Thomas A. Williams, Mallarmé and the language of mysticism, Athens, University of Georgia Press, 1970, 99 p.

<div><p>Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and <i>N</i>-methyl-<i>D</i>-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory.</p></div

Infrared Safety in Factorized Hard Scattering Cross-Sections

The rules of soft-collinear effective theory can be used naively to write hard scattering cross-sections as convolutions of separate hard, jet, and soft functions. One condition required to guarantee the validity of such a factorization is the infrared safety of these functions in perturbation theory. Using e+e- angularity distributions as an example, we propose and illustrate an intuitive method to test this infrared safety at one loop. We look for regions of integration in the sum of Feynman diagrams contributing to the jet and soft functions where the integrals become infrared divergent. Our analysis is independent of an explicit infrared regulator, clarifies how to distinguish infrared and ultraviolet singularities in pure dimensional regularization, and demonstrates the necessity of taking zero-bins into account to obtain infrared-safe jet functions.Comment: 6 pages, 7 figures, uses elsarticle.cls. v2: extended introduction and clarified discussion of ingredients necessary for proving factorizatio

Colocalization of Protein Kinase A with Adenylyl Cyclase Enhances Protein Kinase A Activity during Induction of Long-Lasting Long-Term-Potentiation

The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring

Subjective evaluation of the accuracy of video imaging prediction following orthognathic surgery in chinese pateints

Purpose\ud The aims of this retrospective study were to assess the subjective accuracy of predictions generated by a computer imaging software in Chinese patients who had undergone orthognathic surgery and to determine the influence of initial dysgnathia and complexity of the surgical procedure on prediction accuracy.\ud Patients and Methods\ud \ud The sample consisted of 40 Chinese patients who had completed treatment involving orthodontics and orthognathic surgery. All the patients had lateral cephalometric radiographs and profile photographs taken within 3 months before surgery and at least 6 months after surgery. The computer-generated predicted images and the actual post-treatment images were displayed simultaneously to a panel of orthodontists, oral maxillofacial surgeons and laypersons to allow side-by-side comparison. The panel was asked to determine which image was more esthetic and to rate the likeness between the actual and predicted images using a 10 cm visual analog scale.\ud Results\ud \ud The results showed that the actual image was judged to be more esthetic in 82% of the cases, with the orthodontists more likely to select the actual profile compared to laypersons (P = .005). Orthodontists and surgeons rated the likeness of the images similarly while laypersons rated the likeness significantly lower than the clinicians (P = .012 and P = .015, respectively). Skeletal III cases were judged to be less accurately predicted than skeletal II cases by laypersons (P = .006) and orthodontists (P = .036). Cases treated by single-jaw osteotomy were given better ratings compared to cases with bimaxillary osteotomy by all panel groups but the differences did not reach significant level.\ud Conclusions\ud \ud Skeletal III cases managed by bimaxillary osteotomy were least accurately predicted by the computer program. As there exists a possibility that the predicted image may be judged to be more esthetic than the actual image, clinicians must make extra effort to manage patient expectations when using computer simulations for patient education

Coordination of care by breeders and helpers in the cooperatively breeding long-tailed tit

Abstract In species with biparental and cooperative brood care, multiple carers cooperate by contributing costly investments to raise a shared brood. However, shared benefits and individual costs also give rise to conflict among carers conflict among carers over investment. Coordination of provisioning visits has been hypothesized to facilitate the resolution of this conflict, preventing exploitation, and ensuring collective investment in the shared brood. We used a 26-year study of long-tailed tits, Aegithalos caudatus, a facultative cooperative breeder, to investigate whether care by parents and helpers is coordinated, whether there are consistent differences in coordination between individuals and reproductive roles, and whether coordination varies with helper relatedness to breeders. Coordination takes the form of turn-taking (alternation) or feeding within a short time interval of another carer (synchrony), and both behaviors were observed to occur more than expected by chance, that is, “active” coordination. First, we found that active alternation decreased with group size, whereas active synchrony occurred at all group sizes. Second, we show that alternation was repeatable between observations at the same nest, whereas synchrony was repeatable between observations of the same individual. Active synchrony varied with reproductive status, with helpers synchronizing visits more than breeders, although active alternation did not vary with reproductive status. Finally, we found no significant effect of relatedness on either alternation or synchrony exhibited by helpers. In conclusion, we demonstrate active coordination of provisioning by carers and conclude that coordination is a socially plastic behavior depending on reproductive status and the number of carers raising the brood.</jats:p

Model simulation of cAMP dynamics controlled by mechanisms downstream of AC.

<p><b>A.</b> Traces of the cAMP responses to NMDA alone, and NMDA after ISO in the model with pPDE4 activity twice that of PDE4 activity. Arrows and dashed lines show how response amplitudes were measured, both for the model and for the experiments. Thus, the initial (ISO) part of the NMDA after ISO trace is considered ISO alone. The trace for NMDA alone has been offset 120s for ease of comparison. The NMDA alone traces and the initial (ISO) part of the NMDA after ISO traces agree with the experimentally observed cAMP response to ISO or NMDA alone, including the soma to neurite gradient. Nonetheless, the model cAMP in response to NMDA after ISO does not agree with experimental data, suggesting that some other mechanisms are operating in these cells. The darker, less noisy lines near the center of the traces show the cytosolic concentrations, which are slightly lower than the submembrane value for the soma due to a small gradient. <b>B.</b> Traces showing the dynamics of PDE4 phosphorylation in response to NMDA after ISO. The maximal phosphorylation is reached in ~3 minutes, which is slightly faster than the ~6 minutes reported for PDE4D5 in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004735#pcbi.1004735.ref019" target="_blank">19</a>]. The purpose of the slight increase in rate of phosphorylation was to enhance the operation of the negative feedback loop. Note that pPDE4 increases for both NMDA alone and NMDA after ISO. <b>C.</b> Traces showing that GsαGTP bound adenylyl cyclase increases tremendously after ISO, leading to dramatically increased cAMP production. <b>D.</b> Traces showing that PKA activity is only moderately higher after ISO than with NMDA alone, explaining the modest increase in pPDE4 with ISO compared to NMDA alone. <b>E.</b> Effect of parameter variations on dendritic cAMP response. <b>E1.</b> Increases in pPDE4 activity and GsαGTP activity were not sufficient to reproduce experimental results. Solid bars show response to NMDA after ISO, striped or hatched bars show response to NMDA alone. Similar to experiments, the cAMP response to the NMDA after ISO stimulus is the difference between the peak response to NMDA after ISO and the response to the initial ISO application measured just prior to NMDA application. Though 40x lowered the NMDA response after ISO, the NMDA response without ISO was also reduced to a value below that observed experimentally. <b>E2.</b> Increases in the rate of PKA phosphorylation of PDE4 reduces the difference between NMDA after ISO and NMDA alone, but is not sufficient to make the NMDA after ISO response smaller than the NMDA alone response. ΔISO,N-N is the difference between the NMDA after ISO response and the NMDA alone response.</p

Computational model of βAR- and NMDAR-mediated cAMP signaling pathways.

<p><b>A.</b> Signaling pathways leading to cAMP production, and the downstream mechanisms involving PDE4. <b>B.</b> Morphology implemented for the computational model. Reflective boundary conditions occur at the membrane as well as cut surface of the soma and dendrite. The morphology is discretized with 0.9 μm voxels for the cytosol, with one layer of 0.3 μm submembrane voxels and one layer of 0.6 μm voxels adjacent to the submembrane voxels. <b>C.</b> Signaling pathways involved in Gs-Gi switching and GRK desensitization implemented in the model. <i>p</i> indicates a phosphorylation step.</p

cAMP during experimental perturbation of the cAMP-PKA-PDE4 pathway in cultured hippocampal neurons.

<p><b>A.</b> Effect of rolipram (1 μM) on the cAMP response to NMDA (<i>n</i> = 19) and the NMDA after isoproterenol stimulus (<i>n</i> = 13) in the neurite (<b>A1</b>) and soma (<b>A2</b>). Rolipram prevents the attenuation of the NMDA after ISO response observed in the neurite, but produces no significant effect in the soma. We used a subsaturating dose to focus on the effect of rolipram on the interaction between NMDA and ISO, and to prevent a large change in the NMDA alone or ISO alone cases. In addition, the subsaturating rolipram ensured we did not saturate the FRET sensor. <b>B.</b> Effect of PKA inhibition by H89 (10 μM) on the cAMP response to isoproterenol (<i>n</i> = 8), NMDA (<i>n</i> = 11), and the NMDA after ISO stimulus (<i>n</i> = 8). H89 prevents the attenuation of the NMDA after ISO response in the neurite (<b>B1</b>) and allows ISO pretreatment to enhance the soma response (<b>B2</b>). Note that, for ease of comparison with the averaged cAMP response to NMDA alone, the cAMP response to the NMDA after ISO stimulus is the difference between the peak response to NMDA after ISO and the response to the initial ISO application. All data represent the means and SEM.</p