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

Does Genetic Diversity Predict Health in Humans?

Genetic diversity, especially at genes important for immune functioning within the Major Histocompatibility Complex (MHC), has been associated with fitness-related traits, including disease resistance, in many species. Recently, genetic diversity has been associated with mate preferences in humans. Here we asked whether these preferences are adaptive in terms of obtaining healthier mates. We investigated whether genetic diversity (heterozygosity and standardized mean d2) at MHC and nonMHC microsatellite loci, predicted health in 153 individuals. Individuals with greater allelic diversity (d2) at nonMHC loci and at one MHC locus, linked to HLA-DRB1, reported fewer symptoms over a four-month period than individuals with lower d2. In contrast, there were no associations between MHC or nonMHC heterozygosity and health. NonMHC-d2 has previously been found to predict male preferences for female faces. Thus, the current findings suggest that nonMHC diversity may play a role in both natural and sexual selection acting on human populations

The Effects of NR2 Subunit-Dependent NMDA Receptor Kinetics on Synaptic Transmission and CaMKII Activation

N-Methyl-d-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function

Decreased gastric tone and delayed gastric emptying precede neutrophil infiltration and mucosal lesion formation in indomethacin-induced gastric damage in rats

Gastric antral dysmotility has been implicated in the pathogenesis of indomethacin-induced gastric damage, but the relationship between gastric motor abnormalities and mucosal lesions has not been extensively studied. We investigated whether changes in gastric tone and gastric retention correlate with mucosal lesions and neutrophil migration in indomethacin-induced gastric damage in rats. Indomethacin, either 5 or 20 mg/kg (INDO-5 and INDO-20), was instilled into the stomach, and then gastric damage, neutrophil migration, gastric tone and gastric retention were assessed 1 or 3 h later. Gastric damage was calculated as the sum of the lengths of all mucosal lesions, and neutrophil migration was measured by assaying myeloperoxidase activity. Gastric tone was determined by a plethysmometric method, and gastric retention of either saline or Sustacal® was evaluated by a scintigraphic method. Gastric damage was detectable 3 h after either INDO-5 or INDO-20, but not after 1 h. Neutrophil migration was significantly higher 3 h after INDO-20 as compared with INDO-5 or control group, but not after 1 h. Values of gastric tone 1 and 3 h after either INDO-5 (1 h = 1.73 ± 0.07 ml; 3 h = 1.87 ± 0.03 ml) or INDO-20 (1 h = 1.70 ± 0.02 ml; 3 h = 1.79 ± 0.03 ml) were significantly lower than in controls (1 h = 1.48 ± 0.05 ml; 3 h = 1.60 ± 0.06 ml). Gastric retention of saline was higher 1 h after INDO-5 (58.9 ± 3.3%) or INDO-20 (56.1 ± 3.1%) compared to control (45.5 ± 1.7%), but not after 3 h. There were no differences concerning gastric retention of Sustacal® between the various groups. Indomethacin induced decreased gastric tone and delayed gastric emptying, which precede mucosal lesion and neutrophil infiltration. These results indicate that there is no relationship between these gastric motor abnormalities and mucosal lesion in indomethacin-induced gastropathy

Caracterização química do autolisado de levedura de alambique e avaliação da aceitabilidade do pão de queijo adicionado do autolisado desidratado Chemical characterization of yeast autolysate and assessment of the acceptability of cheese buns containing dried autolysate

OBJETIVO: Esta pesquisa tem como objetivo estudar as propriedades do autolisado de levedura (Saccharomyces cerevisiae) proveniente de cachaça de alambique, investigando a composição centesimal, o perfil acídico e a análise microbiológica do material, bem como realizar análise sensorial do pão de queijo adicionado com o autolisado desidratado. MÉTODOS: O autolisado foi obtido pela lavagem e autólise da biomassa. A secagem foi realizada em secador de bandeja na temperatura de 70ºC. Realizaram-se as seguintes análises: caracterização físico-química (teor lipídico, proteico, fibras totais, fibras solúveis e insolúveis, e cinzas); composição de aminoácidos; análises microbiológicas do produto desidratado; e avaliação sensorial do pão de queijo contendo o autolisado desidratado, através de escala hedônica e teste de atitude. RESULTADOS: O autolisado desidratado apresentou: 1,2% de lipídeos; 24,7% de proteínas; 51,3% de fibras totais, sendo 2,4% de fibras solúveis e 48,9% de insolúveis; e 6,2% de cinzas. As análises microbiológicas mostraram-se dentro do limite recomendado pela Agência Nacional de Vigilância Sanitária. O perfil aminoacídico mostrou deficiência de histidina e metionina+cistina. A análise sensorial do pão de queijo mostrou boa aceitação, tendo apenas cor e aparência recebido notas baixas. A maioria dos participantes disse que "gosta disto e compraria de vez em quando". CONCLUSÃO: Os valores de proteína e aminoácidos encontrados na levedura de cachaça de alambique foram inferiores ao mostrado na literatura para levedura de cervejaria e destilaria de álcool etílico. A levedura desidratada estava microbiologicamente apta para consumo humano. A baixa aceitabilidade da aparência do pão de queijo provavelmente ocorreu pelo fato de os consumidores não estarem habituados à cor escura do produto. Trabalhos futuros poderão sugerir adição em outros produtos que apresentem aparência mais atrativa.<br>OBJECTIVE: This study aimed to study the properties of yeast (Saccharomyces cerevisiae) autolysate obtained from pot still rum, including centesimal composition, amino acid profile and microbiological analysis, and perform a sensory analysis of cheese buns (also known as Brazilian cheese bread or rolls) enriched with dried autolysate. METHODS: Autolysate was obtained by rinsing and autolyzing the biomass and dried on a tray dryer at 70º. Its composition was then determined (fat, protein, total fiber, soluble fiber, insoluble fiber, ash and amino acid contents) followed by microbiological analysis. Finally, cheese buns enriched with dried autolysate were submitted to sensory analysis using the hedonic scale and attitude test. RESULTS: Dried autolysate contained 1.2% fats; 24.7% proteins; 51.3% total fiber, where 2.4% was soluble and 48.9% was insoluble; and 6.2% ash. According to microbiological analysis, the product complied with the microbiological limits established by the Agência Nacional de Vigilância Sanitária. Amino acid profile showed that histidine and methionine-cystine levels were low. Sensory analysis indicated good acceptance of the cheese buns. Only their color and appearance received low scores. Most participants reported liking the cheese buns and willingness to buy them on occasion. CONCLUSION: The protein and amino acid levels found in pot still rum were lower than those reported in the literature for breweries and ethanol distilleries. Dried yeast was microbiologically suitable for human consumption. The low grades given to the appearance of the cheese buns were probably due to their unappealing dark color, as opposed to the usual pale yellow color. Future studies could suggest the addition of dried yeast to products whose visual appeal will not be as affected