Competitive Tuning of Calmodulin Target Protein Activation Drives E-LTP Induction in CA1 Hippocampal Neurons

A number of neurological disorders are caused by disruptions in dynamic neuronal connections called synapses. Normally, electrical activity between neurons activates protein cascades that cause long-lasting, localized changes in the structure and molecular composition of synapses. These changes either increase or decrease the strength of synaptic connections, leading to long-term-potentiation (LTP) or long-term-depression (LTD), respectively. The protein cascades responsible for this synaptic plasticity are initiated in a stimulus-dependent manner by the Ca2+ sensor calmodulin (CaM). Ultimately, it is disruptions within these signaling pathways that cause disease. Traditionally, these protein networks are studied in the laboratory, but limitations in existing experimental technology have created demand for computational models capable of predicting molecular phenomena. These predictions can then guide focused experimental investigations. Although CaM binds and regulates over 100 different target proteins, the competitive dynamics of these proteins and their effect on LTP induction have not been investigated. Using a system of ordinary differential equations to model competition between four neuronal CaM target proteins, we found that the stimulus-dependence of target protein activation is tuned by competition and that this competitive tuning is unique to each protein. We therefore conclude that competition-free models fail to capture the true stimulus-dependence of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 2B (PP2B/calcineurin/CaN) activation. Furthermore, these results suggest that competitive tuning drives early LTP (E-LTP) induction in CA1 hippocampal neurons and is an important dynamic process underlying learning and memory. Therapeutics that re-tune CaM-dependent proteins through competition may be useful in treating neurological disorders

Analysis and modeling of control tasks in dynamic systems

Copyright © 2002 IEEEMost applications of evolutionary algorithms deal with static optimization problems. However, in recent years, there has been a growing interest in time-varying (dynamic) problems, which are typically found in real-world scenarios. One major challenge in this field is the design of realistic test-case generators (TCGs), which requires a systematic analysis of dynamic optimization tasks. So far, only a few TCGs have been suggested. Our investigation leads to the conclusion that these TCGs are not capable of generating realistic dynamic benchmark tests. The result of our research is the design of a new TCG capable of producing realistic nonstationary landscapesRasmus K. Ursem, Thiemo Krink, Mikkel T. Jensen, and Zbigniew Michalewic

Constraint-based probabilistic learning of metabolic pathways from tomato volatiles

Clustering and correlation analysis techniques have become popular tools for the analysis of data produced by metabolomics experiments. The results obtained from these approaches provide an overview of the interactions between objects of interest. Often in these experiments, one is more interested in information about the nature of these relationships, e.g., cause-effect relationships, than in the actual strength of the interactions. Finding such relationships is of crucial importance as most biological processes can only be understood in this way. Bayesian networks allow representation of these cause-effect relationships among variables of interest in terms of whether and how they influence each other given that a third, possibly empty, group of variables is known. This technique also allows the incorporation of prior knowledge as established from the literature or from biologists. The representation as a directed graph of these relationship is highly intuitive and helps to understand these processes. This paper describes how constraint-based Bayesian networks can be applied to metabolomics data and can be used to uncover the important pathways which play a significant role in the ripening of fresh tomatoes. We also show here how this methods of reconstructing pathways is intuitive and performs better than classical techniques. Methods for learning Bayesian network models are powerful tools for the analysis of data of the magnitude as generated by metabolomics experiments. It allows one to model cause-effect relationships and helps in understanding the underlying processes

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

How low can we (reliably) go? A method comparison of thyroid-stimulating hormone assays with a focus on low concentrations

Objective: International guidelines concerning subclinical hyperthyroidism and thyroid cancer advice absolute cut-off values for aiding clinical decisi ons in the low range of thyroid-stimulating hormone (TSH) concentrations. As TSH assays are known to be poorly standardized in the normal to high range, we performed a TSH assay method comparison focusing on the low range. Methods: Sixty samples, selected to cover a wide range of TSH concentrat ions (<0.01 to 120 mIU/L) with oversampling in the lower range (<0.4 mIU/L) , were used for the method comparison between three TSH immunoassays (Cobas, Alinit y and Atellica). In addition, 20 samples were used to assess the coefficient of va riation from duplicate measurements in these three methods. Results: The TSH immunoassays showed standardization differences with a b ias of 7–16% for the total range and 1–14% for the low range. This cou ld lead to a different classification of 1.5% of all measured TSH concentrations <0.40 mIU/L measured in our laboratory over the last 6 months, regarding the clinically imp ortant cut-off value of TSH = 0.1 mIU/L. As the imprecision of the immunoassays varied from 1.6–5.5%, this could lead to a similar reclassification as the bias between imm unoassays. Conclusions: We established the standardization differences of frequently used TSH assays for the total and low concentration ranges. Based on the proportional bias and the imprecision, this effect seems to have limited clinical consequences for the low TSH concentration range. Nevertheless, as guidelines mention absolute TSH values to guide clinical decision-making, caution must be applied when interpreting values close to these cut-offs

On the Runtime Analysis of the Clearing Diversity-Preserving Mechanism

Clearing is a niching method inspired by the principle of assigning the available resources among a niche to a single individual. The clearing procedure supplies these resources only to the best individual of each niche: the winner. So far, its analysis has been focused on experimental approaches that have shown that clearing is a powerful diversity-preserving mechanism. Using rigorous runtime analysis to explain how and why it is a powerful method, we prove that a mutation-based evolutionary algorithm with a large enough population size, and a phenotypic distance function always succeeds in optimising all functions of unitation for small niches in polynomial time, while a genotypic distance function requires exponential time. Finally, we prove that with phenotypic and genotypic distances clearing is able to find both optima for Twomax and several general classes of bimodal functions in polynomial expected time. We use empirical analysis to highlight some of the characteristics that makes it a useful mechanism and to support the theoretical results

Transcriptome profiling of grapevine seedless segregants during berry development reveals candidate genes associated with berry weight

Indexación: Web of Science; PubMedBackground Berry size is considered as one of the main selection criteria in table grape breeding programs. However, this is a quantitative and polygenic trait, and its genetic determination is still poorly understood. Considering its economic importance, it is relevant to determine its genetic architecture and elucidate the mechanisms involved in its expression. To approach this issue, an RNA-Seq experiment based on Illumina platform was performed (14 libraries), including seedless segregants with contrasting phenotypes for berry weight at fruit setting (FST) and 6–8 mm berries (B68) phenological stages. Results A group of 526 differentially expressed (DE) genes were identified, by comparing seedless segregants with contrasting phenotypes for berry weight: 101 genes from the FST stage and 463 from the B68 stage. Also, we integrated differential expression, principal components analysis (PCA), correlations and network co-expression analyses to characterize the transcriptome profiling observed in segregants with contrasting phenotypes for berry weight. After this, 68 DE genes were selected as candidate genes, and seven candidate genes were validated by real time-PCR, confirming their expression profiles. Conclusions We have carried out the first transcriptome analysis focused on table grape seedless segregants with contrasting phenotypes for berry weight. Our findings contributed to the understanding of the mechanisms involved in berry weight determination. Also, this comparative transcriptome profiling revealed candidate genes for berry weight which could be evaluated as selection tools in table grape breeding programs.http://bmcplantbiol.biomedcentral.com/articles/10.1186/s12870-016-0789-

Use of network analysis to capture key traits affecting tomato organoleptic quality

The long-term objective of tomato breeders is to identify metabolites that contribute to defining the target flavour and to design strategies to enhance it. This paper reports the results of network analysis, based on metabolic phenotypic and sensory data, to highlight important relationships among such traits. This tool allowed a reduction in data set complexity, building a network consisting of 35 nodes and 74 links corresponding to the 74 significant (positive or negative) correlations among the variables studied. A number of links among traits contributing to fruit organoleptic quality and to the perception of sensory attributes were identified. Modular partitioning of the characteristics involved in fruit organoleptic perception captured the essential fruit parameters that regulate interactions among different class traits. The main feature of the network was the presence of three nodes interconnected among themselves (dry matter, pH, and °Brix) and with other traits, and nodes with widely different linkage degrees. Identification of strong associations between some metabolic and sensory traits, such as citric acid with tomato smell, glycine with tomato smell, and granulosity with dry matter, suggests a basis for more targeted investigations in the future

A Non-Targeted Approach Unravels the Volatile Network in Peach Fruit

Volatile compounds represent an important part of the plant metabolome and are of particular agronomic and biological interest due to their contribution to fruit aroma and flavor and therefore to fruit quality. By using a non-targeted approach based on HS-SPME-GC-MS, the volatile-compound complement of peach fruit was described. A total of 110 volatile compounds (including alcohols, ketones, aldehydes, esters, lactones, carboxylic acids, phenolics and terpenoids) were identified and quantified in peach fruit samples from different genetic backgrounds, locations, maturity stages and physiological responses. By using a combination of hierarchical cluster analysis and metabolomic correlation network analysis we found that previously known peach fruit volatiles are clustered according to their chemical nature or known biosynthetic pathways. Moreover, novel volatiles that had not yet been described in peach were identified and assigned to co-regulated groups. In addition, our analyses showed that most of the co-regulated groups showed good intergroup correlations that are therefore consistent with the existence of a higher level of regulation orchestrating volatile production under different conditions and/or developmental stages. In addition, this volatile network of interactions provides the ground information for future biochemical studies as well as a useful route map for breeding or biotechnological purposes