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

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Utilisation non médicale des médicaments d’ordonnance chez les adolescents utilisant des drogues au Québec

Abstract : OBJECTIVE: To determine the prevalence and factors associated with nonmedical use of prescription medication (NMUPM) among adolescents who use drugs (ages 12 to 17 years) in Quebec. METHOD: Secondary data analyses were carried out with data from a 6-month study, namely, the 2010-2011 Quebec Health Survey of High School Students-a large-scale survey that sought to gain a better understanding of the health and well-being of young Quebecers in high school. Bivariate and multivariate logistic regression analyses were conducted to study NMUPM among adolescents who use drugs, according to sociodemographic characteristics, peer characteristics, health indicators (anxiety, depression, or attention-deficit disorder [ADD] with or without hyperactivity), self-competency, family environment, and substance use (alcohol and drug use) factors. RESULTS: Among adolescents who had used drugs in the previous 12 months, 5.4% (95% CI 4.9% to 6.0%) reported NMUPM. Based on multivariate analyses, having an ADD (adjusted odds ratio [AOR] 1.47; 95% CI 1.13 to 1.91), anxiety disorder (AOR 2.14; 95% CI 1.57 to 2.92), low self-esteem (AOR 1.62; 95% CI 1.26 to 2.08), low self-control (AOR 1.95; 95% CI 1.55 to 2.45), low parental supervision (AOR 1.43; 95% CI 1.11 to 1.83), regular alcohol use (AOR 1.72; 95% CI 1.36 to 2.16), and polysubstance use (AOR 4.09; 95% CI 3.06 to 5.48) were associated with increased odds of reporting NMUPM. CONCLUSIONS: The observed prevalence of NMUPM was lower than expected. However, the associations noted with certain mental health disorders and regular or heavy use of other psychoactive substances are troubling. Clinical implications are discussed.OBJECTIF: Déterminer la prévalence de l’utilisation non médicale des médicaments d’ordonnance (UNMMO) et les facteurs qui y sont associés chez les adolescents (de 12 à 17 ans) qui utilisent des drogues au Québec. MÉTHODE: Des analyses de données secondaires ont été exécutées avec les données d’une étude de 6 mois, l’Enquête québécoise sur la santé des jeunes du secondaire 2010-2011, une enquête de grande envergure visant à obtenir une meilleure compréhension de la santé et du bien-être des jeunes québécois du secondaire. Des analyses de régression logistique bivariée et multivariée ont été menées pour étudier l’UNMMO chez les adolescents qui utilisent des drogues, selon les facteurs des caractéristiques sociodémographiques, des caractéristiques des pairs, des indicateurs de la santé (anxiété, dépression, ou trouble de déficit de l’attention [TDA] avec ou sans hyperactivité), de l’autoefficacité, de l’environnement familial, et de l’utilisation de substances (utilisation d’alcool et de drogues). RÉSULTATS: Parmi les adolescents qui avaient utilisé des drogues dans les 12 mois précédents, 5,4 % (IC à 95 % 4,9 % à 6,0 %) déclaraient une UNMMO. Selon les analyses multivariées, un TDA (ratio de cotes ajusté [RCC] 1,47; IC à 95 % 1,13 à 1,91), un trouble anxieux (RCC 2,14; IC à 95 % 1,57 à 2,92), une faible estime de soi (RCC 1,62; IC à 95 % 1,26 à 2,08), un faible autocontrôle (RCC 1,95; IC à 95 % 1,55 à 2,45), une faible supervision parentale (RCC 1,43; IC à 95 % 1,11 à 1,83), une utilisation d’alcool régulière (RCC 1,72; IC à 95 % 1,36 à 2,16), et une utilisation de polysubstances (RCC 4,09; IC à 95 % 3,06 à 5,48) étaient associés à des probabilités accrues de déclarer une UNMMO. CONCLUSIONS: La prévalence observée de l’UNMMO était plus faible que prévu. Cependant, les associations notées entre certains troubles de santé mentale et l’utilisation régulière ou intensive d’autres substances psychoactives sont inquiétantes. Les implications cliniques sont discutées

MICE: The muon ionization cooling experiment. Step I: First measurement of emittance with particle physics detectors

Copyright @ 2011 APSThe Muon Ionization Cooling Experiment (MICE) is a strategic R&D project intended to demonstrate the only practical solution to providing high brilliance beams necessary for a neutrino factory or muon collider. MICE is under development at the Rutherford Appleton Laboratory (RAL) in the United Kingdom. It comprises a dedicated beamline to generate a range of input muon emittances and momenta, with time-of-flight and Cherenkov detectors to ensure a pure muon beam. The emittance of the incoming beam will be measured in the upstream magnetic spectrometer with a scintillating fiber tracker. A cooling cell will then follow, alternating energy loss in Liquid Hydrogen (LH2) absorbers to RF cavity acceleration. A second spectrometer, identical to the first, and a second muon identification system will measure the outgoing emittance. In the 2010 run at RAL the muon beamline and most detectors were fully commissioned and a first measurement of the emittance of the muon beam with particle physics (time-of-flight) detectors was performed. The analysis of these data was recently completed and is discussed in this paper. Future steps for MICE, where beam emittance and emittance reduction (cooling) are to be measured with greater accuracy, are also presented.This work was supported by NSF grant PHY-0842798

A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

OBJECTIVE: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. METHODS: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. RESULTS: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. CONCLUSIONS: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant

Routine pattern discovery and anomaly detection in individual travel behavior

Discovering patterns and detecting anomalies in individual travel behavior is a crucial problem in both research and practice. In this paper, we address this problem by building a probabilistic framework to model individual spatiotemporal travel behavior data (e.g., trip records and trajectory data). We develop a two-dimensional latent Dirichlet allocation (LDA) model to characterize the generative mechanism of spatiotemporal trip records of each traveler. This model introduces two separate factor matrices for the spatial dimension and the temporal dimension, respectively, and use a two-dimensional core structure at the individual level to effectively model the joint interactions and complex dependencies. This model can efficiently summarize travel behavior patterns on both spatial and temporal dimensions from very sparse trip sequences in an unsupervised way. In this way, complex travel behavior can be modeled as a mixture of representative and interpretable spatiotemporal patterns. By applying the trained model on future/unseen spatiotemporal records of a traveler, we can detect her behavior anomalies by scoring those observations using perplexity. We demonstrate the effectiveness of the proposed modeling framework on a real-world license plate recognition (LPR) data set. The results confirm the advantage of statistical learning methods in modeling sparse individual travel behavior data. This type of pattern discovery and anomaly detection applications can provide useful insights for traffic monitoring, law enforcement, and individual travel behavior profiling

Capillary electrophoresis-mass spectrometry analysis of trehalose-6-phosphate in Arabidopsis thaliana seedlings

Trehalose-6-phosphate (T6P) is an intermediate in the plant metabolic pathway that results in trehalose production. T6P has been shown to inhibit the sucrose nonfermenting-1-related protein kinase 1, which is a major regulator of metabolism. The quantitation of T6P has proven difficult due to the complexity of the plant matrix and the low abundance of T6P in plant tissues. The aim of this work was to develop a quantitation method for T6P present in Arabidopsis tissues, with capillary electrophoresis (CE) coupled to electrospray ionization-mass spectrometry (MS) with a sheath liquid (SL) interface. The CE-MS method was first optimized with respect to T6P signal intensity and separation of isomers by studying the composition of the background electrolyte (BGE) and SL. The use of triethylamine (TEA) in the BGE was favorable, providing separation of T6P from sucrose-6-phosphate and minimizing ionization suppression. Replacing ammonium acetate with TEA enhanced T6P signal intensities more than four times. The optimized method allowed quantification of T6P in plant extracts with good linearity (r2 > 0.99) within a biologically relevant concentration range. The limit of quantification was 80 nM in Arabidopsis extracts, corresponding to 33 pmol/g plant fresh weight. The CE-MS method was applied to the determination of T6P in seedlings from wild type (WT) Arabidopsis and mutants lacking the trehalase AtTRE1, tre1-1, challenged with trehalose or sorbitol. T6P accumulation in tre1-1 plants grown on sorbitol was about twice the level of T6P found in WT. CE-MS is shown to be a fast and reliable technique to analyze phosphodisaccharides for seedling extracts. The low sample volume requirement of CE and its direct MS coupling makes it an attractive alternative for anion-exchange liquid chromatography–MS

Information and communication technologies for informal carers and paid assistants:Benefits from micro-, meso-, and macro-levels

The aim of this study was to explore the benefits of information and communication technologies (ICT)-based services for informal carers and paid assistants of older people living in the community. We cross-case analysed the effects of twelve initiatives in the EU, the USA and Canada, based on their individual analysis documented through interviews with promoters and a literature review. We carried out the cross-case analysis following a variables-oriented strategy on seven dimensions of impact at micro-, meso- and macro-levels: the quality of life of informal carers and paid assistants, quality of life of care recipients, quality of care, care efficiency and sustainability, acceptability, and infrastructure and accessibility. ICT-based services for informal carers and paid assistants improve the quality of life of older people and their carers and access to qualified care. They also generate savings which contribute to the sustainability of the care systems. These findings constitute a first look at the benefits of the use of ICT-based services for informal carers and paid assistants. Nevertheless, more research using experimental methods is needed to demonstrate the impact of these ICT-based services at meso- and macro-levels. This would help to support policy-makers to deploy these technologies for long-term care delivery.JRC.J.3-Information Societ

Imbalanced pattern completion vs. separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy

<p>Abstract</p> <p>Background</p> <p>Diverse Mouse genetic models of neurodevelopmental, neuropsychiatric, and neurodegenerative causes of impaired cognition exhibit at least four convergent points of synaptic malfunction: 1) Strength of long-term potentiation (LTP), 2) Strength of long-term depression (LTD), 3) Relative inhibition levels (Inhibition), and 4) Excitatory connectivity levels (Connectivity).</p> <p>Results</p> <p>To test the hypothesis that pathological increases or decreases in these synaptic properties could underlie imbalances at the level of basic neural network function, we explored each type of malfunction in a simulation of autoassociative memory. These network simulations revealed that one impact of impairments or excesses in each of these synaptic properties is to shift the trade-off between pattern separation and pattern completion performance during memory storage and recall. Each type of synaptic pathology either pushed the network balance towards intolerable error in pattern separation or intolerable error in pattern completion. Imbalances caused by pathological impairments or excesses in LTP, LTD, inhibition, or connectivity, could all be exacerbated, or rescued, by the simultaneous modulation of any of the other three synaptic properties.</p> <p>Conclusions</p> <p>Because appropriate modulation of any of the synaptic properties could help re-balance network function, regardless of the origins of the imbalance, we propose a new strategy of personalized cognitive therapeutics guided by assay of pattern completion vs. pattern separation function. Simulated examples and testable predictions of this theorized approach to cognitive therapeutics are presented.</p

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres