Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor–Gs Coupling and CREB Activation of Acute Morphine

Chronic morphine causes the mu opioid receptor (MOR) to switch its coupling from Gi/o to Gs, resulting in excitatory signaling via both Gαs and its Gβγ dimer. Ultra-low-dose naloxone (NLX) prevents this switch and attenuates opioid tolerance and dependence. This protective effect is mediated via a high-affinity interaction of NLX to a pentapeptide region in c-terminal filamin A (FLNA), a scaffolding protein interacting with MOR. In organotypic striatal slice cultures, we now show that acute morphine induces a dose-dependent Go-to-Gs coupling switch at 5 and 15 min that resolves by 1 hr. The acute Gs coupling induced by 100 µM morphine was completely prevented by co-treatment with 100 pM NLX, (+)NLX, or naltrexone (NTX), or their pentapeptide binding site (FLNA2561–2565), which we show can act as a decoy for MOR or bind to FLNA itself. All of these co-treatments presumably prevent the MOR–FLNA interaction. Since ultra-low-dose NTX also attenuates the addictive properties of opioids, we assessed striatal cAMP production and CREB phosphorylation at S133. Correlating with the Gs coupling, acute morphine induced elevated cAMP levels and a several-fold increase in pS133CREB that were also completely blocked by NLX, NTX or the FLNA pentapeptide. We propose that acute, robust stimulation of MOR causes an interaction with FLNA that allows an initially transient MOR–Gs coupling, which recovers with receptor recycling but persists when MOR stimulation is repeated or prolonged. The complete prevention of this acute, morphine-induced MOR–Gs coupling by 100 pM NLX/NTX or 10 µM pentapeptide segment of FLNA further elucidates both MOR signaling and the mechanism of action of ultra-low-dose NLX or NTX in attenuating opioid tolerance, dependence and addictive potential

The Short-Term Effect of Video Editing Pace on Children’s Inhibition and N2 and P3 ERP Components during Visual Go/No-Go Task

We investigated the immediate consequences of differently paced videos on behaviour and neural activity during response inhibition. Forty 7-year-olds watched a fast- or slow-paced video and completed a go/no-go task. Compared to the slow-paced-video group, children in the fast-paced-video group made more no-go errors. There was also an interaction between pace and no-go response type (correct, wrong) for the N2 and P3 peak latencies. In the slow-paced group, both components peaked earlier for correct response withholds. This usual pattern of activation was absent in the fast-paced group. Video pace appears to affect behaviour and the neural responses involved in inhibition

Differential Regulation of the Period Genes in Striatal Regions following Cocaine Exposure

Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc) and Caudate Putamen (CP), regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per) genes and Neuronal PAS Domain Protein 2 (Npas2) are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput)) protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional Npas2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and Npas2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2. © 2013 Falcon et al

Phase-field approach to heterogeneous nucleation

We consider the problem of heterogeneous nucleation and growth. The system is described by a phase field model in which the temperature is included through thermal noise. We show that this phase field approach is suitable to describe homogeneous as well as heterogeneous nucleation starting from several general hypotheses. Thus we can investigate the influence of grain boundaries, localized impurities, or any general kind of imperfections in a systematic way. We also put forward the applicability of our model to study other physical situations such as island formation, amorphous crystallization, or recrystallization.Comment: 8 pages including 7 figures. Accepted for publication in Physical Review

Quasi-fission reactions as a probe of nuclear viscosity

Fission fragment mass and angular distributions were measured from the ^{64}Ni+^{197}Au reaction at 418 MeV and 383 MeV incident energy. A detailed data analysis was performed, using the one-body dissipation theory implemented in the code HICOL. The effect of the window and the wall friction on the experimental observables was investigated. Friction stronger than one-body was also considered. The mass and angular distributions were consistent with one-body dissipation. An evaporation code DIFHEAT coupled to HICOL was developed in order to predict reaction time scales required to describe available data on pre-scission neutron multiplicities. The multiplicity data were again consistent with one-body dissipation. The cross-sections for touch, capture and quasi-fission were also obtained.Comment: 25 pages REVTeX, 3 tables, 13 figures, submitted to Phys. Rev

Rabies screen reveals GPe control of cocaine-triggered plasticity.

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations

Relationship between solidification microstructure and hot cracking susceptibility for continuous casting of low-carbon and high-strength low-alloyed steels: A phase-field study

© The Minerals, Metals & Materials Society and ASM International 2013Hot cracking is one of the major defects in continuous casting of steels, frequently limiting the productivity. To understand the factors leading to this defect, microstructure formation is simulated for a low-carbon and two high-strength low-alloyed steels. 2D simulation of the initial stage of solidification is performed in a moving slice of the slab using proprietary multiphase-field software and taking into account all elements which are expected to have a relevant effect on the mechanical properties and structure formation during solidification. To account for the correct thermodynamic and kinetic properties of the multicomponent alloy grades, the simulation software is online coupled to commercial thermodynamic and mobility databases. A moving-frame boundary condition allows traveling through the entire solidification history starting from the slab surface, and tracking the morphology changes during growth of the shell. From the simulation results, significant microstructure differences between the steel grades are quantitatively evaluated and correlated with their hot cracking behavior according to the Rappaz-Drezet-Gremaud (RDG) hot cracking criterion. The possible role of the microalloying elements in hot cracking, in particular of traces of Ti, is analyzed. With the assumption that TiN precipitates trigger coalescence of the primary dendrites, quantitative evaluation of the critical strain rates leads to a full agreement with the observed hot cracking behavior. © 2013 The Minerals, Metals & Materials Society and ASM International

Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS

BAZ1B in Nucleus Accumbens Regulates Reward-Related Behaviors in Response to Distinct Emotional Stimuli

ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins