Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We, therefore, generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse to test this hypothesis. At 12 wk of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80 mmHg plus 1 mu M epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase vs. the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, whereas cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure and modest mitochondrial dysfunction in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression.

MicroRNA expression is differentially altered by xenobiotic drugs in different human cell lines

Several noncoding microRNAs (miR or miRNA) have been shown to regulate the expression of drug-metabolizing enzymes and transporters. Xenobiotic drug-induced changes in enzyme and transporter expression may be associated with the alteration of miRNA expression. Therefore, this study investigated the impact of 19 xenobiotic drugs (e. g. dexamethasone, vinblastine, bilobalide and cocaine) on the expression of ten miRNAs (miR-18a, -27a, -27b, -124a, -148a, -324-3p, -328, -451, -519c and -1291) in MCF-7, Caco-2, SH-SY5Y and BE(2)-M17 cell systems. The data revealed that miRNAs were differentially expressed in human cell lines and the change in miRNA expression was dependent on the drug, as well as the type of cells investigated. Notably, treatment with bilobalide led to a 10-fold increase of miR-27a and a 2-fold decrease of miR-148a in Caco-2 cells, but no change of miR-27a and a 2-fold increase of miR-148a in MCF-7 cells. Neuronal miR-124a was generally down-regulated by psychoactive drugs (e. g. cocaine, methadone and fluoxetine) in BE(2)-M17 and SH-SY5Y cells. Dexamethasone and vinblastine, inducers of drug-metabolizing enzymes and transporters, suppressed the expression of miR-27b, -148a and -451 that down-regulate the enzymes and transporters. These findings should provide increased understanding of the altered gene expression underlying drug disposition, multidrug resistance, drug-drug interactions and neuroplasticity. Copyright (C) 2011 John Wiley & Sons, Ltd.

Xylella fastidiosa: An in vivo system to study possible survival strategies within citrus xylem vessels based on global gene expression analysis

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Transcriptomics and systems biology analysis in identification of specific pathways involved in cacao resistance and susceptibility to witches' broom disease

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Proteome of the phytopathogen Xanthomonas citri subsp citri: a global expression profile

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A machine learning approach for genome-wide prediction of morbid and druggable human genes based on systems-level data

Background: The genome-wide identification of both morbid genes, i.e., those genes whose mutations cause hereditary human diseases, and druggable genes, i.e., genes coding for proteins whose modulation by small molecules elicits phenotypic effects, requires experimental approaches that are time-consuming and laborious. Thus, a computational approach which could accurately predict such genes on a genome-wide scale would be invaluable for accelerating the pace of discovery of causal relationships between genes and diseases as well as the determination of druggability of gene products.Results: In this paper we propose a machine learning-based computational approach to predict morbid and druggable genes on a genome-wide scale. For this purpose, we constructed a decision tree-based meta-classifier and trained it on datasets containing, for each morbid and druggable gene, network topological features, tissue expression profile and subcellular localization data as learning attributes. This meta-classifier correctly recovered 65% of known morbid genes with a precision of 66% and correctly recovered 78% of known druggable genes with a precision of 75%. It was than used to assign morbidity and druggability scores to genes not known to be morbid and druggable and we showed a good match between these scores and literature data. Finally, we generated decision trees by training the J48 algorithm on the morbidity and druggability datasets to discover cellular rules for morbidity and druggability and, among the rules, we found that the number of regulating transcription factors and plasma membrane localization are the most important factors to morbidity and druggability, respectively.Conclusions: We were able to demonstrate that network topological features along with tissue expression profile and subcellular localization can reliably predict human morbid and druggable genes on a genome-wide scale. Moreover, by constructing decision trees based on these data, we could discover cellular rules governing morbidity and druggability.

Reduced allergic lung inflammation in rats following formaldehyde exposure: Long-term effects on multiple effector systems

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Critical temperature for first-order phase transitions in confined systems

We consider the Euclidean D-dimensional -lambda vertical bar phi vertical bar(4)+eta vertical bar rho vertical bar(6) (lambda,eta > 0) model with d (d <= D) compactified dimensions. Introducing temperature by means of the Ginzburg-Landau prescription in the mass term of the Hamiltonian, this model can be interpreted as describing a first-order phase transition for a system in a region of the D-dimensional space, limited by d pairs of parallel planes, orthogonal to the coordinates axis x(1), x(2),..., x(d). The planes in each pair are separated by distances L-1, L-2, ... , L-d. We obtain an expression for the transition temperature as a function of the size of the system, T-c({L-i}), i = 1, 2, ..., d. For D = 3 we particularize this formula, taking L-1 = L-2 = ... = L-d = L for the physically interesting cases d = 1 (a film), d = 2 (an infinitely long wire having a square cross-section), and for d = 3 (a cube). For completeness, the corresponding formulas for second-order transitions are also presented. Comparison with experimental data for superconducting films and wires shows qualitative agreement with our theoretical expressions.

Expression and variability of molecular chaperones in the sugarcane expressome

Molecular chaperones perform folding assistance in newly synthesized polypeptides preventing aggregation processes, recovering proteins from aggregates, among other important cellular functions. Thus their study presents great biotechnological importance. The present work discusses the mining for chaperone-related sequences within the sugarcane EST genome project database, which resulted in approximately 300 different sequences. Since molecular chaperones are highly conserved in most organisms studied so far, the number of sequences related to these proteins in sugarcane was very similar to the number found in the Arabidopsis thaliana genome. The Hsp70 family was the main molecular chaperone system present in the sugarcane expressome. However, many other relevant molecular chaperones systems were also present. A digital RNA blot analysis showed that 5'ESTs from all molecular chaperones were found in every sugarcane library, despite their heterogeneous expression profiles. The results presented here suggest the importance of molecular chaperones to polypeptide metabolism in sugarcane cells, based on their abundance and variability. Finally, these data have being used to guide more in deep analysis, permitting the choice of specific targets to study. (c) 2006 Elsevier GmbH. All rights reserved.

Optimal conductor size selection and reconductoring in radial distribution systems using a mixed-integer LP approach

This paper presents a mixed-integer linear programming model to solve the conductor size selection and reconductoring problem in radial distribution systems. In the proposed model, the steady-state operation of the radial distribution system is modeled through linear expressions. The use of a mixed-integer linear model guarantees convergence to optimality using existing optimization software. The proposed model and a heuristic are used to obtain the Pareto front of the conductor size selection and reconductoring problem considering two different objective functions. The results of one test system and two real distribution systems are presented in order to show the accuracy as well as the efficiency of the proposed solution technique. © 1969-2012 IEEE.

A mixed-integer LP model for the optimal allocation of voltage regulators and capacitors in radial distribution systems

This paper presents a mixed-integer linear programming model to solve the problem of allocating voltage regulators and fixed or switched capacitors (VRCs) in radial distribution systems. The use of a mixed-integer linear model guarantees convergence to optimality using existing optimization software. In the proposed model, the steady-state operation of the radial distribution system is modeled through linear expressions. The results of one test system and one real distribution system are presented in order to show the accuracy as well as the efficiency of the proposed solution technique. An heuristic to obtain the Pareto front for the multiobjective VRCs allocation problem is also presented. © 2012 Elsevier Ltd. All rights reserved.

A mixed-integer linear programming approach for optimal type, size and allocation of distributed generation in radial distribution systems

This paper presents a mixed-integer linear programming approach to solving the problem of optimal type, size and allocation of distributed generators (DGs) in radial distribution systems. In the proposed formulation, (a) the steady-state operation of the radial distribution system, considering different load levels, is modeled through linear expressions; (b) different types of DGs are represented by their capability curves; (c) the short-circuit current capacity of the circuits is modeled through linear expressions; and (d) different topologies of the radial distribution system are considered. The objective function minimizes the annualized investment and operation costs. The use of a mixed-integer linear formulation guarantees convergence to optimality using existing optimization software. The results of one test system are presented in order to show the accuracy as well as the efficiency of the proposed solution technique.© 2012 Elsevier B.V. All rights reserved.

Mass-imbalanced three-body systems in two dimensions

We consider three-body systems in two dimensions with zero-range interactions for general masses and interaction strengths. The momentum-space Schrödinger equation is solved numerically and in the Born-Oppenheimer (BO) approximation. The BO expression is derived using separable potentials and yields a concise adiabatic potential between the two heavy particles. The BO potential is Coulomb-like and exponentially decreasing at small and large distances, respectively. While we find similar qualitative features to previous studies, we find important quantitative differences. Our results demonstrate that mass-imbalanced systems that are accessible in the field of ultracold atomic gases can have a rich three-body bound state spectrum in two-dimensional geometries. Small light-heavy mass ratios increase the number of bound states. For 87Rb-87Rb-6Li and 133Cs- 133Cs-6Li we find respectively three and four bound states. © 2013 IOP Publishing Ltd.

Exploring the multifactorial nature of autism through computational systems biology: Calcium and the Rho GTPase RAC1 under the spotlight

Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication accompanied with repetitive behavioral patterns and unusual stereotyped interests. Autism is considered a highly heterogeneous disorder with diverse putative causes and associated factors giving rise to variable ranges of symptomatology. Incidence seems to be increasing with time, while the underlying pathophysiological mechanisms remain virtually uncharacterized (or unknown). By systematic review of the literature and a systems biology approach, our aims were to examine the multifactorial nature of autism with its broad range of severity, to ascertain the predominant biological processes, cellular components, and molecular functions integral to the disorder, and finally, to elucidate the most central contributions (genetic and/or environmental) in silico. With this goal, we developed an integrative network model for gene-environment interactions (GENVI model) where calcium (Ca2+) was shown to be its most relevant node. Moreover, considering the present data from our systems biology approach together with the results from the differential gene expression analysis of cerebellar samples from autistic patients, we believe that RAC1, in particular, and the RHO family of GTPases, in general, could play a critical role in the neuropathological events associated with autism. © 2013 Springer Science+Business Media New York.

Single-particle momentum distributions of Efimov states in mixed-species systems

We solve the three-body bound-state problem in three dimensions for mass imbalanced systems of two identical bosons and a third particle in the universal limit where the interactions are assumed to be of zero range. The system displays the Efimov effect and we use the momentum-space wave equation to derive formulas for the scaling factor of the Efimov spectrum for any mass ratio assuming either that two or three of the two-body subsystems have a bound state at zero energy. We consider the single-particle momentum distribution analytically and numerically and analyze the tail of the momentum distribution to obtain the three-body contact parameter. Our findings demonstrate that the functional form of the three-body contact term depends on the mass ratio, and we obtain an analytic expression for this behavior. To exemplify our results, we consider mixtures of lithium with either two caesium or rubidium atoms which are systems of current experimental interest. © 2013 American Physical Society.