A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning

Prevention of shoulder subluxation after stroke with electrical stimulation. Stroke

Background and Purpose-Subluxation is a significant problem in poststroke hemiplegia, resulting in pain and loss of function. Current treatments are not proved and not considered effective. It has been demonstrated that cyclical electrical stimulation of the shoulder muscles can reduce existing subluxation. The purpose of this study was to determine whether electrical stimulation could prevent subluxation in both the short and long terms. Methods-A prospective, randomized controlled study was used to determine the efficacy of electrical stimulation in preventing shoulder subluxation in patients after cerebrovascular accidents. Forty patients were selected and randomly assigned to a control or treatment group. They had their first assessment within 48 hours of their stroke, and those in the treatment group were immediately put on a regimen of electrical stimulation for 4 weeks. All patients were assessed at 4 weeks after stroke and then again at 12 weeks after stroke. Assessments were made of shoulder subluxation, pain, and motor control. Results-The treatment group had significantly less subluxation and pain after the treatment period, but at the end of the follow-up period there were no significant differences between the 2 groups. Conclusions-Electrical stimulation can prevent shoulder subluxation, but this effect was not maintained after the withdrawal of treatment. (Stroke. 1999;30:963-968.

Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort

Cocoa flavanols (CF) positively influence physiological processes in ways that suggest their consumption may improve aspects of cognitive function. This study investigated the acute cognitive and subjective effects of CF consumption during sustained mental demand. In this randomized, controlled, double-blinded, balanced, three period crossover trial 30 healthy adults consumed drinks containing 520 mg, 994 mg CF and a matched control, with a three-day washout between drinks. Assessments included the state anxiety inventory and repeated 10-min cycles of a Cognitive Demand Battery comprising of two serial subtraction tasks (Serial Threes and Serial Sevens), a Rapid Visual Information Processing (RVIP) task and a mental fatigue scale, over the course of 1 h. Consumption of both 520 mg and 994 mg CF significantly improved Serial Threes performance. The 994 mg CF beverage significantly speeded RVIP responses but also resulted in more errors during Serial Sevens. Increases in self-reported mental fatigue were significantly attenuated by the consumption of the 520 mg CF beverage only. This is the first report of acute cognitive improvements following CF consumption in healthy adults. While the mechanisms underlying the effects are unknown they may be related to known effects of CF on endothelial function and blood flow

Effects of Genotype and Sleep on Temperament

Supported by the Canadian Institutes of Health Research

Investigation of Neuronal Cell Type-Specific Gene Expression of Ca(2+)/Calmodulin-dependent Protein Kinase II.

The promoter activity of the rat Ca(2+)/calmodulin-dependent protein kinase II gene was analyzed using the luciferase reporter gene in neuronal and non-neuronal cell lines. Neuronal cell type-specific promoter activity was found in the 5'-flanking region of α and β isoform genes of the kinase. Silencer elements were also found further upstream of promoter regions. A brain-specific protein bound to the DNA sequence of the 5'-flanking region of the gene was found by gel mobility shift analysis in the nuclear extract of the rat brain, including the cerebellum, forebrain, and brainstem, but not in that of non-neuronal tissues, including liver, kidney and spleen. The luciferase expression system and gel shift analysis can be used as an additional and better index by which to monitor gene expression in most cell types

On effective actions of BPS branes and their higher derivative corrections

We calculate in detail the disk level S-matrix element of one Ramond-Ramond field and three gauge field vertex operators in the world volume of BPS branes, to find four gauge field couplings to all orders of $\alpha'$ up to on-shell ambiguity. Then using these infinite couplings we find that the massless pole of the field theory amplitude is exactly equal to the massless pole S-matrix element of this amplitude for the $p=n$ case to all orders of $\alpha'$. Finally we show that the infinite massless poles and the contact terms of this amplitude for the $p=n+2$ case can be reproduced by the Born-Infeld action and the Wess-Zumino actions and by their higher derivative corrections.Comment: 26 pages, 2 figures, minor corrections,references added and version published in JHE

Cosmic Flows on 100 Mpc/h Scales: Standardized Minimum Variance Bulk Flow, Shear and Octupole Moments

The low order moments, such as the bulk flow and shear, of the large scale peculiar velocity field are sensitive probes of the matter density fluctuations on very large scales. In practice, however, peculiar velocity surveys are usually sparse and noisy, which can lead to the aliasing of small scale power into what is meant to be a probe of the largest scales. Previously, we developed an optimal ``minimum variance'' (MV) weighting scheme, designed to overcome this problem by minimizing the difference between the measured bulk flow (BF) and that which would be measured by an ideal survey. Here we extend this MV analysis to include the shear and octupole moments, which are designed to have almost no correlations between them so that they are virtually orthogonal. We apply this MV analysis to a compilation of all major peculiar velocity surveys, consisting of 4536 measurements. Our estimate of the BF on scales of ~ 100 Mpc/h has a magnitude of |v|= 416 +/- 78 km/s towards Galactic l = 282 degree +/- 11 degree and b = 6 degree +/- 6 degree. This result is in disagreement with LCDM with WMAP5 cosmological parameters at a high confidence level, but is in good agreement with our previous MV result without an orthogonality constraint, showing that the shear and octupole moments did not contaminate the previous BF measurement. The shear and octupole moments are consistent with WMAP5 power spectrum, although the measurement noise is larger for these moments than for the BF. The relatively low shear moments suggest that the sources responsible for the BF are at large distances.Comment: 13 Pages, 7 figures, 4 tables. Some changes to reflect the published versio

Human exposures to by-products from animals suspected to have died of anthrax in Bangladesh: An exploratory study

Anthrax is a zoonotic disease caused by the bacterium Bacillus anthracis that is considered endemic in Bangladesh, where cases among animals and people have been reported almost annually since 2009. Contaminated by-products from animals are suspected to play a role in transmission to people, but minimal information is known on the supply chain of these potentially contaminated products. Between April 2013 and May 2016, we conducted a qualitative study in 17 villages located in five districts in Bangladesh, which had experienced suspected anthrax outbreaks. The study explored how by-products from suspected animal cases were collected, discarded, processed, distributed and used by people. We conducted open-ended interviews, group discussions and unstructured observations of people's exposure to animal by-products. The practice of slaughtering acutely ill domestic ruminants before they died was common. Respondents reported that moribund animals were typically butchered, and the waste products were discarded in nearby rivers, ditches, bamboo bushes, or on privately owned land. Regardless of health status before death, very few carcasses were buried, and none were incinerated or burned. The hides were reportedly used to make wallets, belts, shoes, balls and clothing. Discarded bones were often ground into granular and powder forms to produce bone meal and fertilizer. Therefore, given anthrax is endemic in the study region, livestock with acute onset of fatal disease or found dead with no known cause of death may be an anthrax case and subsequently pose a health risk to those involved in the collection and processing of the carcass, as well as the end-user of these products. Improved bio-security practices and safe carcass disposal measures could reduce the risk of human exposure, but resource and other constraints make implementation a challenge. Therefore, targeting at-risk animal populations for vaccination may be the most effective strategy to reduce anthrax outbreaks, protect the supply chain and reduce the risk of exposure to B. anthracis

Composite GUTs: models and expectations at the LHC

We investigate grand unified theories (GUTs) in scenarios where electroweak (EW) symmetry breaking is triggered by a light composite Higgs, arising as a Nambu-Goldstone boson from a strongly interacting sector. The evolution of the standard model (SM) gauge couplings can be predicted at leading order, if the global symmetry of the composite sector is a simple group G that contains the SM gauge group. It was noticed that, if the right-handed top quark is also composite, precision gauge unification can be achieved. We build minimal consistent models for a composite sector with these properties, thus demonstrating how composite GUTs may represent an alternative to supersymmetric GUTs. Taking into account the new contributions to the EW precision parameters, we compute the Higgs effective potential and prove that it realizes consistently EW symmetry breaking with little fine-tuning. The G group structure and the requirement of proton stability determine the nature of the light composite states accompanying the Higgs and the top quark: a coloured triplet scalar and several vector-like fermions with exotic quantum numbers. We analyse the signatures of these composite partners at hadron colliders: distinctive final states contain multiple top and bottom quarks, either alone or accompanied by a heavy stable charged particle, or by missing transverse energy.Comment: 55 pages, 13 figures, final version to be published in JHE