated orientation state; whereas in the absence of input, the model cortex resumed its spontaneous cycling. We conclude that the experimentally observed similarities between spontaneous and evoked activity in visual cortex can be explained as the outcome of a learning process that associates external stimuli with a preexisting reservoir of autonomous neural activity states. Our findings hence demonstrate how cortical connectivity can link the maintenance of spontaneous activity in the brain mechanistically to its core cognitive functions.

Endogenous cholinergic tone modulates spontaneous network level neuronal activity in primary cortical cultures grown on multi-electrode arrays

Background Cortical cultures grown long-term on multi-electrode arrays (MEAs) are frequently and extensively used as models of cortical networks in studies of neuronal firing activity, neuropharmacology, toxicology and mechanisms underlying synaptic plasticity. However, in contrast to the predominantly asynchronous neuronal firing activity exhibited by intact cortex, electrophysiological activity of mature cortical cultures is dominated by spontaneous epileptiform-like global burst events which hinders their effective use in network-level studies, particularly for neurally-controlled animat (‘artificial animal’) applications. Thus, the identification of culture features that can be exploited to produce neuronal activity more representative of that seen in vivo could increase the utility and relevance of studies that employ these preparations. Acetylcholine has a recognised neuromodulatory role affecting excitability, rhythmicity, plasticity and information flow in vivo although its endogenous production by cortical cultures and subsequent functional influence upon neuronal excitability remains unknown. Results Consequently, using MEA electrophysiological recording supported by immunohistochemical and RT-qPCR methods, we demonstrate for the first time, the presence of intrinsic cholinergic neurons and significant, endogenous cholinergic tone in cortical cultures with a characterisation of the muscarinic and nicotinic components that underlie modulation of spontaneous neuronal activity. We found that tonic muscarinic ACh receptor (mAChR) activation affects global excitability and burst event regularity in a culture age-dependent manner whilst, in contrast, tonic nicotinic ACh receptor (nAChR) activation can modulate burst duration and the proportion of spikes occurring within bursts in a spatio-temporal fashion. Conclusions We suggest that the presence of significant endogenous cholinergic tone in cortical cultures and the comparability of its modulatory effects to those seen in intact brain tissues support emerging, exploitable commonalities between in vivo and in vitro preparations. We conclude that experimental manipulation of endogenous cholinergic tone could offer a novel opportunity to improve the use of cortical cultures for studies of network-level mechanisms in a manner that remains largely consistent with its functional role.

A robust mechanism for strengthening of the Brewer–Dobson circulation in response to climate change: critical-layer control of subtropical wave breaking

Climate models consistently predict a strengthened Brewer–Dobson circulation in response to greenhouse gas (GHG)-induced climate change. Although the predicted circulation changes are clearly the result of changes in stratospheric wave drag, the mechanism behind the wave-drag changes remains unclear. Here, simulations from a chemistry–climate model are analyzed to show that the changes in resolved wave drag are largely explainable in terms of a simple and robust dynamical mechanism, namely changes in the location of critical layers within the subtropical lower stratosphere, which are known from observations to control the spatial distribution of Rossby wave breaking. In particular, the strengthening of the upper flanks of the subtropical jets that is robustly expected from GHG-induced tropospheric warming pushes the critical layers (and the associated regions of wave drag) upward, allowing more wave activity to penetrate into the subtropical lower stratosphere. Because the subtropics represent the critical region for wave driving of the Brewer–Dobson circulation, the circulation is thereby strengthened. Transient planetary-scale waves and synoptic-scale waves generated by baroclinic instability are both found to play a crucial role in this process. Changes in stationary planetary wave drag are not so important because they largely occur away from subtropical latitudes.

Wave-breaking characteristics of Northern Hemisphere winter blocking: a two-dimensional approach

This paper generalises and applies recently developed blocking diagnostics in a two- dimensional latitude-longitude context, which takes into consideration both mid- and high-latitude blocking. These diagnostics identify characteristics of the associated wave-breaking as seen in the potential temperature (θ) on the dynamical tropopause, in particular the cyclonic or anticyclonic Direction of wave-Breaking (DB index), and the Relative Intensity (RI index) of the air masses that contribute to blocking formation. The methodology is extended to a 2-D domain and a cluster technique is deployed to classify mid- and high-latitude blocking according to the wave-breaking characteristics. Mid-latitude blocking is observed over Europe and Asia, where the meridional gradient of θ is generally weak, whereas high-latitude blocking is mainly present over the oceans, to the north of the jet-stream, where the meridional gradient of θ is much stronger. They occur respectively on the equatorward and poleward flank of the jet- stream, where the horizontal shear ∂u/∂y is positive in the first case and negative in the second case. A regional analysis is also conducted. It is found that cold-anticyclonic and cyclonic blocking divert the storm-track respectively to the south and to the north over the East Atlantic and western Europe. Furthermore, warm-cyclonic blocking over the Pacific and cold-anticyclonic blocking over Europe are identified as the most persistent types and are associated with large amplitude anomalies in temperature and precipitation. Finally, the high-latitude, cyclonic events seem to correlate well with low- frequency modes of variability over the Pacific and Atlantic Ocean.

Rossby wave-breaking analysis of explosive cyclones in the Euro-Atlantic sector

The two-way relationship between Rossby Wave-Breaking (RWB) and intensification of extra tropical cyclones is analysed over the Euro-Atlantic sector. In particular, the timing, intensity and location of cyclone development are related to RWB occurrences. For this purpose, two potential-temperature based indices are used to detect and classify anticyclonic and cyclonic RWB episodes from ERA-40 Re-Analysis data. Results show that explosive cyclogenesis over the North Atlantic (NA) is fostered by enhanced occurrence of RWB on days prior to the cyclone’s maximum intensification. Under such conditions, the eddy-driven jet stream is accelerated over the NA, thus enhancing conditions for cyclogenesis. For explosive cyclogenesis over the eastern NA, enhanced cyclonic RWB over eastern Greenland and anticyclonic RWB over the sub-tropical NA are observed. Typically only one of these is present in any given case, with the RWB over eastern Greenland being more frequent than its southern counterpart. This leads to an intensification of the jet over the eastern NA and enhanced probability of windstorms reaching Western Europe. Explosive cyclones evolving under simultaneous RWB on both sides of the jet feature a higher mean intensity and deepening rates than cyclones preceded by a single RWB event. Explosive developments over the western NA are typically linked to a single area of enhanced cyclonic RWB over western Greenland. Here, the eddy-driven jet is accelerated over the western NA. Enhanced occurrence of cyclonic RWB over southern Greenland and anticyclonic RWB over Europe is also observed after explosive cyclogenesis, potentially leading to the onset of Scandinavian Blocking. However, only very intense developments have a considerable influence on the large-scale atmospheric flow. Non-explosive cyclones depict no sign of enhanced RWB over the whole NA area. We conclude that the links between RWB and cyclogenesis over the Euro-Atlantic sector are sensitive to the cyclone’s maximum intensity, deepening rate and location.

Breaking the impasse: towards a new regime for international climate governance

The reality of the current international order makes it imperative that a just and effective climate regime balance the historical responsibility of developed countries with the increasing absolute emissions from many developing nations. In this short outlook article, key pillars are proposed for a new international climate architecture that envisions replacing the current annex system with two new annexes –Annex α, for countries with high current emissions and historically high emissions, and Annex β, for countries with high current emissions and historically low emissions. Countries in both annexes would implement legally binding targets under this framework. Additionally, this proposal includes tweaks and revisions to funding and technology transfer mechanisms to correct for weaknesses and inequities under the current Kyoto architecture. The proposed framework stems from a belief that a top-down, international approach to climate policy remains the most effective for ensuring environmental integrity. Given the slow rate of institutional learning, reforming and improving the current system is held as a more efficient course of action than abandoning the progress already achieved. It is argued that the proposed framework effectively accommodates key equity, environmental integrity and political feasibility concerns.

The resting-state neurovascular coupling relationship: rapid changes in spontaneous neural activity in the somatosensory cortex are associated with haemodynamic fluctuations that resemble stimulus-evoked haemodynamics

Although promise exists for patterns of resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) brain connectivity to be used as biomarkers of early brain pathology, a full understanding of the nature of the relationship between neural activity and spontaneous fMRI BOLD fluctuations is required before such data can be correctly interpreted. To investigate this issue, we combined electrophysiological recordings of rapid changes in multi-laminar local field potentials from the somatosensory cortex of anaesthetized rats with concurrent two-dimensional optical imaging spectroscopy measurements of resting-state haemodynamics that underlie fluctuations in the BOLD fMRI signal. After neural ‘events’ were identified, their time points served to indicate the start of an epoch in the accompanying haemodynamic fluctuations. Multiple epochs for both neural ‘events’ and the accompanying haemodynamic fluctuations were averaged. We found that the averaged epochs of resting-state haemodynamic fluctuations taken after neural ‘events’ closely resembled the temporal profile of stimulus-evoked cortical haemodynamics. Furthermore, we were able to demonstrate that averaged epochs of resting-state haemodynamic fluctuations resembling the temporal profile of stimulus-evoked haemodynamics could also be found after peaks in neural activity filtered into specific electroencephalographic frequency bands (theta, alpha, beta, and gamma). This technique allows investigation of resting-state neurovascular coupling using methodologies that are directly comparable to that developed for investigating stimulus-evoked neurovascular responses.

Substitutional and orientational disorder in organic crystals: a symmetry-adapted ensemble model

Modelling of disorder in organic crystals is highly desirable since it would allow thermodynamic stabilities and other disorder-sensitive properties to be estimated for such systems. Two disordered organic molecular systems are modeled using a symmetry-adapted ensemble approach, in which the disordered system is treated as an ensemble of the configurations of a supercell with respect to substitution of one disorder component for another. Computation time is kept manageable by performing calculations only on the symmetrically inequivalent configurations. Calculations are presented on a substitutionally disordered system, the dichloro/dibromobenzene solid solution, and on an orientationally disordered system, eniluracil, and the resultant free energies, disorder patterns, and system properties are discussed. The results are found to be in agreement with experiment following manual removal of physically implausible configurations from ensemble averages, highlighting the dangers of a completely automated approach to organic crystal thermodynamics which ignores the barriers to equilibration once the crystal has been formed.

Spontaneous facial mimicry is modulated by joint attention and autistic traits

Joint attention (JA) and spontaneous facial mimicry (SFM) are fundamental processes in social interactions, and they are closely related to empathic abilities. When tested independently, both of these processes have been usually observed to be atypical in individuals with autism spectrum conditions (ASC). However, it is not known how these processes interact with each other in relation to autistic traits. This study addresses this question by testing the impact of JA on SFM of happy faces using a truly interactive paradigm. Sixty-two neurotypical participants engaged in gaze-based social interaction with an anthropomorphic, gaze-contingent virtual agent. The agent either established JA by initiating eye contact or looked away, before looking at an object and expressing happiness or disgust. Eye tracking was used to make the agent's gaze behavior and facial actions contingent to the participants' gaze. SFM of happy expressions was measured by Electromyography (EMG) recording over the Zygomaticus Major muscle. Results showed that JA augments SFM in individuals with low compared with high autistic traits. These findings are in line with reports of reduced impact of JA on action imitation in individuals with ASC. Moreover, they suggest that investigating atypical interactions between empathic processes, instead of testing these processes individually, might be crucial to understanding the nature of social deficits in autism

Self-assembled arginine-capped peptide bolaamphiphile nanosheets for cell culture and controlled wettability surfaces

The spontaneous assembly of a peptide bolaamphiphile in water, namely, RFL4FR (R, arginine; F, phenylalanine; L, leucine) is investigated, along with its novel properties in surface modification and usage as substrates for cell culture. RFL4FR self-assembles into nanosheets through lateral association of the peptide backbone. The L4 sequence is located within the core of the nanosheets, whereas the R moieties are exposed to the water at the surface of the nanosheets. Kinetic assays indicate that the self-assembly is driven by a remarkable two-step process, where a nucleation phase is followed by fast growth of nanosheets with an autocatalysis process. The internal structure of the nanosheets is formed from ultrathin bolaamphiphile monolayers with a crystalline orthorhombic symmetry with cross-β organization. We show that human corneal stromal fibroblast (hCSF) cells can grow on polystyrene films coated with films dried from RFL4FR solutions. For the first time, this type of amphiphilic peptide is used as a substrate to modulate the wettability of solid surfaces for cell culture applications.

Breaking the double-edged sword of effort/trying hard: developmental equilibrium and Longitudinal relations among effort, achievement, and academic self-concept

Ever since the classic research of Nicholls (1976) and others, effort has been recognized as a double-edged sword: whilst it might enhance achievement, it undermines academic self-concept (ASC). However, there has not been a thorough evaluation of the longitudinal reciprocal effects of effort, ASC and achievement,in the context of modern self-concept theory and statistical methodology. Nor have there been developmental equilibrium tests of whether these effects are consistent across the potentially volatile early-to-middle adolescence. Hence, focusing on mathematics, we evaluate reciprocal effects models over the first four years of secondary school, relating effort, achievement (test scores and school grades), ASC, and ASCxEffort interactions for a representative sample of 3,421 German students (Mn age = 11.75 years at Wave 1). ASC, effort and achievement were positively correlated at each wave, and there was a clear pattern of positive reciprocal positive effects among ASC, test scores and school grades—each contributing to the other, after controlling for the prior effects of all others. There was an asymmetrical pattern of effects for effort that is consistent with the double-edged sword premise: prior school grades had positive effects on subsequent effort, but prior effort had non-significant or negative effects on subsequent grades and ASC. However, on the basis of a synergistic application of new theory and methodology, we predicted and found a significant ASC-by-effort interaction, such that prior effort had more positive effects on subsequent ASC and school grades when prior ASC was high—thus providing a key to breaking the double-edged sword.