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Sample records for modeling studies revealed

  1. Novel Polyurethane Matrix Systems Reveal a Particular Sustained Release Behavior Studied by Imaging and Computational Modeling.

    Science.gov (United States)

    Campiñez, María Dolores; Caraballo, Isidoro; Puchkov, Maxim; Kuentz, Martin

    2017-07-01

    The aim of the present work was to better understand the drug-release mechanism from sustained release matrices prepared with two new polyurethanes, using a novel in silico formulation tool based on 3-dimensional cellular automata. For this purpose, two polymers and theophylline as model drug were used to prepare binary matrix tablets. Each formulation was simulated in silico, and its release behavior was compared to the experimental drug release profiles. Furthermore, the polymer distributions in the tablets were imaged by scanning electron microscopy (SEM) and the changes produced by the tortuosity were quantified and verified using experimental data. The obtained results showed that the polymers exhibited a surprisingly high ability for controlling drug release at low excipient concentrations (only 10% w/w of excipient controlled the release of drug during almost 8 h). The mesoscopic in silico model helped to reveal how the novel biopolymers were controlling drug release. The mechanism was found to be a special geometrical arrangement of the excipient particles, creating an almost continuous barrier surrounding the drug in a very effective way, comparable to lipid or waxy excipients but with the advantages of a much higher compactability, stability, and absence of excipient polymorphism.

  2. Genome association study through nonlinear mixed models revealed new candidate genes for pig growth curves

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    Fabyano Fonseca e Silva

    Full Text Available ABSTRACT: Genome association analyses have been successful in identifying quantitative trait loci (QTLs for pig body weights measured at a single age. However, when considering the whole weight trajectories over time in the context of genome association analyses, it is important to look at the markers that affect growth curve parameters. The easiest way to consider them is via the two-step method, in which the growth curve parameters and marker effects are estimated separately, thereby resulting in a reduction of the statistical power and the precision of estimates. One efficient solution is to adopt nonlinear mixed models (NMM, which enables a joint modeling of the individual growth curves and marker effects. Our aim was to propose a genome association analysis for growth curves in pigs based on NMM as well as to compare it with the traditional two-step method. In addition, we also aimed to identify the nearest candidate genes related to significant SNP (single nucleotide polymorphism markers. The NMM presented a higher number of significant SNPs for adult weight (A and maturity rate (K, and provided a direct way to test SNP significance simultaneously for both the A and K parameters. Furthermore, all significant SNPs from the two-step method were also reported in the NMM analysis. The ontology of the three candidate genes (SH3BGRL2, MAPK14, and MYL9 derived from significant SNPs (simultaneously affecting A and K allows us to make inferences with regards to their contribution to the pig growth process in the population studied.

  3. Precise Characterization of the Penumbra Revealed by MRI: A Modified Photothrombotic Stroke Model Study.

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    Cheng Qian

    0.37 on T2-weighted imaging and 27.8% (0.10 of 0.35 on triphenyltetrazolium chloride, representing a high reproducibility (n = 7. While the CV of the lesions in the MCAO stroke mice was only 70% (0.24 of 0.34, n = 4.This study has provided a precise imaging definition of the penumbra based on a reproducible photothrombotic stroke mouse model.

  4. Precise Characterization of the Penumbra Revealed by MRI: A Modified Photothrombotic Stroke Model Study.

    Science.gov (United States)

    Qian, Cheng; Li, Pei-Cheng; Jiao, Yun; Yao, Hong-Hong; Chen, Yu-Chen; Yang, Jian; Ding, Jie; Yang, Xiang-Yu; Teng, Gao-Jun

    2016-01-01

    -weighted imaging and 27.8% (0.10 of 0.35) on triphenyltetrazolium chloride, representing a high reproducibility (n = 7). While the CV of the lesions in the MCAO stroke mice was only 70% (0.24 of 0.34, n = 4). This study has provided a precise imaging definition of the penumbra based on a reproducible photothrombotic stroke mouse model.

  5. Arrangement of ceramide [EOS] in a stratum corneum lipid model matrix: new aspects revealed by neutron diffraction studies.

    Science.gov (United States)

    Kessner, Doreen; Kiselev, Mikhail; Dante, Silvia; Hauss, Thomas; Lersch, Peter; Wartewig, Siegfried; Neubert, Reinhard H H

    2008-07-01

    The lipid matrix in stratum corneum (SC) plays a key role in the barrier function of the mammalian skin. The major lipids are ceramides (CER), cholesterol (CHOL) and free fatty acids (FFA). Especially the unique-structured omega-acylceramide CER[EOS] is regarded to be essential for skin barrier properties by inducing the formation of a long-periodicity phase of 130 angstroms (LPP). In the present study, the arrangement of CER[EOS], either mixed with CER[AP] and CHOL or with CER[AP], CHOL and palmitic acid (PA), inside a SC lipid model membrane has been studied for the first time by neutron diffraction. For a mixed CER[EOS]/CER[AP]/CHOL membrane in a partly dehydrated state, the internal membrane nanostructure, i.e. the neutron scattering length density profile in the direction normal to the surface, was obtained by Fourier synthesis from the experimental diffraction patterns. The membrane repeat distance is equal to that of the formerly used SC lipid model system composed of CER[AP]/CHOL/PA/ChS. By comparing both the neutron scattering length density profiles, a possible arrangement of synthetic long-chain CER[EOS] molecules inside a SC lipid model matrix is suggested. The analysis of the internal membrane nanostructure implies that one CER[EOS] molecule penetrates from one membrane layer into an adjacent layer. A 130 angstroms periodicity phase could not be observed under experimental conditions, either in CER/CHOL mixtures or in CER/CHOL/FFA mixture. CER[EOS] can be arranged inside a phase with a repeat unit of 45.2 angstroms which is predominately formed by short-chain CER[AP] with distinct polarity.

  6. Empirical study of travel mode forecasting improvement for the combined revealed preference/stated preference data–based discrete choice model

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    Yanfu Qiao

    2016-01-01

    Full Text Available The combined revealed preference/stated preference data–based discrete choice model has provided the actual choice-making restraints as well as reduced the prediction errors. But the random error variance of alternatives belonging to different data would impact its universality. In this article, we studied the traffic corridor between Chengdu and Longquan with the revealed preference/stated preference joint model, and the single stated preference data model separately predicted the choice probability of each mode. We found the revealed preference/stated preference joint model is universal only when there is a significant difference between the random error terms in different data. The single stated preference data would amplify the travelers’ preference and cause prediction error. We proposed a universal way that uses revealed preference data to modify the single stated preference data parameter estimation results to achieve the composite utility and reduce the prediction error. And the result suggests that prediction results are more reasonable based on the composite utility than the results based on the single stated preference data, especially forecasting the mode share of bus. The future metro line will be the main travel mode in this corridor, and 45% of passenger flow will transfer to the metro.

  7. Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors.

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    Lin, Zeyu; Cantone, Joseph; Lu, Hao; Nowicka-Sans, Beata; Protack, Tricia; Yuan, Tian; Yang, Hong; Liu, Zheng; Drexler, Dieter; Regueiro-Ren, Alicia; Meanwell, Nicholas A; Cockett, Mark; Krystal, Mark; Lataillade, Max; Dicker, Ira B

    2016-11-01

    HIV-1 maturation inhibitors (MIs) disrupt the final step in the HIV-1 protease-mediated cleavage of the Gag polyprotein between capsid p24 capsid (CA) and spacer peptide 1 (SP1), leading to the production of infectious virus. BMS-955176 is a second generation MI with improved antiviral activity toward polymorphic Gag variants compared to a first generation MI bevirimat (BVM). The underlying mechanistic reasons for the differences in polymorphic coverage were studied using antiviral assays, an LC/MS assay that quantitatively characterizes CA/SP1 cleavage kinetics of virus like particles (VLPs) and a radiolabel binding assay to determine VLP/MI affinities and dissociation kinetics. Antiviral assay data indicates that BVM does not achieve 100% inhibition of certain polymorphs, even at saturating concentrations. This results in the breakthrough of infectious virus (partial antagonism) regardless of BVM concentration. Reduced maximal percent inhibition (MPI) values for BVM correlated with elevated EC50 values, while rates of HIV-1 protease cleavage at CA/SP1 correlated inversely with the ability of BVM to inhibit HIV-1 Gag polymorphic viruses: genotypes with more rapid CA/SP1 cleavage kinetics were less sensitive to BVM. In vitro inhibition of wild type VLP CA/SP1 cleavage by BVM was not maintained at longer cleavage times. BMS-955176 exhibited greatly improved MPI against polymorphic Gag viruses, binds to Gag polymorphs with higher affinity/longer dissociation half-lives and exhibits greater time-independent inhibition of CA/SP1 cleavage compared to BVM. Virological (MPI) and biochemical (CA/SP1 cleavage rates, MI-specific Gag affinities) data were used to create an integrated semi-quantitative model that quantifies CA/SP1 cleavage rates as a function of both MI and Gag polymorph. The model outputs are in accord with in vitro antiviral observations and correlate with observed in vivo MI efficacies. Overall, these findings may be useful to further understand antiviral

  8. DIGE proteome analysis reveals suitability of ischemic cardiac in vitro model for studying cellular response to acute ischemia and regeneration.

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    Sina Haas

    Full Text Available Proteomic analysis of myocardial tissue from patient population is suited to yield insights into cellular and molecular mechanisms taking place in cardiovascular diseases. However, it has been limited by small sized biopsies and complicated by high variances between patients. Therefore, there is a high demand for suitable model systems with the capability to simulate ischemic and cardiotoxic effects in vitro, under defined conditions. In this context, we established an in vitro ischemia/reperfusion cardiac disease model based on the contractile HL-1 cell line. To identify pathways involved in the cellular alterations induced by ischemia and thereby defining disease-specific biomarkers and potential target structures for new drug candidates we used fluorescence 2D-difference gel electrophoresis. By comparing spot density changes in ischemic and reperfusion samples we detected several protein spots that were differentially abundant. Using MALDI-TOF/TOF-MS and ESI-MS the proteins were identified and subsequently grouped by functionality. Most prominent were changes in apoptosis signalling, cell structure and energy-metabolism. Alterations were confirmed by analysis of human biopsies from patients with ischemic cardiomyopathy.With the establishment of our in vitro disease model for ischemia injury target identification via proteomic research becomes independent from rare human material and will create new possibilities in cardiac research.

  9. The role of Smad signaling in vascular and hematopoietic development revealed by studies using genetic mouse models

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Smads are intracellular mediators of transforming growth factor β (TGF-β) superfamily signaling. In this review, we focus on the genetic mouse models for Smad pathways, which have provided functional evidence regarding the complex circuitry in angiogenesis and hematopoiesis during development. In the early stages of vascular development, TGF-β signaling is a contri buting factor in angiogenesis and vascular maturation. Whereas in the later embryogenesis, selected molecules of Smad pathways, such as TGF-β type II receptor (TbRII), ALK5, and Smad5, seem to be dispensable for vessel morphogenesis and integrity. TGF-β signaling is not required in the induction of hematopoietic precursors from mesoderm, but inhibits the subsequent expansion of committed hematopoietic precursors. By contrast, bone morphogenetic protein 4 (BMP4) has long been acknowledged pivotal in mesoderm induction and hematopoietic commitment during development. However, recent genetic evidence shows the BMP4-ALK3 axis is not crucial for the formation of hematopoietic cells from FLK1+ mesoderm. Because of the highly redundant mechanisms within the Smad pathways, the precise role of the Smad signaling involved in vascular and hematopoietic development remains nebulous. The generation of novel cell lineage restricted Cre transgenes would shed new light on the future relevant investigations.

  10. A Study of the Driving Force Model Revealing Changes in Land Utilization Level Based on 3S Technologies--The Example of Yuanmou, Yunnan, China

    Institute of Scientific and Technical Information of China (English)

    HE Jin-feng; CHEN Guo-jie; YANG Zhong

    2005-01-01

    This paper introduced the theory and approaches of building driving force models revealing the changes in land utilization level by integrating RS, GPS, and GIS technologies based on the example of Yuanmou County of Yunnan Province. We first created the land utilization type database, natural driving forces for land utilization database, and human driving forces for land utilization database. Then we obtained the dependent and the independent variables of changes in land utilization level by exploring various data. Lastly we screened major factors affecting changes in land utilization level by using the po- werful spatial correlation analysis and main component analysis module of GIS and obtained a multivariable linear regression model of the changes in land utilization level by using GIS spatial regression analysis module.

  11. Insights revealed by rodent models of sugar binge eating.

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    Murray, Susan M; Tulloch, Alastair J; Chen, Eunice Y; Avena, Nicole M

    2015-12-01

    Binge eating is seen across the spectrum of eating disorder diagnoses as well as among individuals who do not meet diagnostic criteria. Analyses of the specific types of foods that are frequently binged upon reveal that sugar-rich items feature prominently in binge-type meals, making the effects of binge consumption of sugar an important focus of study. One avenue to do this involves the use of animal models. Foundational and recent studies of animal models of sugar bingeing, both outlined here, lend insight into the various neurotransmitters and neuropeptides that may participate in or be altered by this behavior. Further, several preclinical studies incorporating sugar bingeing paradigms have explored the utility of pharmacological agents that target such neural systems for reducing sugar bingeing in an effort to enhance clinical treatment. Indeed, the translational implications of findings generated using animal models of sugar bingeing are considered here, along with potential avenues for further study.

  12. Stochastic heart-rate model can reveal pathologic cardiac dynamics

    Science.gov (United States)

    Kuusela, Tom

    2004-03-01

    A simple one-dimensional Langevin-type stochastic difference equation can simulate the heart-rate fluctuations in a time scale from minutes to hours. The model consists of a deterministic nonlinear part and a stochastic part typical of Gaussian noise, and both parts can be directly determined from measured heart-rate data. Data from healthy subjects typically exhibit the deterministic part with two or more stable fixed points. Studies of 15 congestive heart-failure subjects reveal that the deterministic part of pathologic heart dynamics has no clear stable fixed points. Direct simulations of the stochastic model for normal and pathologic cases can produce statistical parameters similar to those of real subjects. Results directly indicate that pathologic situations simplify the heart-rate control system.

  13. Quantum Model of Catalysis Based on a Mobile Proton Revealed by Subatomic X-ray and Neutron Diffraction Studies of h-aldose Reductase

    Energy Technology Data Exchange (ETDEWEB)

    Blakeley, M. P. [European Molecular Biology Laboratory (EMBL), France; Ruiz, Fredrico [Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS, ULP, INSER; Cachau, Raul [SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD; Hazemann, I. [Institut Laue-Langevin (ILL); Meilleur, Flora [Institut Laue-Langevin (ILL); Mitschler, A. [IGBMC; Ginell, Stephan [Argonne National Laboratory (ANL); Afonine, Pavel [Lawrence Berkeley National Laboratory (LBNL); Ventura, Oscar [Computational Chemical Physics Group, DETEMA, Facultad de Quimica, UdelaR, C.C.1; Cousido-Siah, Alexandra [Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS, ULP, INSER; Haertlein, M. [Institut Laue-Langevin (ILL); Joachimiak, Andrzej [Argonne National Laboratory (ANL); Myles, Dean A A [ORNL; Podjarny, A. [IGBMC

    2008-01-01

    We present results of combined studies of the enzyme human aldose reductase (h-AR, 36 kDa) using single-crystal x-ray data (0.66 Angstroms, 100K; 0.80 Angstroms, 15K; 1.75 Angstroms, 293K), neutron Laue data (2.2 Angstroms, 293K), and quantum mechanical modeling. These complementary techniques unveil the internal organization and mobility of the hydrogen bond network that defines the properties of the catalytic engine, explaining how this promiscuous enzyme overcomes the simultaneous requirements of efficiency and promiscuity offering a general mechanistic view for this class of enzymes.

  14. Model Peptide Studies Reveal a Mixed Histidine-Methionine Cu(I) Binding Site at the N-Terminus of Human Copper Transporter 1.

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    Pushie, M Jake; Shaw, Katharine; Franz, Katherine J; Shearer, Jason; Haas, Kathryn L

    2015-09-08

    Copper is a vital metal cofactor in enzymes that are essential to myriad biological processes. Cellular acquisition of copper is primarily accomplished through the Ctr family of plasma membrane copper transport proteins. Model peptide studies indicate that the human Ctr1 N-terminus binds to Cu(II) with high affinity through an amino terminal Cu(II), Ni(II) (ATCUN) binding site. Unlike typical ATCUN-type peptides, the Ctr1 peptide facilitates the ascorbate-dependent reduction of Cu(II) bound in its ATCUN site by virtue of an adjacent HH (bis-His) sequence in the peptide. It is likely that the Cu(I) coordination environment influences the redox behavior of Cu bound to this peptide; however, the identity and coordination geometry of the Cu(I) site has not been elucidated from previous work. Here, we show data from NMR, XAS, and structural modeling that sheds light on the identity of the Cu(I) binding site of a Ctr1 model peptide. The Cu(I) site includes the same bis-His site identified in previous work to facilitate ascorbate-dependent Cu(II) reduction. The data presented here are consistent with a rational mechanism by which Ctr1 provides coordination environments that facilitate Cu(II) reduction prior to Cu(I) transport.

  15. Integrative modelling reveals mechanisms linking productivity and plant species richness.

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    Grace, James B; Anderson, T Michael; Seabloom, Eric W; Borer, Elizabeth T; Adler, Peter B; Harpole, W Stanley; Hautier, Yann; Hillebrand, Helmut; Lind, Eric M; Pärtel, Meelis; Bakker, Jonathan D; Buckley, Yvonne M; Crawley, Michael J; Damschen, Ellen I; Davies, Kendi F; Fay, Philip A; Firn, Jennifer; Gruner, Daniel S; Hector, Andy; Knops, Johannes M H; MacDougall, Andrew S; Melbourne, Brett A; Morgan, John W; Orrock, John L; Prober, Suzanne M; Smith, Melinda D

    2016-01-21

    How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems.

  16. Structure of the dimeric N-glycosylated form of fungal β-N-acetylhexosaminidase revealed by computer modeling, vibrational spectroscopy, and biochemical studies

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    Sklenář Jan

    2007-05-01

    Full Text Available Abstract Background Fungal β-N-acetylhexosaminidases catalyze the hydrolysis of chitobiose into its constituent monosaccharides. These enzymes are physiologically important during the life cycle of the fungus for the formation of septa, germ tubes and fruit-bodies. Crystal structures are known for two monomeric bacterial enzymes and the dimeric human lysosomal β-N-acetylhexosaminidase. The fungal β-N-acetylhexosaminidases are robust enzymes commonly used in chemoenzymatic syntheses of oligosaccharides. The enzyme from Aspergillus oryzae was purified and its sequence was determined. Results The complete primary structure of the fungal β-N-acetylhexosaminidase from Aspergillus oryzae CCF1066 was used to construct molecular models of the catalytic subunit of the enzyme, the enzyme dimer, and the N-glycosylated dimer. Experimental data were obtained from infrared and Raman spectroscopy, and biochemical studies of the native and deglycosylated enzyme, and are in good agreement with the models. Enzyme deglycosylated under native conditions displays identical kinetic parameters but is significantly less stable in acidic conditions, consistent with model predictions. The molecular model of the deglycosylated enzyme was solvated and a molecular dynamics simulation was run over 20 ns. The molecular model is able to bind the natural substrate – chitobiose with a stable value of binding energy during the molecular dynamics simulation. Conclusion Whereas the intracellular bacterial β-N-acetylhexosaminidases are monomeric, the extracellular secreted enzymes of fungi and humans occur as dimers. Dimerization of the fungal β-N-acetylhexosaminidase appears to be a reversible process that is strictly pH dependent. Oligosaccharide moieties may also participate in the dimerization process that might represent a unique feature of the exclusively extracellular enzymes. Deglycosylation had only limited effect on enzyme activity, but it significantly affected

  17. A Comparative Study of Five Mouse Models of Alzheimer's Disease: Cell Cycle Events Reveal New Insights into Neurons at Risk for Death

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    Luming Li

    2011-01-01

    Full Text Available Ectopic cell cycle events (CCEs in postmitotic neurons link the neurodegenerative process in human Alzheimer's disease (AD with the brain phenotype of transgenic mouse models with known familial AD genes. Most reports on the mouse models use the appearance of brain amyloid pathology as a key outcome measure. In the current paper, we focus on the induction of neurodegeneration using CCEs as markers for impending neuronal loss. We compare 5 mouse models of familial AD for the appearance of CCEs in subcortical regions—deep cerebellar nuclei, amygdala, locus coeruleus, hippocampus, and dorsal raphe. We find that the models differ in their CCE involvement as well as in the appearance of phosphorylated tau and amyloid deposition, suggesting that each model represents a different disease phenotype. Comparison with the pattern of neuron death in human AD suggests that each may represent a distinctly different disease model when used in preclinical trials.

  18. Genome wide association studies using a new nonparametric model reveal the genetic architecture of 17 agronomic traits in an enlarged maize association panel.

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    Yang, Ning; Lu, Yanli; Yang, Xiaohong; Huang, Juan; Zhou, Yang; Ali, Farhan; Wen, Weiwei; Liu, Jie; Li, Jiansheng; Yan, Jianbing

    2014-09-01

    Association mapping is a powerful approach for dissecting the genetic architecture of complex quantitative traits using high-density SNP markers in maize. Here, we expanded our association panel size from 368 to 513 inbred lines with 0.5 million high quality SNPs using a two-step data-imputation method which combines identity by descent (IBD) based projection and k-nearest neighbor (KNN) algorithm. Genome-wide association studies (GWAS) were carried out for 17 agronomic traits with a panel of 513 inbred lines applying both mixed linear model (MLM) and a new method, the Anderson-Darling (A-D) test. Ten loci for five traits were identified using the MLM method at the Bonferroni-corrected threshold -log10 (P) >5.74 (α=1). Many loci ranging from one to 34 loci (107 loci for plant height) were identified for 17 traits using the A-D test at the Bonferroni-corrected threshold -log10 (P) >7.05 (α=0.05) using 556809 SNPs. Many known loci and new candidate loci were only observed by the A-D test, a few of which were also detected in independent linkage analysis. This study indicates that combining IBD based projection and KNN algorithm is an efficient imputation method for inferring large missing genotype segments. In addition, we showed that the A-D test is a useful complement for GWAS analysis of complex quantitative traits. Especially for traits with abnormal phenotype distribution, controlled by moderate effect loci or rare variations, the A-D test balances false positives and statistical power. The candidate SNPs and associated genes also provide a rich resource for maize genetics and breeding.

  19. Genome wide association studies using a new nonparametric model reveal the genetic architecture of 17 agronomic traits in an enlarged maize association panel.

    Directory of Open Access Journals (Sweden)

    Ning Yang

    2014-09-01

    Full Text Available Association mapping is a powerful approach for dissecting the genetic architecture of complex quantitative traits using high-density SNP markers in maize. Here, we expanded our association panel size from 368 to 513 inbred lines with 0.5 million high quality SNPs using a two-step data-imputation method which combines identity by descent (IBD based projection and k-nearest neighbor (KNN algorithm. Genome-wide association studies (GWAS were carried out for 17 agronomic traits with a panel of 513 inbred lines applying both mixed linear model (MLM and a new method, the Anderson-Darling (A-D test. Ten loci for five traits were identified using the MLM method at the Bonferroni-corrected threshold -log10 (P >5.74 (α=1. Many loci ranging from one to 34 loci (107 loci for plant height were identified for 17 traits using the A-D test at the Bonferroni-corrected threshold -log10 (P >7.05 (α=0.05 using 556809 SNPs. Many known loci and new candidate loci were only observed by the A-D test, a few of which were also detected in independent linkage analysis. This study indicates that combining IBD based projection and KNN algorithm is an efficient imputation method for inferring large missing genotype segments. In addition, we showed that the A-D test is a useful complement for GWAS analysis of complex quantitative traits. Especially for traits with abnormal phenotype distribution, controlled by moderate effect loci or rare variations, the A-D test balances false positives and statistical power. The candidate SNPs and associated genes also provide a rich resource for maize genetics and breeding.

  20. Computer modelling in combination with in vitro studies reveals similar binding affinities of Drosophila Crumbs for the PDZ domains of Stardust and DmPar-6.

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    Kempkens, Ozlem; Médina, Emmanuelle; Fernandez-Ballester, Gregorio; Ozüyaman, Susann; Le Bivic, André; Serrano, Luis; Knust, Elisabeth

    2006-08-01

    Formation of multiprotein complexes is a common theme to pattern a cell, thereby generating spatially and functionally distinct entities at specialised regions. Central components of these complexes are scaffold proteins, which contain several protein-protein interaction domains and provide a platform to recruit a variety of additional components. There is increasing evidence that protein complexes are dynamic structures and that their components can undergo various interactions depending on the cellular context. However, little is known so far about the factors regulating this behaviour. One evolutionarily conserved protein complex, which can be found both in Drosophila and mammalian epithelial cells, is composed of the transmembrane protein Crumbs/Crb3 and the scaffolding proteins Stardust/Pals1 and DPATJ/PATJ, respectively, and localises apically to the zonula adherens. Here we show by in vitro analysis that, similar as in vertebrates, the single PDZ domain of Drosophila DmPar-6 can bind to the four C-terminal amino acids (ERLI) of the transmembrane protein Crumbs. To further evaluate the binding capability of Crumbs to DmPar-6 and the MAGUK protein Stardust, analysis of the PDZ structural database and modelling of the interactions between the C-terminus of Crumbs and the PDZ domains of these two proteins were performed. The results suggest that both PDZ domains bind Crumbs with similar affinities. These data are supported by quantitative yeast two-hybrid interactions. In vivo analysis performed in cell cultures and in the Drosophila embryo show that the cytoplasmic domain of Crumbs can recruit DmPar-6 and DaPKC to the plasma membrane. The data presented here are discussed with respect to possible dynamic interactions between these proteins.

  1. Structure and Dynamics Study of LeuT Using the Markov State Model and Perturbation Response Scanning Reveals Distinct Ion Induced Conformational States.

    Science.gov (United States)

    Asciutto, Eliana K; Gedeon, Patrick C; General, Ignacio J; Madura, Jeffry D

    2016-08-25

    The bacterial leucine transporter (LeuT), a close homologue of the eukaryote monoamine transporters (MATs), currently serves as a powerful template for computer simulations of MATs. Transport of the amino acid leucine through the membrane is made possible by the sodium electrochemical potential. Recent reports indicate that the substrate transport mechanism is based on structural changes such as hinge movements of key transmembrane domains. In order to further investigate the role of sodium ions in the uptake of leucine, here we present a Markov state model analysis of atomistic simulations of lipid embedded LeuT in different environments, generated by varying the presence of binding pocket sodium ions and substrate. Six metastable conformations are found, and structural differences between them along with transition probabilities are determined. We complete the analysis with the implementation of perturbation response scanning on our system, determining the most sensitive and influential regions of LeuT, in each environment. Our results show that the occupation of sites Na1 and Na2, along with the presence of the substrate, selectively influences the geometry of LeuT. In particular, the occupation of each site Na1/Na2 has strong effects (in terms of changes in influence and/or sensitivity, as compared to the case without ions) in specific regions of LeuT, and the effects are different for simultaneous occupation. Our results strengthen the rationale and provide a conformational mechanism for a putative transport mechanism in which Na2 is necessary, but may not be sufficient, to initiate and stabilize extracellular substrate access to the binding pocket.

  2. Random field model reveals structure of the protein recombinational landscape.

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    Philip A Romero

    Full Text Available We are interested in how intragenic recombination contributes to the evolution of proteins and how this mechanism complements and enhances the diversity generated by random mutation. Experiments have revealed that proteins are highly tolerant to recombination with homologous sequences (mutation by recombination is conservative; more surprisingly, they have also shown that homologous sequence fragments make largely additive contributions to biophysical properties such as stability. Here, we develop a random field model to describe the statistical features of the subset of protein space accessible by recombination, which we refer to as the recombinational landscape. This model shows quantitative agreement with experimental results compiled from eight libraries of proteins that were generated by recombining gene fragments from homologous proteins. The model reveals a recombinational landscape that is highly enriched in functional sequences, with properties dominated by a large-scale additive structure. It also quantifies the relative contributions of parent sequence identity, crossover locations, and protein fold to the tolerance of proteins to recombination. Intragenic recombination explores a unique subset of sequence space that promotes rapid molecular diversification and functional adaptation.

  3. Demand Model Combining Stated And Revealed Preference Data

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    Luciana Londero Brandli

    2007-10-01

    Full Text Available The revealed and stated preference methods have been contributing a lot for the development of the econometric literature in the attempt of determining the variables that influence the individual decision in a choice process. This article combines preference data, with the objective of obtaining the advantages of the complementarity of the forces and frankness of both types of data. The approach involves the estimate of a model only with RP data, only with SP data and combining RP and SP data. The application is in the housing market, where it is observed, through the literature, that most of the papers of the consumer's choice has restricted the only one approaches. The utility functions obtained show the relative importance of the attributes, the tendency of behavior through the signs and its significance statistical. The results analysis of the models indicates differences and similarities about the attribute’s behavior.

  4. Animal Model Reveals Potential Waterborne Transmission of Helicobacter pylori Infection.

    Science.gov (United States)

    Boehnke, Kevin F; Eaton, Kathryn A; Valdivieso, Manuel; Baker, Laurence H; Xi, Chuanwu

    2015-10-01

    Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne H. pylori could cause gastric infection. Groups of immunocompetent C57/BL6 Helicobacter-free mice were exposed to static concentrations (1.29 × 10(5), 10(6), 10(7), 10(8), and 10(9) CFU/L) of H. pylori in their drinking water for 4 weeks. One group of Helicobacter-free mice was exposed to uncontaminated water as a negative control. H. pylori morphology changes in water were examined using microscopy Live/Dead staining. Following exposure, H. pylori infection and inflammation status in the stomach were evaluated using quantitative culture, PCR, the rapid urease test, and histology. None of the mice in the negative control or 10(5) groups were infected. One of 20 cages (one of 40 mice) of the 10(6) group, three of 19 cages (four of 38 mice) of the 10(7) CFU/L group, 19 of 20 cages (33 of 40 mice) of the 10(8) group, and 20 of 20 cages (39 of 40 mice) of the 10(9) CFU/L group were infected. Infected mice had significantly higher gastric inflammation than uninfected mice (27.86% higher inflammation, p < .0001). We offer proof that H. pylori in water is infectious in mice, suggesting that humans drinking contaminated water may be at risk of contracting H. pylori infection. Much work needs to be performed to better understand the risk of infection from drinking H. pylori-contaminated water. © 2015 John Wiley & Sons Ltd.

  5. Ethiopian population dermatoglyphic study reveals linguistic stratification of diversity.

    Directory of Open Access Journals (Sweden)

    Seile Yohannes

    Full Text Available The manifestation of ethnic, blood type, & gender-wise population variations regarding Dermatoglyphic manifestations are of interest to assess intra-group diversity and differentiation. The present study reports on the analysis of qualitaive and quantitative finger Dermatoglyphic traits of 382 individuals cross-sectionally sampled from an administrative region of Ethiopia, consisting of five ethnic cohorts from the Afro-Asiatic & Nilo-Saharan affiliations. These Dermatoglyphic parameters were then applied in the assessment of diversity & differentiation, including Heterozygosity, Fixation, Panmixia, Wahlund's variance, Nei's measure of genetic diversity, and thumb & finger pattern genotypes, which were inturn used in homology inferences as summarized by a Neighbour-Joining tree constructed from Nei's standard genetic distance. Results revealed significant correlation between Dermatoglyphics & population parameters that were further found to be in concordance with the historical accounts of the ethnic groups. Such inductions as the ancient north-eastern presence and subsequent admixure events of the Oromos (PII= 15.01, the high diversity of the Amharas (H= 0.1978, F= 0.6453, and P= 0.4144, and the Nilo-Saharan origin of the Berta group (PII= 10.66 are evidences to this. The study has further tested the possibility of applying Dermatoglyphics in population genetic & anthropologic research, highlighting on the prospect of developing a method to trace back population origins & ancient movement patterns. Additionally, linguistic clustering was deemed significant for the Ethiopian population, coinciding with recent genome wide studies that have ascertained that linguistic clustering as to being more crucial than the geographical patterning in the Ethiopian context. Finally, Dermatoglyphic markers have been proven to be endowed with a strong potential as non-invasive preliminary tools applicable prior to genetic studies to analyze ethnically sub

  6. Ethiopian population dermatoglyphic study reveals linguistic stratification of diversity.

    Science.gov (United States)

    Yohannes, Seile; Bekele, Endashaw

    2015-01-01

    The manifestation of ethnic, blood type, & gender-wise population variations regarding Dermatoglyphic manifestations are of interest to assess intra-group diversity and differentiation. The present study reports on the analysis of qualitaive and quantitative finger Dermatoglyphic traits of 382 individuals cross-sectionally sampled from an administrative region of Ethiopia, consisting of five ethnic cohorts from the Afro-Asiatic & Nilo-Saharan affiliations. These Dermatoglyphic parameters were then applied in the assessment of diversity & differentiation, including Heterozygosity, Fixation, Panmixia, Wahlund's variance, Nei's measure of genetic diversity, and thumb & finger pattern genotypes, which were inturn used in homology inferences as summarized by a Neighbour-Joining tree constructed from Nei's standard genetic distance. Results revealed significant correlation between Dermatoglyphics & population parameters that were further found to be in concordance with the historical accounts of the ethnic groups. Such inductions as the ancient north-eastern presence and subsequent admixure events of the Oromos (PII= 15.01), the high diversity of the Amharas (H= 0.1978, F= 0.6453, and P= 0.4144), and the Nilo-Saharan origin of the Berta group (PII= 10.66) are evidences to this. The study has further tested the possibility of applying Dermatoglyphics in population genetic & anthropologic research, highlighting on the prospect of developing a method to trace back population origins & ancient movement patterns. Additionally, linguistic clustering was deemed significant for the Ethiopian population, coinciding with recent genome wide studies that have ascertained that linguistic clustering as to being more crucial than the geographical patterning in the Ethiopian context. Finally, Dermatoglyphic markers have been proven to be endowed with a strong potential as non-invasive preliminary tools applicable prior to genetic studies to analyze ethnically sub-divided populations and

  7. REVEAL: An Extensible Reduced Order Model Builder for Simulation and Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Agarwal, Khushbu; Sharma, Poorva; Ma, Jinliang; Lo, Chaomei; Gorton, Ian; Liu, Yan

    2013-04-30

    Many science domains need to build computationally efficient and accurate representations of high fidelity, computationally expensive simulations. These computationally efficient versions are known as reduced-order models. This paper presents the design and implementation of a novel reduced-order model (ROM) builder, the REVEAL toolset. This toolset generates ROMs based on science- and engineering-domain specific simulations executed on high performance computing (HPC) platforms. The toolset encompasses a range of sampling and regression methods that can be used to generate a ROM, automatically quantifies the ROM accuracy, and provides support for an iterative approach to improve ROM accuracy. REVEAL is designed to be extensible in order to utilize the core functionality with any simulator that has published input and output formats. It also defines programmatic interfaces to include new sampling and regression techniques so that users can ‘mix and match’ mathematical techniques to best suit the characteristics of their model. In this paper, we describe the architecture of REVEAL and demonstrate its usage with a computational fluid dynamics model used in carbon capture.

  8. Evolution: Ocean Models Reveal Life in Deep Seas.

    Science.gov (United States)

    Eizaguirre, Christophe

    2016-09-26

    Even though the deep sea represents the largest area in the world, evolution of species from those environments remains largely unstudied. A series of recent papers indicate that combining molecular tools with biophysical models can help us resolve some of these deep mysteries.

  9. Mechanistic species distribution modeling reveals a niche shift during invasion.

    Science.gov (United States)

    Chapman, Daniel S; Scalone, Romain; Štefanić, Edita; Bullock, James M

    2017-06-01

    Niche shifts of nonnative plants can occur when they colonize novel climatic conditions. However, the mechanistic basis for niche shifts during invasion is poorly understood and has rarely been captured within species distribution models. We quantified the consequence of between-population variation in phenology for invasion of common ragweed (Ambrosia artemisiifolia L.) across Europe. Ragweed is of serious concern because of its harmful effects as a crop weed and because of its impact on public health as a major aeroallergen. We developed a forward mechanistic species distribution model based on responses of ragweed development rates to temperature and photoperiod. The model was parameterized and validated from the literature and by reanalyzing data from a reciprocal common garden experiment in which native and invasive populations were grown within and beyond the current invaded range. It could therefore accommodate between-population variation in the physiological requirements for flowering, and predict the potentially invaded ranges of individual populations. Northern-origin populations that were established outside the generally accepted climate envelope of the species had lower thermal requirements for bud development, suggesting local adaptation of phenology had occurred during the invasion. The model predicts that this will extend the potentially invaded range northward and increase the average suitability across Europe by 90% in the current climate and 20% in the future climate. Therefore, trait variation observed at the population scale can trigger a climatic niche shift at the biogeographic scale. For ragweed, earlier flowering phenology in established northern populations could allow the species to spread beyond its current invasive range, substantially increasing its risk to agriculture and public health. Mechanistic species distribution models offer the possibility to represent niche shifts by varying the traits and niche responses of individual

  10. Genetic and Modeling Approaches Reveal Distinct Components of Impulsive Behavior.

    Science.gov (United States)

    Nautiyal, Katherine M; Wall, Melanie M; Wang, Shuai; Magalong, Valerie M; Ahmari, Susanne E; Balsam, Peter D; Blanco, Carlos; Hen, René

    2017-01-18

    Impulsivity is an endophenotype found in many psychiatric disorders including substance use disorders, pathological gambling, and attention deficit hyperactivity disorder. Two behavioral features often considered in impulsive behavior are behavioral inhibition (impulsive action) and delayed gratification (impulsive choice). However, the extent to which these behavioral constructs represent distinct facets of behavior with discrete biological bases is unclear. To test the hypothesis that impulsive action and impulsive choice represent statistically independent behavioral constructs in mice, we collected behavioral measures of impulsivity in a single cohort of mice using well-validated operant behavioral paradigms. Mice with manipulation of serotonin 1B receptor (5-HT1BR) expression were included as a model of disordered impulsivity. A factor analysis was used to characterize correlations between the measures of impulsivity and to identify covariates. Using two approaches, we dissociated impulsive action from impulsive choice. First, the absence of 5-HT1BRs caused increased impulsive action, but not impulsive choice. Second, based on an exploratory factor analysis, a two-factor model described the data well, with measures of impulsive action and choice separating into two independent factors. A multiple-indicator multiple-causes analysis showed that 5-HT1BR expression and sex were significant covariates of impulsivity. Males displayed increased impulsivity in both dimensions, whereas 5-HT1BR expression was a predictor of increased impulsive action only. These data support the conclusion that impulsive action and impulsive choice are distinct behavioral phenotypes with dissociable biological influences that can be modeled in mice. Our work may help inform better classification, diagnosis, and treatment of psychiatric disorders, which present with disordered impulsivity.Neuropsychopharmacology advance online publication, 18 January 2017; doi:10.1038/npp.2016.277.

  11. Robotic and mathematical modeling reveal general principles of appendage control and coordination in terrestrial locomotion

    Science.gov (United States)

    McInroe, Benjamin; Astley, Henry; Gong, Chaohui; Kawano, Sandy; Schiebel, Perrin; Choset, Howie; Goldman, Daniel I.

    The transition from aquatic to terrestrial life presented new challenges to early walkers, necessitating robust locomotion on complex, flowable substrates (e.g. sand, mud). Locomotion on such substrates is sensitive to limb morphology and kinematics. Although early walker morphologies are known, principles of appendage control remain elusive. To reveal limb control strategies that facilitated the invasion of land, we study both robotic and mathematical models. Robot experiments show that an active tail is critical for robust locomotion on granular media, enabling locomotion even with poor foot placement and limited ability to lift the body. Using a granular resistive force theory model, we construct connection vector fields that reveal how appendage coordination and terrain inclination impact locomotor performance. This model replicates experimental results, showing that moving limbs/tail in phase is most effective (suggesting a locomotor template). Varying limb trajectories and contacts, we find gaits for which tail use can be neutral or harmful, suggesting limb-tail coordination to be a nontrivial aspect of locomotion. Our findings show that robot experiments coupled with geometric mechanics provide a general framework to reveal principles of robust terrestrial locomotion. This work was supported by NSF PoLS.

  12. Yeast studies reveal moonlighting functions of the ancient actin cytoskeleton

    Science.gov (United States)

    Sattlegger, Evelyn; Chernova, Tatiana A.; Gogoi, Neeku M.; Pillai, Indu V.; Chernoff, Yury O.; Munn, Alan L.

    2014-01-01

    Classic functions of the actin cytoskeleton include control of cell size and shape and the internal organisation of cells. These functions are manifest in cellular processes of fundamental importance throughout biology such as the generation of cell polarity, cell migration, cell adhesion and cell division. However, studies in the unicellular model eukaryote Saccharomyces cerevisiae (Baker's yeast) are giving insights into other functions in which the actin cytoskeleton plays a critical role. These include endocytosis, control of protein translation and determination of protein 3-dimensional shape (especially conversion of normal cellular proteins into prions). Here we present a concise overview of these new "moonlighting" roles for the actin cytoskeleton and how some of these roles might lie at the heart of important molecular switches. This is an exciting time for researchers interested in the actin cytoskeleton. We show here how studies of actin are leading us into many new and exciting realms at the interface of genetics, biochemistry and cell biology. While many of the pioneering studies have been conducted using yeast, the conservation of the actin cytoskeleton and its component proteins throughout eukaryotes suggests that these new roles for the actin cytoskeleton may not be restricted to yeast cells but rather may reflect new roles for the actin cytoskeleton of all eukaryotes. PMID:25138357

  13. Data-driven modeling reveals cell behaviors controlling self-organization during Myxococcus xanthus development.

    Science.gov (United States)

    Cotter, Christopher R; Schüttler, Heinz-Bernd; Igoshin, Oleg A; Shimkets, Lawrence J

    2017-06-06

    Collective cell movement is critical to the emergent properties of many multicellular systems, including microbial self-organization in biofilms, embryogenesis, wound healing, and cancer metastasis. However, even the best-studied systems lack a complete picture of how diverse physical and chemical cues act upon individual cells to ensure coordinated multicellular behavior. Known for its social developmental cycle, the bacterium Myxococcus xanthus uses coordinated movement to generate three-dimensional aggregates called fruiting bodies. Despite extensive progress in identifying genes controlling fruiting body development, cell behaviors and cell-cell communication mechanisms that mediate aggregation are largely unknown. We developed an approach to examine emergent behaviors that couples fluorescent cell tracking with data-driven models. A unique feature of this approach is the ability to identify cell behaviors affecting the observed aggregation dynamics without full knowledge of the underlying biological mechanisms. The fluorescent cell tracking revealed large deviations in the behavior of individual cells. Our modeling method indicated that decreased cell motility inside the aggregates, a biased walk toward aggregate centroids, and alignment among neighboring cells in a radial direction to the nearest aggregate are behaviors that enhance aggregation dynamics. Our modeling method also revealed that aggregation is generally robust to perturbations in these behaviors and identified possible compensatory mechanisms. The resulting approach of directly combining behavior quantification with data-driven simulations can be applied to more complex systems of collective cell movement without prior knowledge of the cellular machinery and behavioral cues.

  14. Comparison of Models for Bubonic Plague Reveals Unique Pathogen Adaptations to the Dermis.

    Science.gov (United States)

    Gonzalez, Rodrigo J; Weening, Eric H; Lane, M Chelsea; Miller, Virginia L

    2015-07-01

    Vector-borne pathogens are inoculated in the skin of mammals, most likely in the dermis. Despite this, subcutaneous (s.c.) models of infection are broadly used in many fields, including Yersinia pestis pathogenesis. We expand on a previous report where we implemented intradermal (i.d.) inoculations to study bacterial dissemination during bubonic plague and compare this model with an s.c. We found that i.d. inoculations result in faster kinetics of infection and that bacterial dose influenced mouse survival after i.d. but not s.c. inoculation. Moreover, a deletion mutant of rovA, previously shown to be moderately attenuated in the s.c. model, was severely attenuated in the i.d. Lastly, based on previous observations where a population bottleneck from the skin to lymph nodes was observed after i.d., but not after s.c., inoculations, we used the latter model as a strategy to identify an additional bottleneck in bacterial dissemination from lymph nodes to the bloodstream. Our data indicate that the more biologically relevant i.d. model of bubonic plague differs significantly from the s.c. model in multiple aspects of infection. These findings reveal adaptations of Y. pestis to the dermis and how these adaptations can define the progression of disease. They also emphasize the importance of using a relevant route of infection when addressing host-pathogen interactions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  15. The probabilistic niche model reveals substantial variation in the niche structure of empirical food webs.

    Science.gov (United States)

    Williams, Richard J; Purves, Drew W

    2011-09-01

    The structure of food webs, complex networks of interspecies feeding interactions, plays a crucial role in ecosystem resilience and function, and understanding food web structure remains a central problem in ecology. Previous studies have shown that key features of empirical food webs can be reproduced by low-dimensional "niche" models. Here we examine the form and variability of food web niche structure by fitting a probabilistic niche model to 37 empirical food webs, a much larger number of food webs than used in previous studies. The model relaxes previous assumptions about parameter distributions and hierarchy and returns parameter estimates for each species in each web. The model significantly outperforms previous niche model variants and also performs well for several webs where a body-size-based niche model performs poorly, implying that traits other than body size are important in structuring these webs' niche space. Parameter estimates frequently violate previous models' assumptions: in 19 of 37 webs, parameter values are not significantly hierarchical, 32 of 37 webs have nonuniform niche value distributions, and 15 of 37 webs lack a correlation between niche width and niche position. Extending the model to a two-dimensional niche space yields networks with a mixture of one- and two-dimensional niches and provides a significantly better fit for webs with a large number of species and links. These results confirm that food webs are strongly niche-structured but reveal substantial variation in the form of the niche structuring, a result with fundamental implications for ecosystem resilience and function.

  16. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis

    DEFF Research Database (Denmark)

    Huang, Sijia; Chong, Nicole; Lewis, Nathan

    2016-01-01

    . Methods: We propose that higher-order functional representation of metabolomics data, such as pathway-based metabolomic features, can be used as robust biomarkers for breast cancer. Towards this, we have developed a new computational method that uses personalized pathway dysregulation scores for disease...... the Curve, a receiver operating characteristic curve) of 0.968 and 0.934, sensitivities of 0.946 and 0.954, and specificities of 0.934 and 0.918. These two metabolomics-based pathway models are further validated by RNA-Seq-based TCGA (The Cancer Genome Atlas) breast cancer data, with AUCs of 0.995 and 0.......993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. Conclusions: We have successfully developed a new type of pathway-based model to study...

  17. Automatic sleep classification using a data-driven topic model reveals latent sleep states

    DEFF Research Database (Denmark)

    Koch, Henriette; Christensen, Julie Anja Engelhard; Frandsen, Rune

    2014-01-01

    Background: The golden standard for sleep classification uses manual scoring of polysomnography despite points of criticism such as oversimplification, low inter-rater reliability and the standard being designed on young and healthy subjects. New method: To meet the criticism and reveal the latent...... sleep states, this study developed a general and automatic sleep classifier using a data-driven approach. Spectral EEG and EOG measures and eye correlation in 1 s windows were calculated and each sleep epoch was expressed as a mixture of probabilities of latent sleep states by using the topic model...... Latent Dirichlet Allocation. Model application was tested on control subjects and patients with periodic leg movements (PLM) representing a non-neurodegenerative group, and patients with idiopathic REM sleep behavior disorder (iRBD) and Parkinson's Disease (PD) representing a neurodegenerative group...

  18. Multiwavelength Study to Reveal Dust Properties and Cloud 3D Structure

    Science.gov (United States)

    Pagani, Laurent; Lefevre, C.

    2017-06-01

    The study of low-mass prestellar cores is a difficult task which needs to gather several tools, dust and gas observations, radiative transfer modelling. No single tracer can reveal the physical characteristics of these cores. We show that based on observations of N2H+, and dust from 1 µm to 1 mm, one can hope today to have a faithful 3D description of a dark cloud and its prestellar core. Dust being ill-defined, only the combination of absorption, scattering and emission measurements and modelling can alleviate the degeneracy between temperature, density and emissivity of the dust.

  19. Representing Microbial Dormancy in Soil Decomposition Models Improves Model Performance and Reveals Key Ecosystem Controls on Microbial Activity

    Science.gov (United States)

    He, Y.; Yang, J.; Zhuang, Q.; Wang, G.; Liu, Y.

    2014-12-01

    Climate feedbacks from soils can result from environmental change and subsequent responses of plant and microbial communities and nutrient cycling. Explicit consideration of microbial life history traits and strategy may be necessary to predict climate feedbacks due to microbial physiology and community changes and their associated effect on carbon cycling. In this study, we developed an explicit microbial-enzyme decomposition model and examined model performance with and without representation of dormancy at six temperate forest sites with observed soil efflux ranged from 4 to 10 years across different forest types. We then extrapolated the model to all temperate forests in the Northern Hemisphere (25-50°N) to investigate spatial controls on microbial and soil C dynamics. Both models captured the observed soil heterotrophic respiration (RH), yet no-dormancy model consistently exhibited large seasonal amplitude and overestimation in microbial biomass. Spatially, the total RH from temperate forests based on dormancy model amounts to 6.88PgC/yr, and 7.99PgC/yr based on no-dormancy model. However, no-dormancy model notably overestimated the ratio of microbial biomass to SOC. Spatial correlation analysis revealed key controls of soil C:N ratio on the active proportion of microbial biomass, whereas local dormancy is primarily controlled by soil moisture and temperature, indicating scale-dependent environmental and biotic controls on microbial and SOC dynamics. These developments should provide essential support to modeling future soil carbon dynamics and enhance the avenue for collaboration between empirical soil experiment and modeling in the sense that more microbial physiological measurements are needed to better constrain and evaluate the models.

  20. New study reveals twice as many asteroids as previously believed

    Science.gov (United States)

    2002-05-01

    The ISO satellite Credits: ESA ISO An artist's impression of the ISO spacecraft. The ISO Deep Asteroid Search indicates that there are between 1.1 million and 1.9 million 'space rocks' larger than 1 kilometre in diameter in the so-called 'main asteroid belt', about twice as many as previously believed. However, astronomers think it is premature to revise current assessments of the risk of the Earth being hit by an asteroid. Despite being in our own Solar System, asteroids can be more difficult to study than very distant galaxies. With sizes of up to one thousand kilometres in diameter, the brightness of these rocky objects may vary considerably in just a few minutes. They move very quickly with respect to the stars - they have been dubbed 'vermin of the sky' because they often appear as trails on long exposure images. This elusiveness explains why their actual number and size distribution remains uncertain. Most of the almost 40,000 asteroids catalogued so far (1) orbit the Sun forming the 'main asteroid belt', between Mars and Jupiter, too far to pose any threat to Earth. However, space-watchers do keep a closer eye on another category of asteroids, the 'Near Earth Asteroids' or 'NEAs', which are those whose orbits cross, or are likely to cross, that of our planet. The ISO Deep Asteroid Search (IDAS), the first systematic search for these objects performed in infrared light, focused on main belt asteroids. Because it is impossible to simply point the telescope at the whole main belt and count, astronomers choose selected regions of the belt and then use a theoretical model to extrapolate the data to the whole belt. Edward Tedesco (TerraSystems, Inc., New Hampshire, United States) and François-Xavier Desert (Observatoire de Grenoble, France) observed their main belt selected areas in 1996 and 1997 with ESA's ISO. They found that in the middle region of the belt the density of asteroids was 160 asteroids larger than 1 kilometre per square degree - an area of the

  1. Role of chronic toxicology studies in revealing new toxicities.

    Science.gov (United States)

    Galijatovic-Idrizbegovic, Alema; Miller, Judith E; Cornell, Wendy D; Butler, James A; Wollenberg, Gordon K; Sistare, Frank D; DeGeorge, Joseph J

    2016-12-01

    Chronic (>3 months) preclinical toxicology studies are conducted to support the safe conduct of clinical trials exceeding 3 months in duration. We have conducted a review of 32 chronic toxicology studies in non-rodents (22 studies in dogs and 10 in non-human primates) and 27 chronic toxicology studies in rats dosed with Merck compounds to determine the frequency at which additional target organ toxicities are observed in chronic toxicology studies as compared to subchronic studies of 3 months in duration. Our review shows that majority of the findings are observed in the subchronic studies since additional target organs were not observed in 24 chronic non rodent studies and in 21 chronic rodent studies. However, 6 studies in non rodents and 6 studies in rodents yielded new findings that were not seen in studies of 3-month or shorter duration. For 3 compounds the new safety findings did contribute to termination of clinical development plans. Although the incidence of compound termination associated with chronic toxicology study observations is low (∼10%), the observations made in these studies can be important for evaluating human safety risk.

  2. Fibrinogen adsorption mechanisms at the gold substrate revealed by QCM-D measurements and RSA modeling.

    Science.gov (United States)

    Kubiak, Katarzyna; Adamczyk, Zbigniew; Cieśla, Michał

    2016-03-01

    Adsorption kinetics of fibrinogen at a gold substrate at various pHs was thoroughly studied using the QCM-D method. The experimental were interpreted in terms of theoretical calculations performed according to the random sequential adsorption model (RSA). In this way, the hydration functions and water factors of fibrinogen monolayers were quantitatively evaluated at various pHs. It was revealed that for the lower range of fibrinogen coverage the hydration function were considerably lower than previously obtained for the silica sensor [33]. The lower hydration of fibrinogen monolayers on the gold sensor was attributed to its higher roughness. However, for higher fibrinogen coverage the hydration functions for both sensors became identical exhibiting an universal behavior. By using the hydration functions, the fibrinogen adsorption/desorption runs derived from QCM-D measurements were converted to the Γd vs. the time relationships. This allowed to precisely determine the maximum coverage that varied between 1.6mgm(-2) at pH 3.5 and 4.5mgm(-2) at pH 7.4 (for ionic strength of 0.15M). These results agree with theoretical eRSA modeling and previous experimental data derived by using ellipsometry, OWLS and TIRF. Various fibrinogen adsorption mechanisms were revealed by exploiting the maximum coverage data. These results allow one to develop a method for preparing fibrinogen monolayers of well-controlled coverage and molecule orientation. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Study Reveals Brain Biology behind Self-Control

    Science.gov (United States)

    Sparks, Sarah D.

    2011-01-01

    A new neuroscience twist on a classic psychology study offers some clues to what makes one student able to buckle down for hours of homework before a test while his classmates party. The study published in the September 2011 edition of "Proceedings of the National Academy of Science," suggests environmental cues may "hijack" the brain's mechanisms…

  4. Implementing Japanese Lesson Study in Foreign Countries: Misconceptions Revealed

    Science.gov (United States)

    Fujii, Toshiakira

    2014-01-01

    This paper is based on data gathered during visits to Uganda and Malawi, conducted by the International Math-teacher Professionalization Using Lesson Study (IMPULS) project and the Japanese International Cooperation Agency (JICA). The author's observations and experiences highlighted misconceptions about lesson study. The paper concludes that some…

  5. Study Reveals Brain Biology behind Self-Control

    Science.gov (United States)

    Sparks, Sarah D.

    2011-01-01

    A new neuroscience twist on a classic psychology study offers some clues to what makes one student able to buckle down for hours of homework before a test while his classmates party. The study published in the September 2011 edition of "Proceedings of the National Academy of Science," suggests environmental cues may "hijack" the brain's mechanisms…

  6. Immune-correlates analysis of an HIV-1 vaccine efficacy trial reveals an association of nonspecific interferon-γ secretion with increased HIV-1 infection risk: a cohort-based modeling study.

    Directory of Open Access Journals (Sweden)

    Yunda Huang

    Full Text Available BACKGROUND: Elevated risk of HIV-1 infection among recipients of an adenovirus serotype 5 (Ad5-vectored HIV-1 vaccine was previously reported in the Step HIV-1 vaccine efficacy trial. We assessed pre-infection cellular immune responses measured at 4 weeks after the second vaccination to determine their roles in HIV-1 infection susceptibility among Step study male participants. METHODS: We examined ex vivo interferon-γ (IFN-γ secretion from peripheral blood mononuclear cells (PBMC using an ELISpot assay in 112 HIV-infected and 962 uninfected participants. In addition, we performed flow cytometric assays to examine T-cell activation, and ex vivo IFN-γ and interleukin-2 secretion from CD4(+ and CD8(+ T cells. We accounted for the sub-sampling design in Cox proportional hazards models to estimate hazard ratios (HRs of HIV-1 infection per 1-log(e increase of the immune responses. FINDINGS: We found that HIV-specific immune responses were not associated with risk of HIV-1 infection. However, each 1-log(e increase of mock responses measured by the ELISpot assay (i.e., IFN-γ secretion in the absence of antigen-specific stimulation was associated with a 62% increase of HIV-1 infection risk among vaccine recipients (HR = 1.62, 95% CI: (1.28, 2.04, p<0.001. This association remains after accounting for CD4(+ or CD8(+ T-cell activation. We observed a moderate correlation between ELISpot mock responses and CD4(+ T-cells secreting IFN-γ (ρ = 0.33, p = 0.007. In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04. CONCLUSIONS: The proportion of cells, likely CD4(+ T-cells, producing IFN-γ without stimulation by exogenous antigen appears to carry information beyond T-cell activation and baseline characteristics that predict risk of HIV-1 infection. These results motivate additional investigation to

  7. Original mechanism of failure initiation revealed through modelling of naturally occurring microstructures

    Science.gov (United States)

    Gorbatikh, Larissa; Lomov, Stepan V.; Verpoest, Ignaas

    2010-05-01

    Motivated to reveal original mechanisms of failure resistance, we developed a material model that encompasses most reoccurring microstructural features of natural composites. The interesting result of the work is a notion that material failure is governed by the quality of interactions between hierarchical levels in the material microstructure. With intelligent use of the structure, these interactions can be tuned to create a powerful synergetic effect on the material failure behaviour. For example, while exploring different mechanisms of failure initiation in composites with bimodal size reinforcements (an indirect way to model two levels of hierarchy simultaneously) we found that failure initiation could be shifted from stress concentration sites of the higher level to the lower level. One could say that the material behaviour became insensitive to the presence of reinforcements on the higher level—a phenomenon that is counterintuitive to what is commonly known. The new mechanism of failure initiation could only be activated in composites with a highly controlled structural organization—in the studied case, reinforcements of the lower level needed to establish lamellar pathways between reinforcements of the higher level. These pathways lead to formation of an intriguing network-like microstructure. Intelligent communication between reinforcements in such a network created the necessary synergy to change the failure initiation mechanism in a discontinuous fashion. Another finding was that by establishing such a network, tensile stresses near dangerous stress concentration sites were locally transformed into compressive stresses. Resemblance of the revealed mechanism to phenomena on the nano-scale was also discussed. In the course of this work a new method was developed to investigate interactions between reinforcements and their collective input into effective and local properties of a composite. The reinforcement phase was modelled with the use of rigid

  8. A homology model of Xyloglucan Xylosyltransferase 2 reveals critical amino acids involved in substrate binding.

    Science.gov (United States)

    Culbertson, Alan T; Tietze, Alesia A; Tietze, Daniel; Chou, Yi-Hsiang; Smith, Adrienne L; Young, Zachary T; Zabotina, Olga A

    2016-09-01

    In dicotyledonous plants, xyloglucan (XyG) is the most abundant hemicellulose of the primary cell wall. The enzymes involved in XyG biosynthesis have been identified through reverse-genetics and activity was characterized by heterologous expression. Currently, there is no information on the atomic structures or amino acids involved in activity or substrate binding of any of the Golgi-localized XyG biosynthetic enzymes. A homology model of the xyloglucan xylosyltransferase 2 (XXT2) catalytic domain was built on the basis of the crystal structure of A64Rp. Molecular dynamics simulations revealed that the homology model retains the glycosyltransferase (GT)-A fold of the template structure used to build the homology model indicating that XXT2 likely has a GT-A fold. According to the XXT2 homology model, six amino acids (Phe204, Lys207, Asp228, Ser229, Asp230, His378) were selected and their contribution in catalytic activity was investigated. Site-directed mutagenesis studies show that Asp228, Asp230 and His378 are critical for XXT2 activity and are predicted to be involved in coordination of manganese ion. Lys207 was also found to be critical for protein activity and the homology model indicates a critical role in substrate binding. Additionally, Phe204 mutants have less of an impact on XXT2 activity with the largest effect when replaced with a polar residue. This is the first study that investigates the amino acids involved in substrate binding of the XyG-synthesizing xylosyltransferases and contributes to the understanding of the mechanisms of polysaccharide-synthesizing GTs and XyG biosynthesis. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Recent advances in maize nuclear proteomic studies reveal histone modifications.

    Science.gov (United States)

    Casati, Paula

    2012-01-01

    The nucleus of eukaryotic organisms is highly dynamic and complex, containing different types of macromolecules including DNA, RNA, and a wide range of proteins. Novel proteomic applications have led to a better overall determination of nucleus protein content. Although nuclear plant proteomics is only at the initial phase, several studies have been reported and are summarized in this review using different plants species, such as Arabidopsis thaliana, rice, cowpea, onion, garden cress, and barrel clover. These include the description of the total nuclear or phospho-proteome (i.e., Arabidopsis, cowpea, onion), or the analysis of the differential nuclear proteome under different growth environments (i.e., Arabidopsis, rice, cowpea, onion, garden cress, and barrel clover). However, only few reports exist on the analysis of the maize nuclear proteome or its changes under various conditions. This review will present recent data on the study of the nuclear maize proteome, including the analysis of changes in posttranslational modifications in histone proteins.

  10. Recent advances in maize nuclear proteomic studies reveal histone modifications

    Directory of Open Access Journals (Sweden)

    Paula eCasati

    2012-12-01

    Full Text Available The nucleus of eukaryotic organisms is highly dynamic and complex, containing different types of macromolecules including DNA, RNA, and a wide range of proteins. Novel proteomic applications have led to a better overall determination of nucleus protein content. Although nuclear plant proteomics is only at the initial phase, several studies have been reported and are summarized in this review using different plants species, such as Arabidopsis thaliana, rice, cowpea, onion, garden cress, and barrel clover. These include the description of the total nuclear or phospho-proteome (i.e. Arabidopsis, cowpea, onion, or the analysis of the differential nuclear proteome under different growth environments (i.e. Arabidopsis, rice, cowpea, onion, garden cress and barrel clover. However, only few reports exist on the analysis of the maize nuclear proteome or its changes under various conditions. This review will present recent data on the study of the nuclear maize proteome, including the analysis of changes in posttranslational modifications in histone proteins.

  11. Different human gut models reveal the distinct fermentation patterns of Arabinoxylan versus inulin.

    Science.gov (United States)

    Van den Abbeele, Pieter; Venema, Koen; Van de Wiele, Tom; Verstraete, Willy; Possemiers, Sam

    2013-10-16

    Different in vitro models have been developed to assess how food compounds affect the human gut microbiota. Using two such models (SHIME(R) and TIM-2), we compared how long-chain arabinoxylan (LC-AX), a wheat-derived potentially prebiotic fiber, and inulin (IN), a well-established prebiotic compound, modulate SCFA production and bifidobacteria composition. While both the SHIME and TIM-2 differ in experimental design, they both demonstrated that LC-AX and IN specifically increased the health-promoting metabolites propionate and butyrate, respectively. Furthermore, LC-AX stimulated Bifidobacterium longum, while IN stimulated other bifidobacteria including Bifidobacterium adolescentis. The SHIME experiment also revealed that effects of LC-AX were more persistent during the 2-week wash-out period. These results confirm a recent in vivo study, during which humanized rats were treated with the same LC-AX/IN. In conclusion, results from different human gut models suggest that, besides IN, LC-AX are promising prebiotic candidates with high specificity toward Bifidobacterium longum and a selective propionate increase.

  12. Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

    Science.gov (United States)

    Kuzmanov, Uros; Guo, Hongbo; Buchsbaum, Diana; Cosme, Jake; Abbasi, Cynthia; Isserlin, Ruth; Sharma, Parveen; Gramolini, Anthony O.; Emili, Andrew

    2016-01-01

    Phospholamban (PLN) plays a central role in Ca2+ homeostasis in cardiac myocytes through regulation of the sarco(endo)plasmic reticulum Ca2+-ATPase 2A (SERCA2A) Ca2+ pump. An inherited mutation converting arginine residue 9 in PLN to cysteine (R9C) results in dilated cardiomyopathy (DCM) in humans and transgenic mice, but the downstream signaling defects leading to decompensation and heart failure are poorly understood. Here we used precision mass spectrometry to study the global phosphorylation dynamics of 1,887 cardiac phosphoproteins in early affected heart tissue in a transgenic R9C mouse model of DCM compared with wild-type littermates. Dysregulated phosphorylation sites were quantified after affinity capture and identification of 3,908 phosphopeptides from fractionated whole-heart homogenates. Global statistical enrichment analysis of the differential phosphoprotein patterns revealed selective perturbation of signaling pathways regulating cardiovascular activity in early stages of DCM. Strikingly, dysregulated signaling through the Notch-1 receptor, recently linked to cardiomyogenesis and embryonic cardiac stem cell development and differentiation but never directly implicated in DCM before, was a prominently perturbed pathway. We verified alterations in Notch-1 downstream components in early symptomatic R9C transgenic mouse cardiomyocytes compared with wild type by immunoblot analysis and confocal immunofluorescence microscopy. These data reveal unexpected connections between stress-regulated cell signaling networks, specific protein kinases, and downstream effectors essential for proper cardiac function. PMID:27742792

  13. Toxin diversity revealed by a transcriptomic study of Ornithoctonus huwena.

    Directory of Open Access Journals (Sweden)

    Yiya Zhang

    Full Text Available Spider venom comprises a mixture of compounds with diverse biological activities, which are used to capture prey and defend against predators. The peptide components bind a broad range of cellular targets with high affinity and selectivity, and appear to have remarkable structural diversity. Although spider venoms have been intensively investigated over the past few decades, venomic strategies to date have generally focused on high-abundance peptides. In addition, the lack of complete spider genomes or representative cDNA libraries has presented significant limitations for researchers interested in molecular diversity and understanding the genetic mechanisms of toxin evolution. In the present study, second-generation sequencing technologies, combined with proteomic analysis, were applied to determine the diverse peptide toxins in venom of the Chinese bird spider Ornithoctonus huwena. In total, 626 toxin precursor sequences were retrieved from transcriptomic data. All toxin precursors clustered into 16 gene superfamilies, which included six novel superfamilies and six novel cysteine patterns. A surprisingly high number of hypermutations and fragment insertions/deletions were detected, which accounted for the majority of toxin gene sequences with low-level expression. These mutations contribute to the formation of diverse cysteine patterns and highly variable isoforms. Furthermore, intraspecific venom variability, in combination with variable transcripts and peptide processing, contributes to the hypervariability of toxins in venoms, and associated rapid and adaptive evolution of toxins for prey capture and defense.

  14. Revealing Assembly of a Pore-Forming Complex Using Single-Cell Kinetic Analysis and Modeling.

    Science.gov (United States)

    Bischofberger, Mirko; Iacovache, Ioan; Boss, Daniel; Naef, Felix; van der Goot, F Gisou; Molina, Nacho

    2016-04-12

    Many biological processes depend on the sequential assembly of protein complexes. However, studying the kinetics of such processes by direct methods is often not feasible. As an important class of such protein complexes, pore-forming toxins start their journey as soluble monomeric proteins, and oligomerize into transmembrane complexes to eventually form pores in the target cell membrane. Here, we monitored pore formation kinetics for the well-characterized bacterial pore-forming toxin aerolysin in single cells in real time to determine the lag times leading to the formation of the first functional pores per cell. Probabilistic modeling of these lag times revealed that one slow and seven equally fast rate-limiting reactions best explain the overall pore formation kinetics. The model predicted that monomer activation is the rate-limiting step for the entire pore formation process. We hypothesized that this could be through release of a propeptide and indeed found that peptide removal abolished these steps. This study illustrates how stochasticity in the kinetics of a complex process can be exploited to identify rate-limiting mechanisms underlying multistep biomolecular assembly pathways.

  15. Modelling of Yeast Mating Reveals Robustness Strategies for Cell-Cell Interactions.

    Directory of Open Access Journals (Sweden)

    Weitao Chen

    2016-07-01

    Full Text Available Mating of budding yeast cells is a model system for studying cell-cell interactions. Haploid yeast cells secrete mating pheromones that are sensed by the partner which responds by growing a mating projection toward the source. The two projections meet and fuse to form the diploid. Successful mating relies on precise coordination of dynamic extracellular signals, signaling pathways, and cell shape changes in a noisy background. It remains elusive how cells mate accurately and efficiently in a natural multi-cell environment. Here we present the first stochastic model of multiple mating cells whose morphologies are driven by pheromone gradients and intracellular signals. Our novel computational framework encompassed a moving boundary method for modeling both a-cells and α-cells and their cell shape changes, the extracellular diffusion of mating pheromones dynamically coupled with cell polarization, and both external and internal noise. Quantification of mating efficiency was developed and tested for different model parameters. Computer simulations revealed important robustness strategies for mating in the presence of noise. These strategies included the polarized secretion of pheromone, the presence of the α-factor protease Bar1, and the regulation of sensing sensitivity; all were consistent with data in the literature. In addition, we investigated mating discrimination, the ability of an a-cell to distinguish between α-cells either making or not making α-factor, and mating competition, in which multiple a-cells compete to mate with one α-cell. Our simulations were consistent with previous experimental results. Moreover, we performed a combination of simulations and experiments to estimate the diffusion rate of the pheromone a-factor. In summary, we constructed a framework for simulating yeast mating with multiple cells in a noisy environment, and used this framework to reproduce mating behaviors and to identify strategies for robust cell

  16. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

    Science.gov (United States)

    Potter, Paul K; Bowl, Michael R; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E; Simon, Michelle M; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V; Law, Gemma; MacLaren, Robert E; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H; Foster, Russell G; Jackson, Ian J; Peirson, Stuart N; Thakker, Rajesh V; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D M

    2016-08-18

    Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

  17. Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations.

    Directory of Open Access Journals (Sweden)

    Kirsi Kujala

    Full Text Available BACKGROUND: Induced pluripotent stem cells (iPSC provide means to study the pathophysiology of genetic disorders. Catecholaminergic polymorphic ventricular tachycardia (CPVT is a malignant inherited ion channel disorder predominantly caused by mutations in the cardiac ryanodine receptor (RyR2. In this study the cellular characteristics of CPVT are investigated and whether the electrophysiological features of this mutation can be mimicked using iPSC -derived cardiomyocytes (CM. METHODOLOGY/PRINCIPAL FINDINGS: Spontaneously beating CMs were differentiated from iPSCs derived from a CPVT patient carrying a P2328S mutation in RyR2 and from two healthy controls. Calcium (Ca(2+ cycling and electrophysiological properties were studied by Ca(2+ imaging and patch-clamp techniques. Monophasic action potential (MAP recordings and 24h-ECGs of CPVT-P2328S patients were analyzed for the presence of afterdepolarizations. We found defects in Ca(2+ cycling and electrophysiology in CPVT CMs, reflecting the cardiac phenotype observed in the patients. Catecholaminergic stress led to abnormal Ca(2+ signaling and induced arrhythmias in CPVT CMs. CPVT CMs also displayed reduced sarcoplasmic reticulum (SR Ca(2+ content, indicating leakage of Ca(2+ from the SR. Patch-clamp recordings of CPVT CMs revealed both delayed afterdepolarizations (DADs during spontaneous beating and in response to adrenaline and also early afterdepolarizations (EADs during spontaneous beating, recapitulating the changes seen in MAP and 24h-ECG recordings of patients carrying the same mutation. CONCLUSIONS/SIGNIFICANCE: This cell model shows aberrant Ca(2+ cycling characteristic of CPVT and in addition to DADs it displays EADs. This cell model for CPVT provides a platform to study basic pathology, to screen drugs, and to optimize drug therapy.

  18. Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current.

    Science.gov (United States)

    Schutte, Ryan J; Schutte, Soleil S; Algara, Jacqueline; Barragan, Eden V; Gilligan, Jeff; Staber, Cynthia; Savva, Yiannis A; Smith, Martin A; Reenan, Robert; O'Dowd, Diane K

    2014-08-15

    Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induced increase in sodium current activity and seizure phenotype. To determine whether different SCN1A mutations cause distinct phenotypes in Drosophila as they do in humans, this study focuses on a knock-in line carrying a mutation that causes a more severe seizure disorder termed Dravet syndrome (DS). Introduction of the DS SCN1A mutation (S1231R) into the Drosophila sodium channel gene para results in flies that exhibit spontaneous and heat-induced seizures with distinct characteristics and lower onset temperature than the GEFS+ flies. Electrophysiological studies of GABAergic interneurons in the brains of adult DS flies reveal, for the first time in an in vivo model system, that a missense DS mutation causes a constitutive and conditional reduction in sodium current activity and repetitive firing. In addition, feeding with the serotonin precursor 5-HTP suppresses heat-induced seizures in DS but not GEFS+ flies. The distinct alterations of sodium currents in DS and GEFS+ GABAergic interneurons demonstrate that both loss- and gain-of-function alterations in sodium currents are capable of causing reduced repetitive firing and seizure phenotypes. The mutation-specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS.

  19. Distributed Modeling Reveals the Ecohydrological Dynamics Linked with Woody Plant Encroachment in the Sonoran Desert

    Science.gov (United States)

    Pierini, N. A.; Vivoni, E. R.; Anderson, C.; Saripalli, S.; Robles-Morua, A.

    2012-12-01

    moisture and temperature distributions through comparisons of canopy and intercanopy sites. The field and remote sensing observations are then used in simulations using the TIN-based Real-time Integrated Basin Simulator (tRIBS) at high spatiotemporal resolutions over the two study years (2011-2012). Numerical experiments are designed to reveal the influence of the mesquite encroachment patterns on the watershed dynamics. Through the spatiotemporal analysis of model outputs, we identify how and when mesquite trees affect the spatial patterns of energy and water fluxes and their linkage to runoff production. As a result, the distributed model application provides a more complete understanding of the impact of woody encroachment on watershed-scale hydrologic patterns.

  20. Network modeling reveals prevalent negative regulatory relationships between signaling sectors in Arabidopsis immune signaling.

    Directory of Open Access Journals (Sweden)

    Masanao Sato

    Full Text Available Biological signaling processes may be mediated by complex networks in which network components and network sectors interact with each other in complex ways. Studies of complex networks benefit from approaches in which the roles of individual components are considered in the context of the network. The plant immune signaling network, which controls inducible responses to pathogen attack, is such a complex network. We studied the Arabidopsis immune signaling network upon challenge with a strain of the bacterial pathogen Pseudomonas syringae expressing the effector protein AvrRpt2 (Pto DC3000 AvrRpt2. This bacterial strain feeds multiple inputs into the signaling network, allowing many parts of the network to be activated at once. mRNA profiles for 571 immune response genes of 22 Arabidopsis immunity mutants and wild type were collected 6 hours after inoculation with Pto DC3000 AvrRpt2. The mRNA profiles were analyzed as detailed descriptions of changes in the network state resulting from the genetic perturbations. Regulatory relationships among the genes corresponding to the mutations were inferred by recursively applying a non-linear dimensionality reduction procedure to the mRNA profile data. The resulting static network model accurately predicted 23 of 25 regulatory relationships reported in the literature, suggesting that predictions of novel regulatory relationships are also accurate. The network model revealed two striking features: (i the components of the network are highly interconnected; and (ii negative regulatory relationships are common between signaling sectors. Complex regulatory relationships, including a novel negative regulatory relationship between the early microbe-associated molecular pattern-triggered signaling sectors and the salicylic acid sector, were further validated. We propose that prevalent negative regulatory relationships among the signaling sectors make the plant immune signaling network a "sector

  1. Studies Reveal Gene Flow Model of Endangered Plant

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ Shuhua shuibaizhi (Myricaria laxiflora), an endemic riparian plant in the Three Gorges Valley of the Yangtze River, is the only species in the genus Myricaria that grows in low-altitude regions along the Yangtze River. The other species of the genus are distributed in Tibet and neighboring regions.Over the past decades, scientists are puzzled at why the plant exists alone along the Yangtze while its cousins are suffering from the arid and frigid climate. And the researchers are anxious to know more about the plant because its natural habitat will be mostly plunged under water owing to the construction of the Three Gorges Dam.

  2. Integrated metabolic modelling reveals cell-type specific epigenetic control points of the macrophage metabolic network.

    Science.gov (United States)

    Pacheco, Maria Pires; John, Elisabeth; Kaoma, Tony; Heinäniemi, Merja; Nicot, Nathalie; Vallar, Laurent; Bueb, Jean-Luc; Sinkkonen, Lasse; Sauter, Thomas

    2015-10-19

    The reconstruction of context-specific metabolic models from easily and reliably measurable features such as transcriptomics data will be increasingly important in research and medicine. Current reconstruction methods suffer from high computational effort and arbitrary threshold setting. Moreover, understanding the underlying epigenetic regulation might allow the identification of putative intervention points within metabolic networks. Genes under high regulatory load from multiple enhancers or super-enhancers are known key genes for disease and cell identity. However, their role in regulation of metabolism and their placement within the metabolic networks has not been studied. Here we present FASTCORMICS, a fast and robust workflow for the creation of high-quality metabolic models from transcriptomics data. FASTCORMICS is devoid of arbitrary parameter settings and due to its low computational demand allows cross-validation assays. Applying FASTCORMICS, we have generated models for 63 primary human cell types from microarray data, revealing significant differences in their metabolic networks. To understand the cell type-specific regulation of the alternative metabolic pathways we built multiple models during differentiation of primary human monocytes to macrophages and performed ChIP-Seq experiments for histone H3 K27 acetylation (H3K27ac) to map the active enhancers in macrophages. Focusing on the metabolic genes under high regulatory load from multiple enhancers or super-enhancers, we found these genes to show the most cell type-restricted and abundant expression profiles within their respective pathways. Importantly, the high regulatory load genes are associated to reactions enriched for transport reactions and other pathway entry points, suggesting that they are critical regulatory control points for cell type-specific metabolism. By integrating metabolic modelling and epigenomic analysis we have identified high regulatory load as a common feature of metabolic

  3. GROUT HOPPER MODELING STUDY

    Energy Technology Data Exchange (ETDEWEB)

    Lee, S.

    2011-08-30

    The Saltstone facility has a grout hopper tank to provide agitator stirring of the Saltstone feed materials. The tank has about 300 gallon capacity to provide a larger working volume for the grout slurry to be held in case of a process upset, and it is equipped with a mechanical agitator, which is intended to keep the grout in motion and agitated so that it won't start to set up. The dry feeds and the salt solution are already mixed in the mixer prior to being transferred to the hopper tank. The hopper modeling study through this work will focus on fluid stirring and agitation, instead of traditional mixing in the literature, in order to keep the tank contents in motion during their residence time so that they will not be upset or solidified prior to transferring the grout to the Saltstone disposal facility. The primary objective of the work is to evaluate the flow performance for mechanical agitators to prevent vortex pull-through for an adequate stirring of the feed materials and to estimate an agitator speed which provides acceptable flow performance with a 45{sup o} pitched four-blade agitator. In addition, the power consumption required for the agitator operation was estimated. The modeling calculations were performed by taking two steps of the Computational Fluid Dynamics (CFD) modeling approach. As a first step, a simple single-stage agitator model with 45{sup o} pitched propeller blades was developed for the initial scoping analysis of the flow pattern behaviors for a range of different operating conditions. Based on the initial phase-1 results, the phase-2 model with a two-stage agitator was developed for the final performance evaluations. A series of sensitivity calculations for different designs of agitators and operating conditions have been performed to investigate the impact of key parameters on the grout hydraulic performance in a 300-gallon hopper tank. For the analysis, viscous shear was modeled by using the Bingham plastic approximation

  4. GROUT HOPPER MODELING STUDY

    Energy Technology Data Exchange (ETDEWEB)

    Lee, S.

    2011-08-30

    The Saltstone facility has a grout hopper tank to provide agitator stirring of the Saltstone feed materials. The tank has about 300 gallon capacity to provide a larger working volume for the grout slurry to be held in case of a process upset, and it is equipped with a mechanical agitator, which is intended to keep the grout in motion and agitated so that it won't start to set up. The dry feeds and the salt solution are already mixed in the mixer prior to being transferred to the hopper tank. The hopper modeling study through this work will focus on fluid stirring and agitation, instead of traditional mixing in the literature, in order to keep the tank contents in motion during their residence time so that they will not be upset or solidified prior to transferring the grout to the Saltstone disposal facility. The primary objective of the work is to evaluate the flow performance for mechanical agitators to prevent vortex pull-through for an adequate stirring of the feed materials and to estimate an agitator speed which provides acceptable flow performance with a 45{sup o} pitched four-blade agitator. In addition, the power consumption required for the agitator operation was estimated. The modeling calculations were performed by taking two steps of the Computational Fluid Dynamics (CFD) modeling approach. As a first step, a simple single-stage agitator model with 45{sup o} pitched propeller blades was developed for the initial scoping analysis of the flow pattern behaviors for a range of different operating conditions. Based on the initial phase-1 results, the phase-2 model with a two-stage agitator was developed for the final performance evaluations. A series of sensitivity calculations for different designs of agitators and operating conditions have been performed to investigate the impact of key parameters on the grout hydraulic performance in a 300-gallon hopper tank. For the analysis, viscous shear was modeled by using the Bingham plastic approximation

  5. Fourier decomposition of spatial localization errors reveals an idiotropic dominance of an internal model of gravity.

    Science.gov (United States)

    De Sá Teixeira, Nuno Alexandre

    2014-12-01

    Given its conspicuous nature, gravity has been acknowledged by several research lines as a prime factor in structuring the spatial perception of one's environment. One such line of enquiry has focused on errors in spatial localization aimed at the vanishing location of moving objects - it has been systematically reported that humans mislocalize spatial positions forward, in the direction of motion (representational momentum) and downward in the direction of gravity (representational gravity). Moreover, spatial localization errors were found to evolve dynamically with time in a pattern congruent with an anticipated trajectory (representational trajectory). The present study attempts to ascertain the degree to which vestibular information plays a role in these phenomena. Human observers performed a spatial localization task while tilted to varying degrees and referring to the vanishing locations of targets moving along several directions. A Fourier decomposition of the obtained spatial localization errors revealed that although spatial errors were increased "downward" mainly along the body's longitudinal axis (idiotropic dominance), the degree of misalignment between the latter and physical gravity modulated the time course of the localization responses. This pattern is surmised to reflect increased uncertainty about the internal model when faced with conflicting cues regarding the perceived "downward" direction.

  6. Hydrogen-Activation Mechanism of [Fe] Hydrogenase Revealed by Multi-Scale Modeling

    CERN Document Server

    Finkelmann, Arndt Robert; Reiher, Markus

    2014-01-01

    When investigating the mode of hydrogen activation by [Fe] hydrogenases, not only the chemical reactivity at the active site is of importance but also the large-scale conformational change between the so-called open and closed conformations, which leads to a special spatial arrangement of substrate and iron cofactor. To study H2 activation, a complete model of the solvated and cofactor-bound enzyme in complex with the substrate methenyl-H4MPT+ was constructed. Both the closed and open conformations were simulated with classical molecular dynamics on the 100 ns time scale. Quantum-mechanics/molecular-mechanics calculations on snapshots then revealed the features of the active site that enable the facile H2 cleavage. The hydroxyl group of the pyridinol ligand can easily be deprotonated. With the deprotonated hydroxyl group and the structural arrangement in the closed conformation, H2 coordinated to the Fe center is subject to an ionic and orbital push-pull effect and can be rapidly cleaved with a concerted hydr...

  7. Diffusion Modelling Reveals the Decision Making Processes Underlying Negative Judgement Bias in Rats.

    Directory of Open Access Journals (Sweden)

    Claire A Hales

    Full Text Available Human decision making is modified by emotional state. Rodents exhibit similar biases during interpretation of ambiguous cues that can be altered by affective state manipulations. In this study, the impact of negative affective state on judgement bias in rats was measured using an ambiguous-cue interpretation task. Acute treatment with an anxiogenic drug (FG7142, and chronic restraint stress and social isolation both induced a bias towards more negative interpretation of the ambiguous cue. The diffusion model was fit to behavioural data to allow further analysis of the underlying decision making processes. To uncover the way in which parameters vary together in relation to affective state manipulations, independent component analysis was conducted on rate of information accumulation and distances to decision threshold parameters for control data. Results from this analysis were applied to parameters from negative affective state manipulations. These projected components were compared to control components to reveal the changes in decision making processes that are due to affective state manipulations. Negative affective bias in rodents induced by either FG7142 or chronic stress is due to a combination of more negative interpretation of the ambiguous cue, reduced anticipation of the high reward and increased anticipation of the low reward.

  8. Diffusion Modelling Reveals the Decision Making Processes Underlying Negative Judgement Bias in Rats.

    Science.gov (United States)

    Hales, Claire A; Robinson, Emma S J; Houghton, Conor J

    2016-01-01

    Human decision making is modified by emotional state. Rodents exhibit similar biases during interpretation of ambiguous cues that can be altered by affective state manipulations. In this study, the impact of negative affective state on judgement bias in rats was measured using an ambiguous-cue interpretation task. Acute treatment with an anxiogenic drug (FG7142), and chronic restraint stress and social isolation both induced a bias towards more negative interpretation of the ambiguous cue. The diffusion model was fit to behavioural data to allow further analysis of the underlying decision making processes. To uncover the way in which parameters vary together in relation to affective state manipulations, independent component analysis was conducted on rate of information accumulation and distances to decision threshold parameters for control data. Results from this analysis were applied to parameters from negative affective state manipulations. These projected components were compared to control components to reveal the changes in decision making processes that are due to affective state manipulations. Negative affective bias in rodents induced by either FG7142 or chronic stress is due to a combination of more negative interpretation of the ambiguous cue, reduced anticipation of the high reward and increased anticipation of the low reward.

  9. Exome sequencing reveals a nebulin nonsense mutation in a dog model of nemaline myopathy.

    Science.gov (United States)

    Evans, Jacquelyn M; Cox, Melissa L; Huska, Jonathan; Li, Frank; Gaitero, Luis; Guo, Ling T; Casal, Margaret L; Granzier, Henk L; Shelton, G Diane; Clark, Leigh Anne

    2016-10-01

    Nemaline myopathy (NM) is a congenital muscle disorder associated with muscle weakness, hypotonia, and rod bodies in the skeletal muscle fibers. Mutations in 10 genes have been implicated in human NM, but spontaneous cases in dogs have not been genetically characterized. We identified a novel recessive myopathy in a family of line-bred American bulldogs (ABDs); rod bodies in muscle biopsies established this as NM. Using SNP profiles from the nuclear family, we evaluated inheritance patterns at candidate loci and prioritized TNNT1 and NEB for further investigation. Whole exome sequencing of the dam, two affected littermates, and an unaffected littermate revealed a nonsense mutation in NEB (g.52734272 C>A, S8042X). Whole tissue gel electrophoresis and western blots confirmed a lack of full-length NEB in affected tissues, suggesting nonsense-mediated decay. The pathogenic variant was absent from 120 dogs of 24 other breeds and 100 unrelated ABDs, suggesting that it occurred recently and may be private to the family. This study presents the first molecularly characterized large animal model of NM, which could provide new opportunities for therapeutic approaches.

  10. High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model.

    Directory of Open Access Journals (Sweden)

    Chiao-Ling Lo

    2016-08-01

    Full Text Available Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP. This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross resulted in small haplotype blocks (HB with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS, were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50% of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284 and intronic regions (169 with the least in exon's (4, suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a, excitatory receptors (Grin2a, Gria3, Grip1, neurotransmitters (Pomc, and synapses (Snap29. This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits.

  11. High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model.

    Science.gov (United States)

    Lo, Chiao-Ling; Lossie, Amy C; Liang, Tiebing; Liu, Yunlong; Xuei, Xiaoling; Lumeng, Lawrence; Zhou, Feng C; Muir, William M

    2016-08-01

    Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon's (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits.

  12. Structural Model of RNA Polymerase II Elongation Complex with Complete Transcription Bubble Reveals NTP Entry Routes.

    Directory of Open Access Journals (Sweden)

    Lu Zhang

    2015-07-01

    Full Text Available The RNA polymerase II (Pol II is a eukaryotic enzyme that catalyzes the synthesis of the messenger RNA using a DNA template. Despite numerous biochemical and biophysical studies, it remains elusive whether the "secondary channel" is the only route for NTP to reach the active site of the enzyme or if the "main channel" could be an alternative. On this regard, crystallographic structures of Pol II have been extremely useful to understand the structural basis of transcription, however, the conformation of the unpaired non-template DNA part of the full transcription bubble (TB is still unknown. Since diffusion routes of the nucleoside triphosphate (NTP substrate through the main channel might overlap with the TB region, gaining structural information of the full TB is critical for a complete understanding of Pol II transcription process. In this study, we have built a structural model of Pol II with a complete transcription bubble based on multiple sources of existing structural data and used Molecular Dynamics (MD simulations together with structural analysis to shed light on NTP entry pathways. Interestingly, we found that although both channels have enough space to allow NTP loading, the percentage of MD conformations containing enough space for NTP loading through the secondary channel is twice higher than that of the main channel. Further energetic study based on MD simulations with NTP loaded in the channels has revealed that the diffusion of the NTP through the main channel is greatly disfavored by electrostatic repulsion between the NTP and the highly negatively charged backbones of nucleotides in the non-template DNA strand. Taken together, our results suggest that the secondary channel is the major route for NTP entry during Pol II transcription.

  13. Structural Model of RNA Polymerase II Elongation Complex with Complete Transcription Bubble Reveals NTP Entry Routes.

    Science.gov (United States)

    Zhang, Lu; Silva, Daniel-Adriano; Pardo-Avila, Fátima; Wang, Dong; Huang, Xuhui

    2015-07-01

    The RNA polymerase II (Pol II) is a eukaryotic enzyme that catalyzes the synthesis of the messenger RNA using a DNA template. Despite numerous biochemical and biophysical studies, it remains elusive whether the "secondary channel" is the only route for NTP to reach the active site of the enzyme or if the "main channel" could be an alternative. On this regard, crystallographic structures of Pol II have been extremely useful to understand the structural basis of transcription, however, the conformation of the unpaired non-template DNA part of the full transcription bubble (TB) is still unknown. Since diffusion routes of the nucleoside triphosphate (NTP) substrate through the main channel might overlap with the TB region, gaining structural information of the full TB is critical for a complete understanding of Pol II transcription process. In this study, we have built a structural model of Pol II with a complete transcription bubble based on multiple sources of existing structural data and used Molecular Dynamics (MD) simulations together with structural analysis to shed light on NTP entry pathways. Interestingly, we found that although both channels have enough space to allow NTP loading, the percentage of MD conformations containing enough space for NTP loading through the secondary channel is twice higher than that of the main channel. Further energetic study based on MD simulations with NTP loaded in the channels has revealed that the diffusion of the NTP through the main channel is greatly disfavored by electrostatic repulsion between the NTP and the highly negatively charged backbones of nucleotides in the non-template DNA strand. Taken together, our results suggest that the secondary channel is the major route for NTP entry during Pol II transcription.

  14. Multiscale models of skeletal muscle reveal the complex effects of muscular dystrophy on tissue mechanics and damage susceptibility.

    Science.gov (United States)

    Virgilio, Kelley M; Martin, Kyle S; Peirce, Shayn M; Blemker, Silvia S

    2015-04-06

    Computational models have been increasingly used to study the tissue-level constitutive properties of muscle microstructure; however, these models were not created to study or incorporate the influence of disease-associated modifications in muscle. The purpose of this paper was to develop a novel multiscale muscle modelling framework to elucidate the relationship between microstructural disease adaptations and modifications in both mechanical properties of muscle and strain in the cell membrane. We used an agent-based model to randomly generate new muscle fibre geometries and mapped them into a finite-element model representing a cross section of a muscle fascicle. The framework enabled us to explore variability in the shape and arrangement of fibres, as well as to incorporate disease-related changes. We applied this method to reveal the trade-offs between mechanical properties and damage susceptibility in Duchenne muscular dystrophy (DMD). DMD is a fatal genetic disease caused by a lack of the transmembrane protein dystrophin, leading to muscle wasting and death due to cardiac or pulmonary complications. The most prevalent microstructural variations in DMD include: lack of transmembrane proteins, fibrosis, fatty infiltration and variation in fibre cross-sectional area. A parameter analysis of these variations and case study of DMD revealed that the nature of fibrosis and density of transmembrane proteins strongly affected the stiffness of the muscle and susceptibility to membrane damage.

  15. Disaggregate Traffic Mode Choice Model Based on Combination of Revealed and Stated Preference Data

    Institute of Scientific and Technical Information of China (English)

    JIAO Pengpeng; LU Huapu; YANG Lang

    2006-01-01

    The conventional traffic demand forecasting methods based on revealed preference (RP) data are not able to predict the modal split. Passengers' stated intentions are indispensable for modal split forecasting and evaluation of new traffic modes. This paper analyzed the biases and errors included in stated preference data, put forward the new stochastic utility functions, and proposed an unbiased disaggregate model and its approximate model based on the combination of RP and stated preference (SP) data, with analysis of the parameter estimation algorithm. The model was also used to forecast rail transit passenger volumes to the Beijing Capital International Airport and the shift ratios from current traffic modes to rail transit. Experimental results show that the model can greatly increase forecasting accuracy of the modal split ratio of current traffic modes and can accurately forecast the shift ratios from current modes to the new mode.

  16. Power-Law Modeling of Cancer Cell Fates Driven by Signaling Data to Reveal Drug Effects

    Science.gov (United States)

    Zhang, Fan; Wu, Min; Kwoh, Chee Keong; Zheng, Jie

    2016-01-01

    Extracellular signals are captured and transmitted by signaling proteins inside a cell. An important type of cellular responses to the signals is the cell fate decision, e.g., apoptosis. However, the underlying mechanisms of cell fate regulation are still unclear, thus comprehensive and detailed kinetic models are not yet available. Alternatively, data-driven models are promising to bridge signaling data with the phenotypic measurements of cell fates. The traditional linear model for data-driven modeling of signaling pathways has its limitations because it assumes that the a cell fate is proportional to the activities of signaling proteins, which is unlikely in the complex biological systems. Therefore, we propose a power-law model to relate the activities of all the measured signaling proteins to the probabilities of cell fates. In our experiments, we compared our nonlinear power-law model with the linear model on three cancer datasets with phosphoproteomics and cell fate measurements, which demonstrated that the nonlinear model has superior performance on cell fates prediction. By in silico simulation of virtual protein knock-down, the proposed model is able to reveal drug effects which can complement traditional approaches such as binding affinity analysis. Moreover, our model is able to capture cell line specific information to distinguish one cell line from another in cell fate prediction. Our results show that the power-law data-driven model is able to perform better in cell fate prediction and provide more insights into the signaling pathways for cancer cell fates than the linear model. PMID:27764199

  17. Storm-time Distortion of the Near Magnetosphere as Revealed by Data-Based Models

    Science.gov (United States)

    Sitnov, M. I.; Tsyganenko, N. A.

    2007-05-01

    An overview will be given of recent progress in the empirical modeling of the geomagnetic field, focused on the storm-time reconfiguration of the inner magnetosphere. Data-based modeling still remains one of primary techniques for representing and forecasting the structure and dynamics of the inner magnetosphere, an extremely hard task for the first-principle approaches. The storm-time evolution of the inner geomagnetic field was quantitatively modeled by Tsyganenko, Singer, and Kasper [2003], where it was shown for the first time that a global dramatic distortion of the magnetic field during strong storms could penetrate as deep as to only R ~ 3RE. The dynamical aspects of storm-time magnetic field distortions were further elaborated in the TS05 model [Tsyganenko and Sitnov, 2005]. It was shown, in particular, that the magnetospheric response to the solar wind loading is drastically different for major current systems (ring, tail, and field-aligned currents), with the fastest response for field-aligned currents and the slowest for the symmetrical ring current. Finally, to resolve the complex spatial structure of storm-time magnetic field distortions Tsyganenko and Sitnov [2007] elaborated a new model with a high-resolution extensible approximation for the field of equatorial currents combined with a flexible field-aligned current module. The new model was fitted to a new database of space magnetometer data from Geotail, Polar, Cluster, IMP-8, and Goes-8,-9,-10, and -12, as well as concurrent solar wind and IMF data, spanning more than a decade (1995-2005). The new high-resolution magnetic field modeling revealed many interesting effects that were conjectured earlier based on other (largely indirect) methods, such as the pile-up of the magnetic flux near the magnetopause for northward IMF and the strong erosion/depression of the dayside field during intervals of southward IMF. It also revealed a dramatic difference between the global configurations of equatorial

  18. Climate Sensitivity of Franz-Josef Glacier, New Zealand, as revealed by numerical modelling

    NARCIS (Netherlands)

    Oerlemans, J.

    1997-01-01

    The sensitivity of Franz Josef Glacier is studied with a numerical ice-flow model. The model calculates ice mass flux along a central flow line and deals with the three-dimensional geometry in a parameterized way. Forcing is provided through a mass balance model that generates specific balance from

  19. {sup 1}H NMR-based metabolic profiling reveals inherent biological variation in yeast and nematode model systems

    Energy Technology Data Exchange (ETDEWEB)

    Szeto, Samuel S. W.; Reinke, Stacey N.; Lemire, Bernard D., E-mail: bernard.lemire@ualberta.ca [University of Alberta, Department of Biochemistry, School of Molecular and Systems Medicine (Canada)

    2011-04-15

    The application of metabolomics to human and animal model systems is poised to provide great insight into our understanding of disease etiology and the metabolic changes that are associated with these conditions. However, metabolomic studies have also revealed that there is significant, inherent biological variation in human samples and even in samples from animal model systems where the animals are housed under carefully controlled conditions. This inherent biological variability is an important consideration for all metabolomics analyses. In this study, we examined the biological variation in {sup 1}H NMR-based metabolic profiling of two model systems, the yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans. Using relative standard deviations (RSD) as a measure of variability, our results reveal that both model systems have significant amounts of biological variation. The C. elegans metabolome possesses greater metabolic variance with average RSD values of 29 and 39%, depending on the food source that was used. The S. cerevisiae exometabolome RSD values ranged from 8% to 12% for the four strains examined. We also determined whether biological variation occurs between pairs of phenotypically identical yeast strains. Multivariate statistical analysis allowed us to discriminate between pair members based on their metabolic phenotypes. Our results highlight the variability of the metabolome that exists even for less complex model systems cultured under defined conditions. We also highlight the efficacy of metabolic profiling for defining these subtle metabolic alterations.

  20. Genome-Scale Model Reveals Metabolic Basis of Biomass Partitioning in a Model Diatom.

    Directory of Open Access Journals (Sweden)

    Jennifer Levering

    Full Text Available Diatoms are eukaryotic microalgae that contain genes from various sources, including bacteria and the secondary endosymbiotic host. Due to this unique combination of genes, diatoms are taxonomically and functionally distinct from other algae and vascular plants and confer novel metabolic capabilities. Based on the genome annotation, we performed a genome-scale metabolic network reconstruction for the marine diatom Phaeodactylum tricornutum. Due to their endosymbiotic origin, diatoms possess a complex chloroplast structure which complicates the prediction of subcellular protein localization. Based on previous work we implemented a pipeline that exploits a series of bioinformatics tools to predict protein localization. The manually curated reconstructed metabolic network iLB1027_lipid accounts for 1,027 genes associated with 4,456 reactions and 2,172 metabolites distributed across six compartments. To constrain the genome-scale model, we determined the organism specific biomass composition in terms of lipids, carbohydrates, and proteins using Fourier transform infrared spectrometry. Our simulations indicate the presence of a yet unknown glutamine-ornithine shunt that could be used to transfer reducing equivalents generated by photosynthesis to the mitochondria. The model reflects the known biochemical composition of P. tricornutum in defined culture conditions and enables metabolic engineering strategies to improve the use of P. tricornutum for biotechnological applications.

  1. Genome-Scale Model Reveals Metabolic Basis of Biomass Partitioning in a Model Diatom.

    Science.gov (United States)

    Levering, Jennifer; Broddrick, Jared; Dupont, Christopher L; Peers, Graham; Beeri, Karen; Mayers, Joshua; Gallina, Alessandra A; Allen, Andrew E; Palsson, Bernhard O; Zengler, Karsten

    2016-01-01

    Diatoms are eukaryotic microalgae that contain genes from various sources, including bacteria and the secondary endosymbiotic host. Due to this unique combination of genes, diatoms are taxonomically and functionally distinct from other algae and vascular plants and confer novel metabolic capabilities. Based on the genome annotation, we performed a genome-scale metabolic network reconstruction for the marine diatom Phaeodactylum tricornutum. Due to their endosymbiotic origin, diatoms possess a complex chloroplast structure which complicates the prediction of subcellular protein localization. Based on previous work we implemented a pipeline that exploits a series of bioinformatics tools to predict protein localization. The manually curated reconstructed metabolic network iLB1027_lipid accounts for 1,027 genes associated with 4,456 reactions and 2,172 metabolites distributed across six compartments. To constrain the genome-scale model, we determined the organism specific biomass composition in terms of lipids, carbohydrates, and proteins using Fourier transform infrared spectrometry. Our simulations indicate the presence of a yet unknown glutamine-ornithine shunt that could be used to transfer reducing equivalents generated by photosynthesis to the mitochondria. The model reflects the known biochemical composition of P. tricornutum in defined culture conditions and enables metabolic engineering strategies to improve the use of P. tricornutum for biotechnological applications.

  2. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation.

    Science.gov (United States)

    Xue, Jia; Schmidt, Susanne V; Sander, Jil; Draffehn, Astrid; Krebs, Wolfgang; Quester, Inga; De Nardo, Dominic; Gohel, Trupti D; Emde, Martina; Schmidleithner, Lisa; Ganesan, Hariharasudan; Nino-Castro, Andrea; Mallmann, Michael R; Labzin, Larisa; Theis, Heidi; Kraut, Michael; Beyer, Marc; Latz, Eicke; Freeman, Tom C; Ulas, Thomas; Schultze, Joachim L

    2014-02-20

    Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.

  3. Molecular Biological and Biochemical Studies Reveal New Pathways Important for Cotton Fiber Development

    Institute of Scientific and Technical Information of China (English)

    Yu Xu; Hong-Bin Li; Yu-Xian Zhu

    2007-01-01

    As one of the longest single-celled seed trichomes, fibers provide an excellent model for studying fundamental biological processes such as cell differentiation, cell expansion, and cell wall biosynthesis. In this review, we summarize recent progress in cotton functional genomic studies that characterize the dynamic changes in the transcriptomes of fiber cells. Extensive expression profilings of cotton fiber transcriptomes have provided comprehensive information, as quite a number of transcription factors and enzyme-coding genes have been shown to express preferentially during the fiber elongation period. Biosynthesis of the plant hormone ethylene is found significantly upregulated during the fiber growth period as revealed by both microarray analysis and by biochemical and physiological studies. It is suggested that genetic engineering of the ethylene pathway may improve the quality and the productivity of cotton lint. Many metabolic pathways, such as biosynthesis of celiulose and matrix polysaccharides are preferentially expressed in actively growing fiber cells. Five gene families, including proline-rich proteins (PRP), arabinogalactan proteins (AGP), expansins, tubulins and lipid transfer proteins (LTP) are activated during early fiber development,indicating that they may also be needed for cell elongation. In conclusion, we identify a few areas of future research for cotton functional genomic studies.

  4. Probabilistic Inference: Task Dependency and Individual Differences of Probability Weighting Revealed by Hierarchical Bayesian Modeling.

    Science.gov (United States)

    Boos, Moritz; Seer, Caroline; Lange, Florian; Kopp, Bruno

    2016-01-01

    Cognitive determinants of probabilistic inference were examined using hierarchical Bayesian modeling techniques. A classic urn-ball paradigm served as experimental strategy, involving a factorial two (prior probabilities) by two (likelihoods) design. Five computational models of cognitive processes were compared with the observed behavior. Parameter-free Bayesian posterior probabilities and parameter-free base rate neglect provided inadequate models of probabilistic inference. The introduction of distorted subjective probabilities yielded more robust and generalizable results. A general class of (inverted) S-shaped probability weighting functions had been proposed; however, the possibility of large differences in probability distortions not only across experimental conditions, but also across individuals, seems critical for the model's success. It also seems advantageous to consider individual differences in parameters of probability weighting as being sampled from weakly informative prior distributions of individual parameter values. Thus, the results from hierarchical Bayesian modeling converge with previous results in revealing that probability weighting parameters show considerable task dependency and individual differences. Methodologically, this work exemplifies the usefulness of hierarchical Bayesian modeling techniques for cognitive psychology. Theoretically, human probabilistic inference might be best described as the application of individualized strategic policies for Bayesian belief revision.

  5. Data-driven modeling of sleep EEG and EOG reveals characteristics indicative of pre-Parkinson's and Parkinson's disease

    DEFF Research Database (Denmark)

    Christensen, Julie Anja Engelhard; Zoetmulder, Marielle; Koch, Henriette

    2014-01-01

    classifying iRBD/PD patients. Comparison with existing method: The topics showed visual accordance with the manually scored sleep stages, and the features revealed sleep characteristics containing information indicative of neurodegeneration. Conclusions: This study suggests that the amount of N3......Background: Manual scoring of sleep relies on identifying certain characteristics in polysomnograph (PSG) signals. However, these characteristics are disrupted in patients with neurodegenerative diseases. New method: This study evaluates sleep using a topic modeling and unsupervised learning...... approach to identify sleep topics directly from electroencephalography (EEG) and electrooculography (EOG). PSG data from control subjects were used to develop an EOG and an EEG topic model. The models were applied to PSG data from 23 control subjects, 25 patients with periodic leg movements (PLMs), 31...

  6. Probabilistic inference: Task dependency and individual differences of probability weighting revealed by hierarchical Bayesian modelling

    Directory of Open Access Journals (Sweden)

    Moritz eBoos

    2016-05-01

    Full Text Available Cognitive determinants of probabilistic inference were examined using hierarchical Bayesian modelling techniques. A classic urn-ball paradigm served as experimental strategy, involving a factorial two (prior probabilities by two (likelihoods design. Five computational models of cognitive processes were compared with the observed behaviour. Parameter-free Bayesian posterior probabilities and parameter-free base rate neglect provided inadequate models of probabilistic inference. The introduction of distorted subjective probabilities yielded more robust and generalizable results. A general class of (inverted S-shaped probability weighting functions had been proposed; however, the possibility of large differences in probability distortions not only across experimental conditions, but also across individuals, seems critical for the model’s success. It also seems advantageous to consider individual differences in parameters of probability weighting as being sampled from weakly informative prior distributions of individual parameter values. Thus, the results from hierarchical Bayesian modelling converge with previous results in revealing that probability weighting parameters show considerable task dependency and individual differences. Methodologically, this work exemplifies the usefulness of hierarchical Bayesian modelling techniques for cognitive psychology. Theoretically, human probabilistic inference might be best described as the application of individualized strategic policies for Bayesian belief revision.

  7. Valuing snorkeling visits to the Florida Keys with stated and revealed preference models.

    Science.gov (United States)

    Park, Timothy; Bowker, J M; Leeworthy, Vernon R

    2002-07-01

    Coastal coral reefs, especially in the Florida Keys, are declining at a disturbing rate. Marine ecologists and reef scientists have emphasized the importance of establishing nonmarket values of coral reefs to assess the cost effectiveness of coral reef management and remediation programs. The purpose of this paper is to develop a travel cost-contingent valuation model of demand for trips to the Florida Keys focusing on willingness to pay (WTP) to preserve the current water quality and health of the coral reefs. The stated and revealed preference models allow the marginal valuation of recreationists to adjust depending on current and planned trip commitments in valuing nonmarginal policy changes in recreational opportunities. The integrated model incorporates key factors for establishing baseline amenity values for tourist dive sites, including perceptions of reef quality and dive conditions, the role of substitute sites, and the quality and availability of tourist facilities and recreation opportunities. The travel cost and WTP model differ in identifying critical variables and provide insight into the adjustment of trip decisions across alternative destination sites and the valuation of trips. In contrast to the travel cost model, a measure of the availability of substitute sites and total recreation activities does not have a significant impact on WTP valuations reported by snorkelers. Snorkelers engage in a relatively focused set of activities, suggesting that these recreationists may not shift expenditures to other sites or other recreation activities in the Florida Keys when confronted with increased access costs for the snorkeling experience.

  8. Mechanical models of sandfish locomotion reveal principles of high performance subsurface sand-swimming

    Science.gov (United States)

    Maladen, Ryan D.; Ding, Yang; Umbanhowar, Paul B.; Kamor, Adam; Goldman, Daniel I.

    2011-01-01

    We integrate biological experiment, empirical theory, numerical simulation and a physical model to reveal principles of undulatory locomotion in granular media. High-speed X-ray imaging of the sandfish lizard, Scincus scincus, in 3 mm glass particles shows that it swims within the medium without using its limbs by propagating a single-period travelling sinusoidal wave down its body, resulting in a wave efficiency, η, the ratio of its average forward speed to the wave speed, of approximately 0.5. A resistive force theory (RFT) that balances granular thrust and drag forces along the body predicts η close to the observed value. We test this prediction against two other more detailed modelling approaches: a numerical model of the sandfish coupled to a discrete particle simulation of the granular medium, and an undulatory robot that swims within granular media. Using these models and analytical solutions of the RFT, we vary the ratio of undulation amplitude to wavelength (A/λ) and demonstrate an optimal condition for sand-swimming, which for a given A results from the competition between η and λ. The RFT, in agreement with the simulated and physical models, predicts that for a single-period sinusoidal wave, maximal speed occurs for A/λ ≈ 0.2, the same kinematics used by the sandfish. PMID:21378020

  9. Climate model biases in seasonally of continental water storage revealed by satellite gravimetry

    Science.gov (United States)

    Swenson, S.C.; Milly, P.C.D.

    2006-01-01

    Satellite gravimetric observations of monthly changes in continental water storage are compared with outputs from five climate models. All models qualitatively reproduce the global pattern of annual storage amplitude, and the seasonal cycle of global average storage is reproduced well, consistent with earlier studies. However, global average agreements mask systematic model biases in low latitudes. Seasonal extrema of low-latitude, hemispheric storage generally occur too early in the models, and model-specific errors in amplitude of the low-latitude annual variations are substantial. These errors are potentially explicable in terms of neglected or suboptimally parameterized water stores in the land models and precipitation biases in the climate models. Copyright 2006 by the American Geophysical Union.

  10. The Effects of Revealed Information on Catastrophe Loss Projection Models' Characterization of Risk: Damage Vulnerability Evidence from Florida.

    Science.gov (United States)

    Karl, J Bradley; Medders, Lorilee A; Maroney, Patrick F

    2016-06-01

    We examine whether the risk characterization estimated by catastrophic loss projection models is sensitive to the revelation of new information regarding risk type. We use commercial loss projection models from two widely employed modeling firms to estimate the expected hurricane losses of Florida Atlantic University's building stock, both including and excluding secondary information regarding hurricane mitigation features that influence damage vulnerability. We then compare the results of the models without and with this revealed information and find that the revelation of additional, secondary information influences modeled losses for the windstorm-exposed university building stock, primarily evidenced by meaningful percent differences in the loss exceedance output indicated after secondary modifiers are incorporated in the analysis. Secondary risk characteristics for the data set studied appear to have substantially greater impact on probable maximum loss estimates than on average annual loss estimates. While it may be intuitively expected for catastrophe models to indicate that secondary risk characteristics hold value for reducing modeled losses, the finding that the primary value of secondary risk characteristics is in reduction of losses in the "tail" (low probability, high severity) events is less intuitive, and therefore especially interesting. Further, we address the benefit-cost tradeoffs that commercial entities must consider when deciding whether to undergo the data collection necessary to include secondary information in modeling. Although we assert the long-term benefit-cost tradeoff is positive for virtually every entity, we acknowledge short-term disincentives to such an effort. © 2015 Society for Risk Analysis.

  11. A multi-scale model of hepcidin promoter regulation reveals factors controlling systemic iron homeostasis.

    Directory of Open Access Journals (Sweden)

    Guillem Casanovas

    2014-01-01

    Full Text Available Systemic iron homeostasis involves a negative feedback circuit in which the expression level of the peptide hormone hepcidin depends on and controls the iron blood levels. Hepcidin expression is regulated by the BMP6/SMAD and IL6/STAT signaling cascades. Deregulation of either pathway causes iron-related diseases such as hemochromatosis or anemia of inflammation. We quantitatively analyzed how BMP6 and IL6 control hepcidin expression. Transcription factor (TF phosphorylation and reporter gene expression were measured under co-stimulation conditions, and the promoter was perturbed by mutagenesis. Using mathematical modeling, we systematically analyzed potential mechanisms of cooperative and competitive promoter regulation by the transcription factors, and experimentally validated the model predictions. Our results reveal that hepcidin cross-regulation primarily occurs by combinatorial transcription factor binding to the promoter, whereas signaling crosstalk is insignificant. We find that the presence of two BMP-responsive elements enhances the steepness of the promoter response towards the iron-sensing BMP signaling axis, which promotes iron homeostasis in vivo. IL6 co-stimulation reduces the promoter sensitivity towards the BMP signal, because the SMAD and STAT transcription factors compete for recruiting RNA polymerase to the transcription start site. This may explain why inflammatory signals disturb iron homeostasis in anemia of inflammation. Taken together, our results reveal why the iron homeostasis circuit is sensitive to perturbations implicated in disease.

  12. Non-parametric Bayesian graph models reveal community structure in resting state fMRI

    DEFF Research Database (Denmark)

    Andersen, Kasper Winther; Madsen, Kristoffer H.; Siebner, Hartwig Roman

    2014-01-01

    Modeling of resting state functional magnetic resonance imaging (rs-fMRI) data using network models is of increasing interest. It is often desirable to group nodes into clusters to interpret the communication patterns between nodes. In this study we consider three different nonparametric Bayesian...

  13. Seeing the forest and the trees: multilevel models reveal both species and community patterns

    Science.gov (United States)

    Michelle M. Jackson; Monica G. Turner; Scott M. Pearson; Anthony R. Ives

    2012-01-01

    Studies designed to understand species distributions and community assemblages typically use separate analytical approaches (e.g., logistic regression and ordination) to model the distribution of individual species and to relate community composition to environmental variation. Multilevel models (MLMs) offer a promising strategy for integrating species and community-...

  14. Gene set based integrated data analysis reveals phenotypic differences in a brain cancer model.

    Directory of Open Access Journals (Sweden)

    Kjell Petersen

    Full Text Available A key challenge in the data analysis of biological high-throughput experiments is to handle the often low number of samples in the experiments compared to the number of biomolecules that are simultaneously measured. Combining experimental data using independent technologies to illuminate the same biological trends, as well as complementing each other in a larger perspective, is one natural way to overcome this challenge. In this work we investigated if integrating proteomics and transcriptomics data from a brain cancer animal model using gene set based analysis methodology, could enhance the biological interpretation of the data relative to more traditional analysis of the two datasets individually. The brain cancer model used is based on serial passaging of transplanted human brain tumor material (glioblastoma--GBM through several generations in rats. These serial transplantations lead over time to genotypic and phenotypic changes in the tumors and represent a medically relevant model with a rare access to samples and where consequent analyses of individual datasets have revealed relatively few significant findings on their own. We found that the integrated analysis both performed better in terms of significance measure of its findings compared to individual analyses, as well as providing independent verification of the individual results. Thus a better context for overall biological interpretation of the data can be achieved.

  15. Molecular tools and bumble bees: revealing hidden details of ecology and evolution in a model system

    Science.gov (United States)

    Bumble bees are a longstanding model system for studies on behavior, ecology, and evolution, due to their well-studied social lifestyle, invaluable roles as both wild and managed pollinators, and their ubiquity and diversity across temperate ecosystems. Yet despite their importance, many aspects of ...

  16. PhyloChip microarray analysis reveals altered gastrointestinal microbial communities in a rat model of colonic hypersensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, T.A.; Holmes, S.; Alekseyenko, A.V.; Shenoy, M.; DeSantis, T.; Wu, C.H.; Andersen, G.L.; Winston, J.; Sonnenburg, J.; Pasricha, P.J.; Spormann, A.

    2010-12-01

    Irritable bowel syndrome (IBS) is a chronic, episodic gastrointestinal disorder that is prevalent in a significant fraction of western human populations; and changes in the microbiota of the large bowel have been implicated in the pathology of the disease. Using a novel comprehensive, high-density DNA microarray (PhyloChip) we performed a phylogenetic analysis of the microbial community of the large bowel in a rat model in which intracolonic acetic acid in neonates was used to induce long lasting colonic hypersensitivity and decreased stool water content and frequency, representing the equivalent of human constipation-predominant IBS. Our results revealed a significantly increased compositional difference in the microbial communities in rats with neonatal irritation as compared with controls. Even more striking was the dramatic change in the ratio of Firmicutes relative to Bacteroidetes, where neonatally irritated rats were enriched more with Bacteroidetes and also contained a different composition of species within this phylum. Our study also revealed differences at the level of bacterial families and species. The PhyloChip is a useful and convenient method to study enteric microflora. Further, this rat model system may be a useful experimental platform to study the causes and consequences of changes in microbial community composition associated with IBS.

  17. An atomic model of HIV-1 capsid-SP1 reveals structures regulating assembly and maturation.

    Science.gov (United States)

    Schur, Florian K M; Obr, Martin; Hagen, Wim J H; Wan, William; Jakobi, Arjen J; Kirkpatrick, Joanna M; Sachse, Carsten; Kräusslich, Hans-Georg; Briggs, John A G

    2016-07-29

    Immature HIV-1 assembles at and buds from the plasma membrane before proteolytic cleavage of the viral Gag polyprotein induces structural maturation. Maturation can be blocked by maturation inhibitors (MIs), thereby abolishing infectivity. The CA (capsid) and SP1 (spacer peptide 1) region of Gag is the key regulator of assembly and maturation and is the target of MIs. We applied optimized cryo-electron tomography and subtomogram averaging to resolve this region within assembled immature HIV-1 particles at 3.9 angstrom resolution and built an atomic model. The structure reveals a network of intra- and intermolecular interactions mediating immature HIV-1 assembly. The proteolytic cleavage site between CA and SP1 is inaccessible to protease. We suggest that MIs prevent CA-SP1 cleavage by stabilizing the structure, and MI resistance develops by destabilizing CA-SP1.

  18. Revealing topographic lineaments through IHS enhancement of DEM data. [Digital Elevation Model

    Science.gov (United States)

    Murdock, Gary

    1990-01-01

    Intensity-hue-saturation (IHS) processing of slope (dip), aspect (dip direction), and elevation to reveal subtle topographic lineaments which may not be obvious in the unprocessed data are used to enhance digital elevation model (DEM) data from northwestern Nevada. This IHS method of lineament identification was applied to a mosiac of 12 square degrees using a Cray Y-MP8/864. Square arrays from 3 x 3 to 31 x 31 points were tested as well as several different slope enhancements. When relatively few points are used to fit the plane, lineaments of various lengths are observed and a mechanism for lineament classification is described. An area encompassing the gold deposits of the Carlin trend and including the Rain in the southeast to Midas in the northwest is investigated in greater detail. The orientation and density of lineaments may be determined on the gently sloping pediment surface as well as in the more steeply sloping ranges.

  19. Dynamics between cancer cell subpopulations reveals a model coordinating with both hierarchical and stochastic concepts.

    Directory of Open Access Journals (Sweden)

    Weikang Wang

    Full Text Available Tumors are often heterogeneous in which tumor cells of different phenotypes have distinct properties. For scientific and clinical interests, it is of fundamental importance to understand their properties and the dynamic variations among different phenotypes, specifically under radio- and/or chemo-therapy. Currently there are two controversial models describing tumor heterogeneity, the cancer stem cell (CSC model and the stochastic model. To clarify the controversy, we measured probabilities of different division types and transitions of cells via in situ immunofluorescence. Based on the experiment data, we constructed a model that combines the CSC with the stochastic concepts, showing the existence of both distinctive CSC subpopulations and the stochastic transitions from NSCCs to CSCs. The results showed that the dynamic variations between CSCs and non-stem cancer cells (NSCCs can be simulated with the model. Further studies also showed that the model can be used to describe the dynamics of the two subpopulations after radiation treatment. More importantly, analysis demonstrated that the experimental detectable equilibrium CSC proportion can be achieved only when the stochastic transitions from NSCCs to CSCs occur, indicating that tumor heterogeneity may exist in a model coordinating with both the CSC and the stochastic concepts. The mathematic model based on experimental parameters may contribute to a better understanding of the tumor heterogeneity, and provide references on the dynamics of CSC subpopulation during radiotherapy.

  20. Stochastic kinetic model of two component system signalling reveals all-or-none, graded and mixed mode stochastic switching responses.

    Science.gov (United States)

    Kierzek, Andrzej M; Zhou, Lu; Wanner, Barry L

    2010-03-01

    Two-component systems (TCSs) are prevalent signal transduction systems in bacteria that control innumerable adaptive responses to environmental cues and host-pathogen interactions. We constructed a detailed stochastic kinetic model of two component signalling based on published data. Our model has been validated with flow cytometry data and used to examine reporter gene expression in response to extracellular signal strength. The model shows that, depending on the actual kinetic parameters, TCSs exhibit all-or-none, graded or mixed mode responses. In accordance with other studies, positively autoregulated TCSs exhibit all-or-none responses. Unexpectedly, our model revealed that TCSs lacking a positive feedback loop exhibit not only graded but also mixed mode responses, in which variation of the signal strength alters the level of gene expression in induced cells while the regulated gene continues to be expressed at the basal level in a substantial fraction of cells. The graded response of the TCS changes to mixed mode response by an increase of the translation initiation rate of the histidine kinase. Thus, a TCS is an evolvable design pattern capable of implementing deterministic regulation and stochastic switches associated with both graded and threshold responses. This has implications for understanding the emergence of population diversity in pathogenic bacteria and the design of genetic circuits in synthetic biology applications. The model is available in systems biology markup language (SBML) and systems biology graphical notation (SBGN) formats and can be used as a component of large-scale biochemical reaction network models.

  1. Reporting guidelines for modelling studies

    Directory of Open Access Journals (Sweden)

    Bennett Carol

    2012-11-01

    Full Text Available Abstract Background Modelling studies are used widely to help inform decisions about health care and policy and their use is increasing. However, in order for modelling to gain strength as a tool for health policy, it is critical that key model factors are transparent so that users of models can have a clear understanding of the model and its limitations.Reporting guidelines are evidence-based tools that specify minimum criteria for authors to report their research such that readers can both critically appraise and interpret study findings. This study was conducted to determine whether there is an unmet need for population modelling reporting guidelines. Methods We conducted a review of the literature to identify: 1 guidance for reporting population modelling studies; and, 2 evidence on the quality of reporting of population modelling studies. Guidance for reporting was analysed using a thematic approach and the data was summarised as frequencies. Evidence on the quality of reporting was reviewed and summarized descriptively. Results There were no guidelines that specifically addressed the reporting of population modelling studies. We identified a number of reporting guidelines for economic evaluation studies, some of which had sections that were relevant population modelling studies. Amongst seven relevant records, we identified 69 quality criteria that have distinct reporting characteristics. We identified two papers that addressed reporting practices of modelling studies. Overall, with the exception of describing the data used for calibration, there was little consistency in reporting. Conclusions While numerous guidelines exist for developing and evaluating health technology assessment and economic evaluation models, which by extension could be applicable to population modelling studies, there is variation in their comprehensiveness and in the consistency of reporting these methods. Population modelling studies may be an area which would

  2. STUDYING A CHAOTIC SPIKING NEURAL MODEL

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    Mohammad Alhawarat

    2013-09-01

    Full Text Available Dynamics of a chaotic spiking neuron model are being studied mathematically and experimentally. The Nonlinear Dynamic State neuron (NDS is analysed to further understand the model and improve it. Chaos has many interesting properties such as sensitivity to initial conditions, space filling, control and synchronization. As suggested by biologists, these properties may be exploited and play vital role in carrying out computational tasks in human brain. The NDS model has some limitations; in thus paper the model is investigated to overcome some of these limitations in order to enhance the model. Therefore, the model’s parameters are tuned and the resulted dynamics are studied. Also, the discretization method of the model is considered. Moreover, a mathematical analysis is carried out to reveal the underlying dynamics of the model after tuning of its parameters. The results of the aforementioned methods revealed some facts regarding the NDS attractor and suggest the stabilization of a large number of unstable periodic orbits (UPOs which might correspond to memories in phase space.

  3. Local-scale models reveal ecological niche variability in amphibian and reptile communities from two contrasting biogeographic regions

    Directory of Open Access Journals (Sweden)

    Alberto Muñoz

    2016-10-01

    Full Text Available Ecological Niche Models (ENMs are widely used to describe how environmental factors influence species distribution. Modelling at a local scale, compared to a large scale within a high environmental gradient, can improve our understanding of ecological species niches. The main goal of this study is to assess and compare the contribution of environmental variables to amphibian and reptile ENMs in two Spanish national parks located in contrasting biogeographic regions, i.e., the Mediterranean and the Atlantic area. The ENMs were built with maximum entropy modelling using 11 environmental variables in each territory. The contributions of these variables to the models were analysed and classified using various statistical procedures (Mann–Whitney U tests, Principal Components Analysis and General Linear Models. Distance to the hydrological network was consistently the most relevant variable for both parks and taxonomic classes. Topographic variables (i.e., slope and altitude were the second most predictive variables, followed by climatic variables. Differences in variable contribution were observed between parks and taxonomic classes. Variables related to water availability had the larger contribution to the models in the Mediterranean park, while topography variables were decisive in the Atlantic park. Specific response curves to environmental variables were in accordance with the biogeographic affinity of species (Mediterranean and non-Mediterranean species and taxonomy (amphibians and reptiles. Interestingly, these results were observed for species located in both parks, particularly those situated at their range limits. Our findings show that ecological niche models built at local scale reveal differences in habitat preferences within a wide environmental gradient. Therefore, modelling at local scales rather than assuming large-scale models could be preferable for the establishment of conservation strategies for herptile species in natural

  4. Adiponectin fine-tuning of liver regeneration dynamics revealed through cellular network modeling.

    Science.gov (United States)

    Correnti, Jason M; Cook, Daniel; Aksamitiene, Edita; Swarup, Aditi; Ogunnaike, Babatunde; Vadigepalli, Rajanikanth; Hoek, Jan B

    2014-11-10

    Following partial hepatectomy, the liver initiates a regenerative program involving hepatocyte priming and replication driven by coordinated cytokine and growth factor actions. We investigated the mechanisms underlying Adiponectin's (Adn) regulation of liver regeneration through modulation of these mediators. Adn-/- mice showed delayed onset of hepatocyte replication, but accelerated cell cycle progression relative to wild-type mice, suggesting Adn has multiple effects fine-tuning the kinetics of liver regeneration. We developed a computational model describing the molecular and physiological kinetics of liver regeneration in Adn-/- mice. We employed this computational model to evaluate the underlying regulatory mechanisms. Our analysis predicted that Adn is required for an efficient early cytokine response to partial hepatectomy, but is inhibitory to later growth factor actions. Consistent with this prediction, Adn knockout reduced hepatocyte responses to IL-6 during the priming phase, but enhanced growth factor levels through peak hepatocyte replication. By contrast, supraphysiological concentrations of Adn resulting from rosiglitazone treatment suppressed regeneration by reducing growth factor levels during S phase, consistent with computational predictions. Together, these results revealed that Adn fine-tunes the progression of liver regeneration through dynamically modulating molecular mediator networks and cellular interactions within the liver. This article is protected by copyright. All rights reserved.

  5. Adiponectin fine-tuning of liver regeneration dynamics revealed through cellular network modelling.

    Science.gov (United States)

    Correnti, Jason M; Cook, Daniel; Aksamitiene, Edita; Swarup, Aditi; Ogunnaike, Babatunde; Vadigepalli, Rajanikanth; Hoek, Jan B

    2015-01-15

    Following partial hepatectomy, the liver initiates a regenerative programme involving hepatocyte priming and replication driven by the coordinated actions of cytokine and growth factors. We investigated the mechanisms underlying adiponectin's (Adn) regulation of liver regeneration through modulation of these mediators. Adn(-/-) mice showed delayed onset of hepatocyte replication, but accelerated cell cycle progression relative to wild-type mice, suggesting Adn has multiple effects fine-tuning the kinetics of liver regeneration. We developed a computational model describing the molecular and physiological kinetics of liver regeneration in Adn(-/-) mice. We employed this computational model to evaluate the underlying regulatory mechanisms. Our analysis predicted that Adn is required for an efficient early cytokine response to partial hepatectomy, but is inhibitory to later growth factor actions. Consistent with this prediction, Adn knockout reduced hepatocyte responses to interleukin-6 during the priming phase, but enhanced growth factor levels through peak hepatocyte replication. By contrast, supraphysiological concentrations of Adn resulting from rosiglitazone treatment suppressed regeneration by reducing growth factor levels during S phase, consistent with computational predictions. Together, these results revealed that Adn fine-tunes the progression of liver regeneration through dynamically modulating molecular mediator networks and cellular interactions within the liver.

  6. Placental programming of anxiety in adulthood revealed by Igf2-null models.

    Science.gov (United States)

    Mikaelsson, Mikael Allan; Constância, Miguel; Dent, Claire L; Wilkinson, Lawrence S; Humby, Trevor

    2013-01-01

    Imprinted, maternally silenced insulin-like growth factor-2 is expressed in both the foetus and placenta and has been shown to have roles in foetal and placental development in animal models. Here we compared mice engineered to be null for the placenta-specific P0 transcript (insulin-like growth factor-2-P0 KO) to mice with disruptions of all four insulin-like growth factor-2 transcripts, and therefore null for insulin-like growth factor-2 in both placenta and foetus (insulin-like growth factor-2-total KO). Both models lead to intrauterine growth restriction but dissociate between a situation where there is an imbalance between foetal demand and placental supply of nutrients (the insulin-like growth factor-2-P0 KO) and one where demand and supply is more balanced (the insulin-like growth factor-2-total KO). Increased reactivity to anxiety-provoking stimuli is manifested later in life only in those animals where there is a mismatch between placental supply and foetal demand for nutrients during gestation. Our findings further distinguish placental dysfunction from intrauterine growth restriction and reveal a role for the placenta in long-term programming of emotional behaviour.

  7. Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.

    Science.gov (United States)

    Keller, Roland; Klein, Marcus; Thomas, Maria; Dräger, Andreas; Metzger, Ute; Templin, Markus F; Joos, Thomas O; Thasler, Wolfgang E; Zell, Andreas; Zanger, Ulrich M

    2016-01-01

    During various inflammatory processes circulating cytokines including IL-6, IL-1β, and TNFα elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the simultaneous downregulation of many drug metabolizing enzymes and transporter genes. To address the question whether a common mechanism is involved we treated human primary hepatocytes with IL-6, the major mediator of the acute phase response in liver, and characterized acute phase and detoxification responses in quantitative gene expression and (phospho-)proteomics data sets. Selective inhibitors were used to disentangle the roles of JAK/STAT, MAPK, and PI3K signaling pathways. A prior knowledge-based fuzzy logic model comprising signal transduction and gene regulation was established and trained with perturbation-derived gene expression data from five hepatocyte donors. Our model suggests a greater role of MAPK/PI3K compared to JAK/STAT with the orphan nuclear receptor RXRα playing a central role in mediating transcriptional downregulation. Validation experiments revealed a striking similarity of RXRα gene silencing versus IL-6 induced negative gene regulation (rs = 0.79; P<0.0001). These results concur with RXRα functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism.

  8. Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling

    Directory of Open Access Journals (Sweden)

    Dai Qiuxia

    2011-05-01

    Full Text Available Abstract Background Progressive remodeling of the left ventricle (LV following myocardial infarction (MI can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to determine the key factors and elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches. Results By examining the extracellular matrix (ECM gene expression and plasma analyte levels in C57/BL6J mice LV post-MI and ECM gene responses to transforming growth factor (TGF-β1 in cultured cardiac fibroblasts, we found that key factors in LV remodeling included macrophages, fibroblasts, transforming growth factor-β1, matrix metalloproteinase-9 (MMP-9, and specific collagen subtypes. We established a mathematical model to study LV remodeling post-MI by quantifying the dynamic balance between ECM construction and destruction. The mathematical model incorporated the key factors and demonstrated that TGF-β1 stimuli and MMP-9 interventions with different strengths and intervention times lead to different LV remodeling outcomes. The predictions of the mathematical model fell within the range of experimental measurements for these interventions, providing validation for the model. Conclusions In conclusion, our results demonstrated that the balance between ECM synthesis and degradation, controlled by interactions of specific key factors, determines the LV remodeling outcomes. Our mathematical model, based on the balance between ECM construction and destruction, provides a useful tool for studying the regulatory mechanisms and for predicting LV remodeling outcomes.

  9. Improvising in music: A learning biography study to reveal skill acquisition

    NARCIS (Netherlands)

    Wopereis, Iwan; Van Merriënboer, Jeroen; Kirschner, Paul A.

    2010-01-01

    Wopereis, I. G. J. H., Van Merriënboer, J. J. G., & Kirschner, P. A. (2010). Improvising in music: A learning biography study to reveal skill acquisition. In K. Gomez, L. Lyons, & J. Radinsky (Eds.), Proceedings of the 9th International Conference of the Learning Sciences: Vol. 2 (pp. 419-420). Chic

  10. Improvising in music: A learning biography study to reveal skill acquisition

    NARCIS (Netherlands)

    Wopereis, Iwan; Van Merriënboer, Jeroen; Kirschner, Paul A.

    2010-01-01

    Wopereis, I. G. J. H., Van Merriënboer, J. J. G., & Kirschner, P. A. (2010). Improvising in music: A learning biography study to reveal skill acquisition. In K. Gomez, L. Lyons, & J. Radinsky (Eds.), Proceedings of the 9th International Conference of the Learning Sciences: Vol. 2 (pp. 419-420). Chic

  11. Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity.

    Science.gov (United States)

    Le, Sarah N; Porebski, Benjamin T; McCoey, Julia; Fodor, James; Riley, Blake; Godlewska, Marlena; Góra, Monika; Czarnocka, Barbara; Banga, J Paul; Hoke, David E; Kass, Itamar; Buckle, Ashley M

    2015-01-01

    Thyroid peroxidase (TPO) catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease--the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B). TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO)-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its conformational

  12. Complex mean circulation over the inner shelf south of Martha's Vineyard revealed by observations and a high-resolution model

    Science.gov (United States)

    Ganju, Neil K.; Lentz, Steven J.; Kirincich, Anthony R.; Farrar, J. Thomas

    2011-01-01

    Inner-shelf circulation is governed by the interaction between tides, baroclinic forcing, winds, waves, and frictional losses; the mean circulation ultimately governs exchange between the coast and ocean. In some cases, oscillatory tidal currents interact with bathymetric features to generate a tidally rectified flow. Recent observational and modeling efforts in an overlapping domain centered on the Martha's Vineyard Coastal Observatory (MVCO) provided an opportunity to investigate the spatial and temporal complexity of circulation on the inner shelf. ADCP and surface radar observations revealed a mean circulation pattern that was highly variable in the alongshore and cross-shore directions. Nested modeling incrementally improved representation of the mean circulation as grid resolution increased and indicated tidal rectification as the generation mechanism of a counter-clockwise gyre near the MVCO. The loss of model skill with decreasing resolution is attributed to insufficient representation of the bathymetric gradients (Δh/h), which is important for representing nonlinear interactions between currents and bathymetry. The modeled momentum balance was characterized by large spatial variability of the pressure gradient and horizontal advection terms over short distances, suggesting that observed inner-shelf momentum balances may be confounded. Given the available observational and modeling data, this work defines the spatially variable mean circulation and its formation mechanism—tidal rectification—and illustrates the importance of model resolution for resolving circulation and constituent exchange near the coast. The results of this study have implications for future observational and modeling studies near the MVCO and other inner-shelf locations with alongshore bathymetric variability.

  13. Constrained solution scattering modelling of human antibodies and complement proteins reveals novel biological insights.

    Science.gov (United States)

    Perkins, Stephen J; Okemefuna, Azubuike I; Nan, Ruodan; Li, Keying; Bonner, Alexandra

    2009-10-06

    X-ray and neutron-scattering techniques characterize proteins in solution and complement high-resolution structural studies. They are useful when either a large protein cannot be crystallized, in which case scattering yields a solution structure, or a crystal structure has been determined and requires validation in solution. These solution structures are determined by the application of constrained modelling methods based on known subunit structures. First, an appropriate starting model is generated. Next, its conformation is randomized to generate thousands of models for trial-and-error fits. Comparison with the experimental data identifies a small family of best-fit models. Finally, their significance for biological function is assessed. We illustrate this in application to structure determinations for secretory immunoglobulin A, the most prevalent antibody in the human body and a first line of defence in mucosal immunity. We also discuss the applications to the large multi-domain proteins of the complement system, most notably its major regulator factor H, which is important in age-related macular degeneration and renal diseases. We discuss the importance of complementary data from analytical ultracentrifugation, and structural studies of protein-protein complexes. We conclude that constrained scattering modelling makes useful contributions to our understanding of antibody and complement structure and function.

  14. Cell type-specific functions of period genes revealed by novel adipocyte and hepatocyte circadian clock models.

    Directory of Open Access Journals (Sweden)

    Chidambaram Ramanathan

    2014-04-01

    Full Text Available In animals, circadian rhythms in physiology and behavior result from coherent rhythmic interactions between clocks in the brain and those throughout the body. Despite the many tissue specific clocks, most understanding of the molecular core clock mechanism comes from studies of the suprachiasmatic nuclei (SCN of the hypothalamus and a few other cell types. Here we report establishment and genetic characterization of three cell-autonomous mouse clock models: 3T3 fibroblasts, 3T3-L1 adipocytes, and MMH-D3 hepatocytes. Each model is genetically tractable and has an integrated luciferase reporter that allows for longitudinal luminescence recording of rhythmic clock gene expression using an inexpensive off-the-shelf microplate reader. To test these cellular models, we generated a library of short hairpin RNAs (shRNAs against a panel of known clock genes and evaluated their impact on circadian rhythms. Knockdown of Bmal1, Clock, Cry1, and Cry2 each resulted in similar phenotypes in all three models, consistent with previous studies. However, we observed cell type-specific knockdown phenotypes for the Period and Rev-Erb families of clock genes. In particular, Per1 and Per2, which have strong behavioral effects in knockout mice, appear to play different roles in regulating period length and amplitude in these peripheral systems. Per3, which has relatively modest behavioral effects in knockout mice, substantially affects period length in the three cellular models and in dissociated SCN neurons. In summary, this study establishes new cell-autonomous clock models that are of particular relevance to metabolism and suitable for screening for clock modifiers, and reveals previously under-appreciated cell type-specific functions of clock genes.

  15. Hitting the moving target: modelling ontogenetic shifts with stable isotopes reveals the importance of isotopic turnover.

    Science.gov (United States)

    Hertz, Eric; Trudel, Marc; El-Sabaawi, Rana; Tucker, Strahan; Dower, John F; Beacham, Terry D; Edwards, Andrew M; Mazumder, Asit

    2016-05-01

    Ontogenetic niche shifts are widely prevalent in nature and are important in shaping the structure and dynamics of ecosystems. Stable isotope analysis is a powerful tool to assess these shifts, with δ(15) N providing a measure of trophic level and δ(13) C a measure of energy source. Previous applications of stable isotopes to study ontogenetic niche shifts have not considered the appreciable time lag between diet and consumer tissue associated with isotopic turnover. These time lags introduce significant complexity into field studies of ontogenetic niche shifts. Juvenile Chinook salmon (Oncorhynchus tshawytscha) migrate from freshwater to marine ecosystems and shift their diet from feeding primarily on invertebrates to feeding primarily on fish. This dual ontogenetic habitat and diet shift, in addition to the long time lag associated with isotopic turnover, suggests that there is potential for a disconnect between the prey sources that juvenile salmon are consuming, and the inferred prey sources from stable isotopes. We developed a model that considered ontogenetic niche shifts and time lags associated with isotopic turnover, and compared this 'ontogeny' model to one that considered only isotopic turnover. We used a Bayesian framework to explicitly account for parameter uncertainty. Data showed overwhelming support for the ontogeny model relative to the isotopic turnover model. Estimated variables from best model fits indicate that the ontogeny model predicts a much greater reliance on fish prey than does the stomach content data. Overall, we found that this method of quantifying ontogenetic niche shifts effectively accounted for both isotopic turnover and ontogenetic diet shifts; a finding that could be widely applicable to a variety of systems.

  16. Ambiguity Revealed

    OpenAIRE

    Subir Bose; Matthew Polisson; Ludovic Renou

    2012-01-01

    We derive necessary and suffcient conditions for data sets composed of state-contingent prices and consumption to be consistent with two prominent models of decision making under ambiguity: variational preferences and smooth ambiguity. The revealed preference conditions for the maxmin expected utility and subjective expected utility models are characterized as special cases.

  17. Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis.

    Science.gov (United States)

    Caulin, Aleah F; Graham, Trevor A; Wang, Li-San; Maley, Carlo C

    2015-07-19

    Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.

  18. Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia.

    Science.gov (United States)

    Ooga, Takushi; Sato, Hajime; Nagashima, Atsushi; Sasaki, Kazunori; Tomita, Masaru; Soga, Tomoyoshi; Ohashi, Yoshiaki

    2011-04-01

    Metabolomics is an emerging technology that reveals homeostatic imbalances in biological systems. Global determination of metabolite concentrations in body fluid and tissues provides novel anatomical aspects of pathological conditions that cannot be obtained from target-specific measurements. Here, we characterised metabolic imbalance in Watanabe heritable hyperlipidaemic rabbits as a model of hypercholesterolaemia. Using a mass spectrometry-based system, we measured a total of 335 metabolites in plasma and tissues (liver, aorta, cardiac muscle, and brain) from WHHL and healthy control rabbits. From the comparison between two metabolomic profiles, pathophysiological features including glutathione and phosphatidylcholine metabolism indicated the occurrence of oxidative stress in several tissues. Especially for the liver, imbalanced purine catabolism shed light on the transcriptional activation of xanthine oxidase, which is thought to act in absorbing or possibly triggering oxidative stress. We also applied this system to assess the therapeutic effects of simvastatin administration. After the treatment, a portion of the metabolomic features in pathological conditions showed alterations suggesting restoration of metabolism to the healthy condition. These changes were considered to be due to the pleiotropic action of statin, including antioxidant effects, rather than its main inhibitory action on cholesterol biosynthesis.

  19. Robust hierarchical state-space models reveal diel variation in travel rates of migrating leatherback turtles.

    Science.gov (United States)

    Jonsen, Ian D; Myers, Ransom A; James, Michael C

    2006-09-01

    1. Biological and statistical complexity are features common to most ecological data that hinder our ability to extract meaningful patterns using conventional tools. Recent work on implementing modern statistical methods for analysis of such ecological data has focused primarily on population dynamics but other types of data, such as animal movement pathways obtained from satellite telemetry, can also benefit from the application of modern statistical tools. 2. We develop a robust hierarchical state-space approach for analysis of multiple satellite telemetry pathways obtained via the Argos system. State-space models are time-series methods that allow unobserved states and biological parameters to be estimated from data observed with error. We show that the approach can reveal important patterns in complex, noisy data where conventional methods cannot. 3. Using the largest Atlantic satellite telemetry data set for critically endangered leatherback turtles, we show that the diel pattern in travel rates of these turtles changes over different phases of their migratory cycle. While foraging in northern waters the turtles show similar travel rates during day and night, but on their southward migration to tropical waters travel rates are markedly faster during the day. These patterns are generally consistent with diving data, and may be related to changes in foraging behaviour. Interestingly, individuals that migrate southward to breed generally show higher daytime travel rates than individuals that migrate southward in a non-breeding year. 4. Our approach is extremely flexible and can be applied to many ecological analyses that use complex, sequential data.

  20. Modeling development and quantitative trait mapping reveal independent genetic modules for leaf size and shape.

    Science.gov (United States)

    Baker, Robert L; Leong, Wen Fung; Brock, Marcus T; Markelz, R J Cody; Covington, Michael F; Devisetty, Upendra K; Edwards, Christine E; Maloof, Julin; Welch, Stephen; Weinig, Cynthia

    2015-10-01

    Improved predictions of fitness and yield may be obtained by characterizing the genetic controls and environmental dependencies of organismal ontogeny. Elucidating the shape of growth curves may reveal novel genetic controls that single-time-point (STP) analyses do not because, in theory, infinite numbers of growth curves can result in the same final measurement. We measured leaf lengths and widths in Brassica rapa recombinant inbred lines (RILs) throughout ontogeny. We modeled leaf growth and allometry as function valued traits (FVT), and examined genetic correlations between these traits and aspects of phenology, physiology, circadian rhythms and fitness. We used RNA-seq to construct a SNP linkage map and mapped trait quantitative trait loci (QTL). We found genetic trade-offs between leaf size and growth rate FVT and uncovered differences in genotypic and QTL correlations involving FVT vs STPs. We identified leaf shape (allometry) as a genetic module independent of length and width and identified selection on FVT parameters of development. Leaf shape is associated with venation features that affect desiccation resistance. The genetic independence of leaf shape from other leaf traits may therefore enable crop optimization in leaf shape without negative effects on traits such as size, growth rate, duration or gas exchange.

  1. Whisker movements reveal spatial attention: a unified computational model of active sensing control in the rat.

    Science.gov (United States)

    Mitchinson, Ben; Prescott, Tony J

    2013-01-01

    Spatial attention is most often investigated in the visual modality through measurement of eye movements, with primates, including humans, a widely-studied model. Its study in laboratory rodents, such as mice and rats, requires different techniques, owing to the lack of a visual fovea and the particular ethological relevance of orienting movements of the snout and the whiskers in these animals. In recent years, several reliable relationships have been observed between environmental and behavioural variables and movements of the whiskers, but the function of these responses, as well as how they integrate, remains unclear. Here, we propose a unifying abstract model of whisker movement control that has as its key variable the region of space that is the animal's current focus of attention, and demonstrate, using computer-simulated behavioral experiments, that the model is consistent with a broad range of experimental observations. A core hypothesis is that the rat explicitly decodes the location in space of whisker contacts and that this representation is used to regulate whisker drive signals. This proposition stands in contrast to earlier proposals that the modulation of whisker movement during exploration is mediated primarily by reflex loops. We go on to argue that the superior colliculus is a candidate neural substrate for the siting of a head-centred map guiding whisker movement, in analogy to current models of visual attention. The proposed model has the potential to offer a more complete understanding of whisker control as well as to highlight the potential of the rodent and its whiskers as a tool for the study of mammalian attention.

  2. Model-based reasoning: using visual tools to reveal student learning.

    Science.gov (United States)

    Luckie, Douglas; Harrison, Scott H; Ebert-May, Diane

    2011-03-01

    Using visual models is common in science and should become more common in classrooms. Our research group has developed and completed studies on the use of a visual modeling tool, the Concept Connector. This modeling tool consists of an online concept mapping Java applet that has automatic scoring functions we refer to as Robograder. The Concept Connector enables students in large introductory science courses to visualize their thinking through online model building. The Concept Connector's flexible scoring system, based on tested grading schemes as well as instructor input, has enabled >1,000 physiology students to build maps of their ideas about plant and animal physiology with the guidance of automatic and immediate online scoring of homework. Criterion concept maps developed by instructors in this project contain numerous expert-generated or "correct" propositions connecting two concept words together with a linking phrase. In this study, holistic algorithms were used to test automated methods of scoring concept maps that might work as well as a human grader.

  3. Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity.

    Directory of Open Access Journals (Sweden)

    Sarah N Le

    Full Text Available Thyroid peroxidase (TPO catalyses the biosynthesis of thyroid hormones and is a major autoantigen in Hashimoto's disease--the most common organ-specific autoimmune disease. Epitope mapping studies have shown that the autoimmune response to TPO is directed mainly at two surface regions on the molecule: immunodominant regions A and B (IDR-A, and IDR-B. TPO has been a major target for structural studies for over 20 years; however, to date, the structure of TPO remains to be determined. We have used a molecular modelling approach to investigate plausible modes of TPO structure and dimer organisation. Sequence features of the C-terminus are consistent with a coiled-coil dimerization motif that most likely anchors the TPO dimer in the apical membrane of thyroid follicular cells. Two contrasting models of TPO were produced, differing in the orientation and exposure of their active sites relative to the membrane. Both models are equally plausible based upon the known enzymatic function of TPO. The "trans" model places IDR-B on the membrane-facing side of the myeloperoxidase (MPO-like domain, potentially hindering access of autoantibodies, necessitating considerable conformational change, and perhaps even dissociation of the dimer into monomers. IDR-A spans MPO- and CCP-like domains and is relatively fragmented compared to IDR-B, therefore most likely requiring domain rearrangements in order to coalesce into one compact epitope. Less epitope fragmentation and higher solvent accessibility of the "cis" model favours it slightly over the "trans" model. Here, IDR-B clusters towards the surface of the MPO-like domain facing the thyroid follicular lumen preventing steric hindrance of autoantibodies. However, conformational rearrangements may still be necessary to allow full engagement with autoantibodies, with IDR-B on both models being close to the dimer interface. Taken together, the modelling highlights the need to consider the oligomeric state of TPO, its

  4. A transgenic mouse model expressing an ERα folding biosensor reveals the effects of Bisphenol A on estrogen receptor signaling

    Science.gov (United States)

    Sekar, Thillai V.; Foygel, Kira; Massoud, Tarik F.; Gambhir, Sanjiv S.; Paulmurugan, Ramasamy

    2016-01-01

    Estrogen receptor-α (ERα) plays an important role in normal and abnormal physiology of the human reproductive system by interacting with the endogenous ligand estradiol (E2). However, other ligands, either analogous or dissimilar to E2, also bind to ERα. This may create unintentional activation of ER signaling in reproductive tissues that can lead to cancer development. We developed a transgenic mouse model that constitutively expresses a firefly luciferase (FLuc) split reporter complementation biosensor (NFLuc-ER-LBDG521T-CFLuc) to simultaneously evaluate the dynamics and potency of ligands that bind to ERα. We first validated this model using various ER ligands, including Raloxifene, Diethylstilbestrol, E2, and 4-hydroxytamoxifen, by employing FLuc-based optical bioluminescence imaging of living mice. We then used the model to investigate the carcinogenic property of Bisphenol A (BPA), an environmental estrogen, by long-term exposure at full and half environmental doses. We showed significant carcinogenic effects on female animals while revealing activated downstream ER signaling as measured by bioluminescence imaging. BPA induced tumor-like outgrowths in female transgenic mice, histopathologically confirmed to be neoplastic and epithelial in origin. This transgenic mouse model expressing an ERα folding-biosensor is useful in evaluation of estrogenic ligands and their downstream effects, and in studying environmental estrogen induced carcinogenesis in vivo. PMID:27721470

  5. Mechanics of the IL2RA Gene Activation Revealed by Modeling and Atomic Force Microscopy

    OpenAIRE

    Pascale Milani; Monique Marilley; Albert Sanchez-Sevilla; Jean Imbert; Cédric Vaillant; Françoise Argoul; Jean-Marc Egly; José Rocca-Serra; Alain Arneodo

    2011-01-01

    Transcription implies recruitment of RNA polymerase II and transcription factors (TFs) by DNA melting near transcription start site (TSS). Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites), located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studi...

  6. Knock-in model of Dravet syndrome reveals a constitutive and conditional reduction in sodium current

    OpenAIRE

    Schutte, Ryan J.; Schutte, Soleil S.; Algara, Jacqueline; Barragan, Eden V.; Gilligan, Jeff; Staber, Cynthia; Savva, Yiannis A.; Smith, Martin A.; Reenan, Robert; O'Dowd, Diane K.

    2014-01-01

    Hundreds of mutations in the SCN1A sodium channel gene confer a wide spectrum of epileptic disorders, requiring efficient model systems to study cellular mechanisms and identify potential therapeutic targets. We recently demonstrated that Drosophila knock-in flies carrying the K1270T SCN1A mutation known to cause a form of genetic epilepsy with febrile seizures plus (GEFS+) exhibit a heat-induced increase in sodium current activity and seizure phenotype. To determine whether different SCN1A m...

  7. Mathematical Modelling Research in Turkey: A Content Analysis Study

    Science.gov (United States)

    Çelik, H. Coskun

    2017-01-01

    The aim of the present study was to examine the mathematical modelling studies done between 2004 and 2015 in Turkey and to reveal their tendencies. Forty-nine studies were selected using purposeful sampling based on the term, "mathematical modelling" with Higher Education Academic Search Engine. They were analyzed with content analysis.…

  8. Integrated Experimental and Model-based Analysis Reveals the Spatial Aspects of EGFR Activation Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Shankaran, Harish; Zhang, Yi; Chrisler, William B.; Ewald, Jonathan A.; Wiley, H. S.; Resat, Haluk

    2012-10-02

    The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases, and controls a diverse set of cellular responses relevant to development and tumorigenesis. ErbB activation is a complex process involving receptor-ligand binding, receptor dimerization, phosphorylation, and trafficking (internalization, recycling and degradation), which together dictate the spatio-temporal distribution of active receptors within the cell. The ability to predict this distribution, and elucidation of the factors regulating it, would help to establish a mechanistic link between ErbB expression levels and the cellular response. Towards this end, we constructed mathematical models for deconvolving the contributions of receptor dimerization and phosphorylation to EGFR activation, and to examine the dependence of these processes on sub-cellular location. We collected experimental datasets for EGFR activation dynamics in human mammary epithelial cells, with the specific goal of model parameterization, and used the data to estimate parameters for several alternate models. Model-based analysis indicated that: 1) signal termination via receptor dephosphorylation in late endosomes, prior to degradation, is an important component of the response, 2) less than 40% of the receptors in the cell are phosphorylated at any given time, even at saturating ligand doses, and 3) receptor dephosphorylation rates at the cell surface and early endosomes are comparable. We validated the last finding by measuring EGFR dephosphorylation rates at various times following ligand addition both in whole cells, and in endosomes using ELISAs and fluorescent imaging. Overall, our results provide important information on how EGFR phosphorylation levels are regulated within cells. Further, the mathematical model described here can be extended to determine receptor dimer abundances in cells co-expressing various levels of ErbB receptors. This study demonstrates that an iterative cycle of

  9. Mouse Genetic Models Reveal Surprising Functions of IκB Kinase Alpha in Skin Development and Skin Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Xiaojun [The Methodist Hospital Research Institute, Houston, TX 77030 (United States); Park, Eunmi [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 (United States); Fischer, Susan M. [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78967 (United States); Hu, Yinling, E-mail: huy2@mail.nih.gov [Cancer and Inflammation Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701 (United States)

    2013-02-15

    Gene knockout studies unexpectedly reveal a pivotal role for IκB kinase alpha (IKKα) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikkα heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKα deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikkα floxed mice. On the other hand, transgenic mice overexpressing IKKα in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKα represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKα deletion mediated by a mutation, which generates a stop codon in the Ikkα gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKα and Ikkα mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKα in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside.

  10. Revealing the network of periodic orbits in galaxy models with a prolate or an oblate dark matter halo component

    CERN Document Server

    Zotos, Euaggelos E

    2016-01-01

    Locating the position of periodic orbits in galaxies is undoubtedly an issue of paramount importance. We reveal the position and the stability of periodic orbits of stars moving in the meridional plane $(R,z)$ of an axially symmetric galactic model with a disk, a spherical nucleus, and a biaxial dark matter halo component. In particular, we study how all the involved parameters of the dynamical system influence the position and the stability of all resonant families. To locate the position and measure the stability of periodic orbits we use a highly sensitive numerical code which is able to identify resonant periodic orbits of the type $n:m$. Two cases are studied for every parameter: (i) the case where the dark matter halo component is prolate and (ii) the case where an oblate dark matter halo is present. Our numerical exploration reveals that all the dynamical quantities affect, more or less, the position and the stability of the periodic orbits. It is shown that the mass of the nucleus, the mass of the dis...

  11. An integrated multi-omics study revealed metabolic alterations underlying the effects of coffee consumption.

    Directory of Open Access Journals (Sweden)

    Shoko Takahashi

    Full Text Available Many epidemiological studies have indicated that coffee consumption may reduce the risks of developing obesity and diabetes, but the underlying mechanisms of these effects are poorly understood. Our previous study revealed the changes on gene expression profiles in the livers of C57BL/6J mice fed a high-fat diet containing three types of coffee (caffeinated, decaffeinated and green unroasted coffee, using DNA microarrays. The results revealed remarkable alterations in lipid metabolism-related molecules which may be involved in the anti-obesity effects of coffee. We conducted the present study to further elucidate the metabolic alterations underlying the effects of coffee consumption through comprehensive proteomic and metabolomic analyses. Proteomics revealed an up-regulation of isocitrate dehydrogenase (a key enzyme in the TCA cycle and its related proteins, suggesting increased energy generation. The metabolomics showed an up-regulation of metabolites involved in the urea cycle, with which the transcriptome data were highly consistent, indicating accelerated energy expenditure. The TCA cycle and the urea cycle are likely be accelerated in a concerted manner, since they are directly connected by mutually providing each other's intermediates. The up-regulation of these pathways might result in a metabolic shift causing increased ATP turnover, which is related to the alterations of lipid metabolism. This mechanism may play an important part in the suppressive effects of coffee consumption on obesity, inflammation, and hepatosteatosis. This study newly revealed global metabolic alterations induced by coffee intake, providing significant insights into the association between coffee intake and the prevention of type 2 diabetes, utilizing the benefits of multi-omics analyses.

  12. An integrated multi-omics study revealed metabolic alterations underlying the effects of coffee consumption.

    Science.gov (United States)

    Takahashi, Shoko; Saito, Kenji; Jia, Huijuan; Kato, Hisanori

    2014-01-01

    Many epidemiological studies have indicated that coffee consumption may reduce the risks of developing obesity and diabetes, but the underlying mechanisms of these effects are poorly understood. Our previous study revealed the changes on gene expression profiles in the livers of C57BL/6J mice fed a high-fat diet containing three types of coffee (caffeinated, decaffeinated and green unroasted coffee), using DNA microarrays. The results revealed remarkable alterations in lipid metabolism-related molecules which may be involved in the anti-obesity effects of coffee. We conducted the present study to further elucidate the metabolic alterations underlying the effects of coffee consumption through comprehensive proteomic and metabolomic analyses. Proteomics revealed an up-regulation of isocitrate dehydrogenase (a key enzyme in the TCA cycle) and its related proteins, suggesting increased energy generation. The metabolomics showed an up-regulation of metabolites involved in the urea cycle, with which the transcriptome data were highly consistent, indicating accelerated energy expenditure. The TCA cycle and the urea cycle are likely be accelerated in a concerted manner, since they are directly connected by mutually providing each other's intermediates. The up-regulation of these pathways might result in a metabolic shift causing increased ATP turnover, which is related to the alterations of lipid metabolism. This mechanism may play an important part in the suppressive effects of coffee consumption on obesity, inflammation, and hepatosteatosis. This study newly revealed global metabolic alterations induced by coffee intake, providing significant insights into the association between coffee intake and the prevention of type 2 diabetes, utilizing the benefits of multi-omics analyses.

  13. Reduced ENSO variability at the LGM revealed by an isotope-enabled Earth system model

    Science.gov (United States)

    Zhu, Jiang; Liu, Zhengyu; Brady, Esther; Otto-Bliesner, Bette; Zhang, Jiaxu; Noone, David; Tomas, Robert; Nusbaumer, Jesse; Wong, Tony; Jahn, Alexandra; Tabor, Clay

    2017-07-01

    Studying the El Niño-Southern Oscillation (ENSO) in the past can help us better understand its dynamics and improve its future projections. However, both paleoclimate reconstructions and model simulations of ENSO strength at the Last Glacial Maximum (LGM; 21 ka B.P.) have led to contradicting results. Here we perform model simulations using the recently developed water isotope-enabled Community Earth System Model (iCESM). For the first time, model-simulated oxygen isotopes are directly compared with those from ENSO reconstructions using the individual foraminifera analysis (IFA). We find that the LGM ENSO is most likely weaker comparing with the preindustrial. The iCESM suggests that total variance of the IFA records may only reflect changes in the annual cycle instead of ENSO variability as previously assumed. Furthermore, the interpretation of subsurface IFA records can be substantially complicated by the habitat depth of thermocline-dwelling foraminifera and their vertical migration with a temporally varying thermocline.

  14. Empirical evaluation reveals best fit of a logistic mutation model for human Y-chromosomal microsatellites.

    Science.gov (United States)

    Jochens, Arne; Caliebe, Amke; Rösler, Uwe; Krawczak, Michael

    2011-12-01

    The rate of microsatellite mutation is dependent upon both the allele length and the repeat motif, but the exact nature of this relationship is still unknown. We analyzed data on the inheritance of human Y-chromosomal microsatellites in father-son duos, taken from 24 published reports and comprising 15,285 directly observable meioses. At the six microsatellites analyzed (DYS19, DYS389I, DYS390, DYS391, DYS392, and DYS393), a total of 162 mutations were observed. For each locus, we employed a maximum-likelihood approach to evaluate one of several single-step mutation models on the basis of the data. For five of the six loci considered, a novel logistic mutation model was found to provide the best fit according to Akaike's information criterion. This implies that the mutation probability at the loci increases (nonlinearly) with allele length at a rate that differs between upward and downward mutations. For DYS392, the best fit was provided by a linear model in which upward and downward mutation probabilities increase equally with allele length. This is the first study to empirically compare different microsatellite mutation models in a locus-specific fashion.

  15. Functional Sphere Profiling Reveals the Complexity of Neuroblastoma Tumor-Initiating Cell Model

    Directory of Open Access Journals (Sweden)

    Aurélie Coulon

    2011-10-01

    Full Text Available Neuroblastoma (NB is a neural crest-derived childhood tumor characterized by a remarkable phenotypic diversity, ranging from spontaneous regression to fatal metastatic disease. Although the cancer stem cell (CSC model provides a trail to characterize the cells responsible for tumor onset, the NB tumor-initiating cell (TIC has not been identified. In this study, the relevance of the CSC model in NB was investigated by taking advantage of typical functional stem cell characteristics. A predictive association was established between self-renewal, as assessed by serial sphere formation, and clinical aggressiveness in primary tumors. Moreover, cell subsets gradually selected during serial sphere culture harbored increased in vivo tumorigenicity, only highlighted in an orthotopic microenvironment. A microarray time course analysis of serial spheres passages from metastatic cells allowed us to specifically “profile” the NB stem cell-like phenotype and to identify CD133, ABC transporter, and WNT and NOTCH genes as spheres markers. On the basis of combined sphere markers expression, at least two distinct tumorigenic cell subpopulations were identified, also shown to preexist in primary NB. However, sphere markers-mediated cell sorting of parental tumor failed to recapitulate the TIC phenotype in the orthotopic model, highlighting the complexity of the CSC model. Our data support the NB stem-like cells as a dynamic and heterogeneous cell population strongly dependent on microenvironmental signals and add novel candidate genes as potential therapeutic targets in the control of high-risk NB.

  16. Establishment of a rat and guinea pig aortic interposition graft model reveals model-specific patterns of intimal hyperplasia.

    Science.gov (United States)

    Gregory, Elaine K; Vercammen, Janet M; Flynn, Megan E; Kibbe, Melina R

    2016-12-01

    Although the aortic interposition bypass model has been widely used to evaluate biomaterials for bypass grafting, there is no comprehensive description of the procedure or of the distribution of intimal hyperplasia that results. The objectives of this study were to (1) review and summarize approaches of aortic interposition grafting in animal models, (2) determine the pertinent anatomy for this procedure, (3) validate this model in the rat and guinea pig, and (4) compare the distribution of intimal hyperplasia that develops in each species. A literature search was performed in PubMed from 1980 to the present to analyze the use of anesthesia, anticoagulation, antiplatelet agents, graft material, suture, and anastomotic techniques. Using 10-week-old male Sprague-Dawley rats and Hartley guinea pigs, we established pertinent aortic anatomy, developed comparable models, and assessed complications for each model. At 30 days, the graft and associated aorta were explanted, intimal formation was assessed morphometrically, and cellularity was assessed via nuclear counting. We reviewed 30 articles and summarized the pertinent procedural findings. Upon establishing both animal models, key anatomic differences between the species that affect this model were noted. Guinea pigs have a much larger cecum, increased retroperitoneal fat, and lack the iliolumbar vessels compared with the rat. Surgical outcomes for the rat model included a 53% technical success rate and a 32% technical error rate. Surgical outcomes for the guinea pig model included a 69% technical success rate and a 31% technical error rate. These two species demonstrated unique distribution of intimal hyperplasia at 30 days. Intimal hyperplasia in the rat model was greatest at two areas, the proximal graft (5400 μm(2); P hyperplasia throughout the graft (4500-5100 μm(2); P < .01). In this report, we summarize the literature on the aortic interposition graft model, present a detailed description of the anatomy

  17. Automated Behavioral Phenotyping Reveals Presymptomatic Alterations in a SCA3 Genetrap Mouse Model

    Institute of Scientific and Technical Information of China (English)

    Jeannette Hübener; Nicolas Casadei; Peter Teismann; Mathias W. Seeliger; Maria Bj(o)rkqvist; Stephan von H(o)rsten; Olaf Riess; Huu Phuc Nguyen

    2012-01-01

    Characterization of disease models of neurodegenerative disorders requires a systematic and comprehensive phenotyping in a highly standardized manner,Therefore,automated high-resolution behavior test systems such as the homecage based LabMaster system are of particular interest.We demonstrate the power of the automated LabMaster system by discovering previously unrecognized features of a recently characterized atxn3 mutant mouse model.This model provided neurological symptoms including gait ataxia,tremor,weight loss and premature death at the age of t2 months usually detectable just 2 weeks before the mice died.Moreover,using the LabMaster system we were able to detect hypoactivity in presymptomatic mutant mice in the dark as well as light phase.Additionally,we analyzed inflammation,immunological and hematological parameters,which indicated a reduced immune defense in phenotypic mice.Here we demonstrate thai a detailed characterization even of organ systems that are usually not affected in SCA3 is important for further studies of pathogenesis and required for the preclinical therapeutic studies.

  18. Drosophila Mutant Model of Parkinson's Disease Revealed an Unexpected Olfactory Performance: Morphofunctional Evidences

    Science.gov (United States)

    De Rose, Francescaelena; Corda, Valentina; Belcari, Antonio; Poddighe, Simone; Marrosu, Francesco

    2016-01-01

    Parkinson's disease (PD) is one of the most common neurodegenerative diseases characterized by the clinical triad: tremor, akinesia, and rigidity. Several studies have suggested that PD patients show disturbances in olfaction as one of the earliest, nonspecific nonmotor symptoms of disease onset. We sought to use the fruit fly Drosophila melanogaster as a model organism to explore olfactory function in LRRK loss-of-function mutants, which was previously demonstrated to be a useful model for PD. Surprisingly, our results showed that the LRRK mutant, compared to the wild flies, presents a dramatic increase in the amplitude of the electroantennogram responses and this is coupled with a higher number of olfactory sensilla. In spite of the above reported results, the behavioural response to olfactory stimuli in mutant flies is impaired compared to that obtained in wild type flies. Thus, behaviour modifications and morphofunctional changes in the olfaction of LRRK loss-of-function mutants might be used as an index to explore the progression of parkinsonism in this specific model, also with the aim of studying and developing new treatments. PMID:27648340

  19. Studies of Catalytic Model Systems

    DEFF Research Database (Denmark)

    Holse, Christian

    The overall topic of this thesis is within the field of catalysis, were model systems of different complexity have been studied utilizing a multipurpose Ultra High Vacuum chamber (UHV). The thesis falls in two different parts. First a simple model system in the form of a ruthenium single crystal...... is investigated. Second the development of a complex Cu/ZnO nanoparticle model system is described and gas-induced dynamical changes in the model system is investigated. The ruthenium crystal serves as an extremely simple model for studying CO dissociation which is the rate limiting step of the methanation...... process. The Ru(0 1 54) surface is studied by means of Scanning Tunneling Microscopy (STM), Temperature Programmed Desoprtion (TPD), and Oxygen Titration (OT) experiments. Real space evidence of periodic features on every second monatomic step is observed via STM when the a clean ruthenium surface...

  20. Dosage and Dose Schedule Screening of Drug Combinations in Agent-Based Models Reveals Hidden Synergies.

    Science.gov (United States)

    Barros de Andrade E Sousa, Lisa C; Kühn, Clemens; Tyc, Katarzyna M; Klipp, Edda

    2015-01-01

    The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research.

  1. Dosage and dose schedule screening of drug combinations in agent-based models reveals hidden synergies

    Directory of Open Access Journals (Sweden)

    Lisa Corina Barros de Andrade e Sousa1

    2016-01-01

    Full Text Available The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research.

  2. Revealing the Organization of Complex Adaptive Systems through Multivariate Time Series Modeling

    Directory of Open Access Journals (Sweden)

    David G. Angeler

    2011-09-01

    Full Text Available Revealing the adaptive responses of ecological, social, and economic systems to a transforming biosphere is crucial for understanding system resilience and preventing collapse. However, testing the theory that underpins complex adaptive system organization (e.g., panarchy theory is challenging. We used multivariate time series modeling to identify scale-specific system organization and, by extension, apparent resilience mechanisms. We used a 20-year time series of invertebrates and phytoplankton from 26 Swedish lakes to test the proposition that a few key-structuring environmental variables at specific scales create discontinuities in community dynamics. Cross-scale structure was manifested in two independent species groups within both communities across lakes. The first species group showed patterns of directional temporal change, which was related to environmental variables that acted at broad spatiotemporal scales (reduced sulfate deposition, North Atlantic Oscillation. The second species group showed fluctuation patterns, which often could not be explained by environmental variables. However, when significant relationships were found, species-group trends were predicted by variables (total organic carbon, nutrients that acted at narrower spatial scales (i.e., catchment and lake. Although the sets of environmental variables that predicted the species groups differed between phytoplankton and invertebrates, the scale-specific imprints of keystone environmental variables for creating cross-scale structure were clear for both communities. Temporal trends of functional groups did not track the observed structural changes, suggesting functional stability despite structural change. Our approach allows for identifying scale-specific patterns and processes, thus providing opportunities for better characterization of complex adaptive systems organization and dynamics. This, in turn, holds potential for more accurate evaluation of resilience in

  3. Anti-inflammatory Effects of Fungal Metabolites in Mouse Intestine as Revealed by In vitro Models

    Directory of Open Access Journals (Sweden)

    Dominik Schreiber

    2017-08-01

    Full Text Available Inflammatory bowel diseases (IBD, which include Crohn's disease and ulcerative colitis, are chronic inflammatory disorders that can affect the whole gastrointestinal tract or the colonic mucosal layer. Current therapies aiming to suppress the exaggerated immune response in IBD largely rely on compounds with non-satisfying effects or side-effects. Therefore, new therapeutical options are needed. In the present study, we investigated the anti-inflammatory effects of the fungal metabolites, galiellalactone, and dehydrocurvularin in both an in vitro intestinal inflammation model, as well as in isolated myenteric plexus and enterocyte cells. Administration of a pro-inflammatory cytokine mix through the mesenteric artery of intestinal segments caused an up-regulation of inflammatory marker genes. Treatment of the murine intestinal segments with galiellalactone or dehydrocurvularin by application through the mesenteric artery significantly prevented the expression of pro-inflammatory marker genes on the mRNA and the protein level. Comparable to the results in the perfused intestine model, treatment of primary enteric nervous system (ENS cells from the murine intestine with the fungal compounds reduced expression of cytokines such as IL-6, TNF-α, IL-1β, and inflammatory enzymes such as COX-2 and iNOS on mRNA and protein levels. Similar anti-inflammatory effects of the fungal metabolites were observed in the human colorectal adenocarcinoma cell line DLD-1 after stimulation with IFN-γ (10 ng/ml, TNF-α (10 ng/ml, and IL-1β (5 ng/ml. Our results show that the mesenterially perfused intestine model provides a reliable tool for the screening of new therapeutics with limited amounts of test compounds. Furthermore, we could characterize the anti-inflammatory effects of two novel active compounds, galiellalactone, and dehydrocurvularin which are interesting candidates for studies with chronic animal models of IBD.

  4. Czochralski crystal growth: Modeling study

    Science.gov (United States)

    Dudukovic, M. P.; Ramachandran, P. A.; Srivastava, R. K.; Dorsey, D.

    1986-01-01

    The modeling study of Czochralski (Cz) crystal growth is reported. The approach was to relate in a quantitative manner, using models based on first priniciples, crystal quality to operating conditions and geometric variables. The finite element method is used for all calculations.

  5. Monitoring studies should consider temporal variability to reveal relations between cyanobacterial abundance and environmental variables

    Directory of Open Access Journals (Sweden)

    JULIANA WOJCIECHOWSKI

    2015-09-01

    Full Text Available One of the main goals of monitoring cyanobacteria blooms in aquatic environments is to reveal the relationship between cyanobacterial abundance and environmental variables. Studies typically correlate data that were simultaneously sampled. However, samplings occur sparsely over time and may not reveal the short-term responses of cyanobacterial abundance to environmental changes. In this study, we tested the hypothesis that stronger cyanobacteria x environment relationships in monitoring are found when the temporal variability of sampling points is incorporated in the statistical analyses. To this end, we investigated relationships between cyanobacteria and seven environmental variables that were sampled twice yearly for three years across 11 reservoirs, and data from an intensive monitoring in one of these reservoirs. Poor correlations were obtained when correlating data simultaneously sampled. In fact, the 'highly recurrent' role of phosphorus in cyanobacteria blooms is not properly observed in all sampling periods. On the other hand, the strongest correlation values for the total phosphorus x cyanobacteria relationship were observed when we used the variation of sampling points. We have also shown that environment variables better explain cyanobacteria when a time lag is considered. We conclude that, in cyanobacteria monitoring, the best approach to reveal determinants of cyanobacteria blooms is to consider environmental variability.

  6. Chick embryo xenograft model reveals a novel perineural niche for human adipose-derived stromal cells

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    Ingrid R. Cordeiro

    2015-09-01

    Full Text Available Human adipose-derived stromal cells (hADSC are a heterogeneous cell population that contains adult multipotent stem cells. Although it is well established that hADSC have skeletal potential in vivo in adult organisms, in vitro assays suggest further differentiation capacity, such as into glia. Thus, we propose that grafting hADSC into the embryo can provide them with a much more instructive microenvironment, allowing the human cells to adopt diverse fates or niches. Here, hADSC spheroids were grafted into either the presumptive presomitic mesoderm or the first branchial arch (BA1 regions of chick embryos. Cells were identified without previous manipulations via human-specific Alu probes, which allows efficient long-term tracing of heterogeneous primary cultures. When grafted into the trunk, in contrast to previous studies, hADSC were not found in chondrogenic or osteogenic territories up to E8. Surprisingly, 82.5% of the hADSC were associated with HNK1+ tissues, such as peripheral nerves. Human skin fibroblasts showed a smaller tropism for nerves. In line with other studies, hADSC also adopted perivascular locations. When grafted into the presumptive BA1, 74.6% of the cells were in the outflow tract, the final goal of cardiac neural crest cells, and were also associated with peripheral nerves. This is the first study showing that hADSC could adopt a perineural niche in vivo and were able to recognize cues for neural crest cell migration of the host. Therefore, we propose that xenografts of human cells into chick embryos can reveal novel behaviors of heterogeneous cell populations, such as response to migration cues.

  7. Arabidopsis thaliana model system reveals a continuum of responses to root endophyte colonization.

    Science.gov (United States)

    Mandyam, Keerthi G; Roe, Judith; Jumpponen, Ari

    2013-04-01

    We surveyed the non-mycorrhizal model plant Arabidopsis thaliana microscopically for its ability to form dark septate endophyte (DSE) symbioses in field, greenhouse, and laboratory studies. The laboratory studies were also used to estimate host growth responses to 34 Periconia macrospinosa and four Microdochium sp. isolates. Consistent with broad host range observed in previous experiments, field-, greenhouse-, and laboratory-grown A. thaliana were colonized by melanized inter- and intracellular hyphae and microsclerotia or chlamydospores indicative of DSE symbiosis. Host responses to colonization were variable and depended on the host ecotype. On average, two A. thaliana accessions (Col-0 and Cvi-0) responded negatively, whereas one (Kin-1) was unresponsive, a conclusion consistent with our previous analyses with forbs native to the field site where the fungi originate. Despite the average negative responses, examples of positive responses were also observed, a conclusion also congruent with earlier studies. Our results suggest that A. thaliana has potential as a model for more detailed dissection of the DSE symbiosis. Furthermore, our data suggest that host responses are controlled by variability in the host and endophyte genotypes.

  8. Revealing the regime of shallow coral reefs at patch scale by continuous spatial modeling

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    Antoine eCollin

    2014-11-01

    Full Text Available Reliably translating real-world spatial patterns of ecosystems is critical for understanding processes susceptible to reinforce resilience. However the great majority of studies in spatial ecology use thematic maps to describe habitats and species in a binary scheme. By discretizing the transitional areas and neglecting the gradual replacement across a given space, the thematic approach may suffer from substantial limitations when interpreting patterns created by many continuous variables. Here, local and regional spectral proxies were used to design and spatially map at very fine scale a continuous index dedicated to one of the most complex seascapes, the coral reefscape. Through a groundbreaking merge of bottom-up and top-down approach, we demonstrate that three to seven-habitat continuous indices can be modeled by nine, six, four and three spectral proxies, respectively, at 0.5 m spatial resolution using hand- and spaceborne measurements. We map the seven-habitat continuous index, spanning major Indo-Pacific coral reef habitats through the far red-green normalized difference ratio over the entire lagoon of a low (Tetiaroa atoll and a high volcanic (Moorea island in French Polynesia with 84% and 82% accuracy, respectively. Further examinations of the two resulting spatial models using a customized histoscape (density function of model values distributed on a concentric strip across the reef crest-coastline distance show that Tetiaroa exhibits a greater variety of coral reef habitats than Moorea. By designing such easy-to-implement, transferrable spectral proxies of coral reef regime, this study initiates a framework for spatial ecologists tackling coral reef biodiversity, responses to stresses, perturbations and shifts. We discuss the limitations and contributions of our findings towards the study of worldwide coral reef resilience following stochastic environmental change.

  9. Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

    Science.gov (United States)

    Guaitoli, Giambattista; Raimondi, Francesco; Gilsbach, Bernd K.; Gómez-Llorente, Yacob; Deyaert, Egon; Renzi, Fabiana; Li, Xianting; Schaffner, Adam; Jagtap, Pravin Kumar Ankush; Boldt, Karsten; von Zweydorf, Felix; Gotthardt, Katja; Lorimer, Donald D.; Yue, Zhenyu; Burgin, Alex; Janjic, Nebojsa; Sattler, Michael; Versées, Wim; Ueffing, Marius; Ubarretxena-Belandia, Iban; Kortholt, Arjan; Gloeckner, Christian Johannes

    2016-01-01

    Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein containing two catalytic domains: a Ras of complex proteins (Roc) G-domain and a kinase domain. Mutations associated with familial and sporadic Parkinson’s disease (PD) have been identified in both catalytic domains, as well as in several of its multiple putative regulatory domains. Several of these mutations have been linked to increased kinase activity. Despite the role of LRRK2 in the pathogenesis of PD, little is known about its overall architecture and how PD-linked mutations alter its function and enzymatic activities. Here, we have modeled the 3D structure of dimeric, full-length LRRK2 by combining domain-based homology models with multiple experimental constraints provided by chemical cross-linking combined with mass spectrometry, negative-stain EM, and small-angle X-ray scattering. Our model reveals dimeric LRRK2 has a compact overall architecture with a tight, multidomain organization. Close contacts between the N-terminal ankyrin and C-terminal WD40 domains, and their proximity—together with the LRR domain—to the kinase domain suggest an intramolecular mechanism for LRRK2 kinase activity regulation. Overall, our studies provide, to our knowledge, the first structural framework for understanding the role of the different domains of full-length LRRK2 in the pathogenesis of PD. PMID:27357661

  10. CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa.

    Science.gov (United States)

    Wu, Wen-Hsuan; Tsai, Yi-Ting; Justus, Sally; Lee, Ting-Ting; Zhang, Lijuan; Lin, Chyuan-Sheng; Bassuk, Alexander G; Mahajan, Vinit B; Tsang, Stephen H

    2016-08-01

    Massive parallel sequencing enables identification of numerous genetic variants in mutant organisms, but determining pathogenicity of any one mutation can be daunting. The most commonly studied preclinical model of retinitis pigmentosa called the "rodless" (rd1) mouse is homozygous for two mutations: a nonsense point mutation (Y347X) and an intronic insertion of a leukemia virus (Xmv-28). Distinguishing which mutation causes retinal degeneration is still under debate nearly a century after the discovery of this model organism. Here, we performed gene editing using the CRISPR/Cas9 system and demonstrated that the Y347X mutation is the causative variant of disease. Genome editing in the first generation produced animals that were mosaic for the corrected allele but still showed neurofunction preservation despite low repair frequencies. Furthermore, second-generation CRISPR-repaired mice showed an even more robust rescue and amelioration of the disease. This predicts excellent outcomes for gene editing in diseased human tissue, as Pde6b, the mutated gene in rd1 mice, has an orthologous intron-exon relationship comparable with the human PDE6B gene. Not only do these findings resolve the debate surrounding the source of neurodegeneration in the rd1 model, but they also provide the first example of homology-directed recombination-mediated gene correction in the visual system.

  11. Model quality and safety studies

    DEFF Research Database (Denmark)

    Petersen, K.E.

    1997-01-01

    The paper describes the EC initiative on model quality assessment and emphasizes some of the problems encountered in the selection of data from field tests used in the evaluation process. Further, it discusses the impact of model uncertainties in safety studies of industrial plants. The model...... that most of these have never been through a procedure of evaluation, but nonetheless are used to assist in making decisions that may directly affect the safety of the public and the environment. As a major funder of European research on major industrial hazards, DGXII is conscious of the importance......-tain model is appropriate for use in solving a given problem. Further, the findings from the REDIPHEM project related to dense gas dispersion will be highlighted. Finally, the paper will discuss the need for model quality assessment in safety studies....

  12. A study of mental models

    Directory of Open Access Journals (Sweden)

    A. Tarciso Borges

    1997-09-01

    Full Text Available The concept of mental models is being used in several areas of knowledge in order to study the representations users have about physical systems and events, as well as the content of such representations. However, it cannot be considered a unitary concept. This paper discusses the assumptions envolved in different areas of knowledge and describes a study of the mental model of magnetism held by students and professionals such as electricians physics teachers, and engineers. The identified model stress two aspects: what is the origin of permanent magnets and what is the mechanism of the magnetic interaction.

  13. Integrative modeling reveals the principles of multi-scale chromatin boundary formation in human nuclear organization.

    Science.gov (United States)

    Moore, Benjamin L; Aitken, Stuart; Semple, Colin A

    2015-05-27

    Interphase chromosomes adopt a hierarchical structure, and recent data have characterized their chromatin organization at very different scales, from sub-genic regions associated with DNA-binding proteins at the order of tens or hundreds of bases, through larger regions with active or repressed chromatin states, up to multi-megabase-scale domains associated with nuclear positioning, replication timing and other qualities. However, we have lacked detailed, quantitative models to understand the interactions between these different strata. Here we collate large collections of matched locus-level chromatin features and Hi-C interaction data, representing higher-order organization, across three human cell types. We use quantitative modeling approaches to assess whether locus-level features are sufficient to explain higher-order structure, and identify the most influential underlying features. We identify structurally variable domains between cell types and examine the underlying features to discover a general association with cell-type-specific enhancer activity. We also identify the most prominent features marking the boundaries of two types of higher-order domains at different scales: topologically associating domains and nuclear compartments. We find parallel enrichments of particular chromatin features for both types, including features associated with active promoters and the architectural proteins CTCF and YY1. We show that integrative modeling of large chromatin dataset collections using random forests can generate useful insights into chromosome structure. The models produced recapitulate known biological features of the cell types involved, allow exploration of the antecedents of higher-order structures and generate testable hypotheses for further experimental studies.

  14. Hypothalamus proteomics from mouse models with obesity and anorexia reveals therapeutic targets of appetite regulation.

    Science.gov (United States)

    Manousopoulou, A; Koutmani, Y; Karaliota, S; Woelk, C H; Manolakos, E S; Karalis, K; Garbis, S D

    2016-04-25

    This study examined the proteomic profile of the hypothalamus in mice exposed to a high-fat diet (HFD) or with the anorexia of acute illness. This comparison could provide insight on the effects of these two opposite states of energy balance on appetite regulation. Four to six-week-old male C56BL/6J mice were fed a normal (control 1 group; n=7) or a HFD (HFD group; n=10) for 8 weeks. The control 2 (n=7) and lipopolysaccharide (LPS) groups (n=10) were fed a normal diet for 8 weeks before receiving an injection of saline and LPS, respectively. Hypothalamic regions were analysed using a quantitative proteomics method based on a combination of techniques including iTRAQ stable isotope labeling, orthogonal two-dimensional liquid chromatography hyphenated with nanospray ionization and high-resolution mass spectrometry. Key proteins were validated with quantitative PCR. Quantitative proteomics of the hypothalamous regions profiled a total of 9249 protein groups (qhypothalamus under the HFD and LPS nutritional conditions. Literature research with in silico bioinformatics interpretation of the differentiated proteome identified key biological relevant proteins and implicated pathways. Furthermore, the study identified potential pharmacologic targets. In the LPS groups, the anorexigen pro-opiomelanocortin was downregulated. In mice with obesity, nuclear factor-κB, glycine receptor subunit alpha-4 (GlyR) and neuropeptide Y levels were elevated, whereas serotonin receptor 1B levels decreased. High-precision quantitative proteomics revealed that under acute systemic inflammation in the hypothalamus as a response to LPS, homeostatic mechanisms mediating loss of appetite take effect. Conversely, under chronic inflammation in the hypothalamus as a response to HFD, mechanisms mediating a sustained 'perpetual cycle' of appetite enhancement were observed. The GlyR protein may constitute a novel treatment target for the reduction of central orexigenic signals in obesity.

  15. Studying a Chaotic Spiking Neural Model

    Directory of Open Access Journals (Sweden)

    Mohammad Alhawarat

    2013-09-01

    Full Text Available Dynamics of a chaotic spiking neuron model are being studied mathematically and experimentally. The Nonlinear Dynamic State neuron (NDS is analysed to further understand the model and improve it.Chaos has many interesting properties such as sensitivity to initial conditions, space filling, control and synchronization. As suggested by biologists, these properties may be exploited and play vital role in carrying out computational tasks in human brain. The NDS model has some limitations; in thus paper the model is investigated to overcomesome of these limitations in order to enhance the model. Therefore,the model’s parameters are tuned and the resulted dynamics are studied. Also, the discretization method of the model is considered. Moreover, a mathematical analysis is carried out to reveal the underlying dynamics of the model after tuning of its parameters. The results of the aforementioned methods revealedsome facts regarding the NDS attractor and suggest the stabilization of a large number of unstable periodic orbits (UPOs which might correspond to memories in phase space

  16. A heterotrimer model of the complete Microprocessor complex revealed by single-molecule subunit counting.

    Science.gov (United States)

    Herbert, Kristina M; Sarkar, Susanta K; Mills, Maria; Delgado De la Herran, Hilda C; Neuman, Keir C; Steitz, Joan A

    2016-02-01

    During microRNA (miRNA) biogenesis, the Microprocessor complex (MC), composed minimally of Drosha, an RNaseIII enzyme, and DGCR8, a double-stranded RNA-binding protein, cleaves the primary-miRNA (pri-miRNA) to release the pre-miRNA stem-loop structure. Size-exclusion chromatography of the MC, isolated from mammalian cells, suggested multiple copies of one or both proteins in the complex. However, the exact stoichiometry was unknown. Initial experiments suggested that DGCR8 bound pri-miRNA substrates specifically, and given that Drosha could not be bound or cross-linked to RNA, a sequential model for binding was established in which DGCR8 bound first and recruited Drosha. Therefore, many laboratories have studied DGCR8 binding to RNA in the absence of Drosha and have shown that deletion constructs of DGCR8 can multimerize in the presence of RNA. More recently, it was demonstrated that Drosha can bind pri-miRNA substrates in the absence of DGCR8, casting doubt on the sequential model of binding. In the same study, using a single-molecule photobleaching assay, fluorescent protein-tagged deletion constructs of DGCR8 and Drosha assembled into a heterotrimeric complex on RNA, comprising two DGCR8 molecules and one Drosha molecule. To determine the stoichiometry of Drosha and DGCR8 within the MC in the absence of added RNA, we also used a single-molecule photobleaching assay and confirmed the heterotrimeric model of the human MC. We demonstrate that a heterotrimeric complex is likely preformed in the absence of RNA and exists even when full-length proteins are expressed and purified from human cells, and when hAGT-derived tags are used rather than fluorescent proteins.

  17. Structure of naturally hydrated ferrihydrite revealed through neutron diffraction and first-principles modeling

    Science.gov (United States)

    Chappell, Helen F.; Thom, William; Bowron, Daniel T.; Faria, Nuno; Hasnip, Philip J.; Powell, Jonathan J.

    2017-08-01

    Ferrihydrite, with a ``two-line'' x-ray diffraction pattern (2L-Fh), is the most amorphous of the iron oxides and is ubiquitous in both terrestrial and aquatic environments. It also plays a central role in the regulation and metabolism of iron in bacteria, algae, higher plants, and animals, including humans. In this study, we present a single-phase model for ferrihydrite that unifies existing analytical data while adhering to fundamental chemical principles. The primary particle is small (20-50 Å) and has a dynamic and variably hydrated surface, which negates long-range order; collectively, these features have hampered complete characterization and frustrated our understanding of the mineral's reactivity and chemical/biochemical function. Near and intermediate range neutron diffraction (NIMROD) and first-principles density functional theory (DFT) were employed in this study to generate and interpret high-resolution data of naturally hydrated, synthetic 2L-Fh at standard temperature. The structural optimization overcomes transgressions of coordination chemistry inherent within previously proposed structures, to produce a robust and unambiguous single-phase model.

  18. Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States.

    Science.gov (United States)

    Witek, Jagna; Keller, Bettina G; Blatter, Markus; Meissner, Axel; Wagner, Trixie; Riniker, Sereina

    2016-08-22

    The membrane permeability of cyclic peptides and peptidomimetics, which are generally larger and more complex than typical drug molecules, is likely strongly influenced by the conformational behavior of these compounds in polar and apolar environments. The size and complexity of peptides often limit their bioavailability, but there are known examples of peptide natural products such as cyclosporin A (CsA) that can cross cell membranes by passive diffusion. CsA is an undecapeptide with seven methylated backbone amides. Its crystal structure shows a "closed" twisted β-pleated sheet conformation with four intramolecular hydrogen bonds that is also observed in NMR measurements of CsA in chloroform. When binding to its target cyclophilin, on the other hand, CsA adopts an "open" conformation without intramolecular hydrogen bonds. In this study, we attempted to sample the complete conformational space of CsA in chloroform and in water by molecular dynamics simulations in order to better understand its conformational behavior in these two environments and to rationalize the good membrane permeability of CsA observed experimentally. From 10 μs molecular dynamics simulations in each solvent, Markov state models were constructed to characterize the metastable conformational states. The model in chloroform is compared to nuclear Overhauser effect NMR spectroscopy data reported in this study and taken from the literature. The conformational landscapes in the two solvents show significant overlap but also clearly distinct features.

  19. N-gram analysis of 970 microbial organisms reveals presence of biological language models

    Directory of Open Access Journals (Sweden)

    Ganapathiraju Madhavi K

    2011-01-01

    Full Text Available Abstract Background It has been suggested previously that genome and proteome sequences show characteristics typical of natural-language texts such as "signature-style" word usage indicative of authors or topics, and that the algorithms originally developed for natural language processing may therefore be applied to genome sequences to draw biologically relevant conclusions. Following this approach of 'biological language modeling', statistical n-gram analysis has been applied for comparative analysis of whole proteome sequences of 44 organisms. It has been shown that a few particular amino acid n-grams are found in abundance in one organism but occurring very rarely in other organisms, thereby serving as genome signatures. At that time proteomes of only 44 organisms were available, thereby limiting the generalization of this hypothesis. Today nearly 1,000 genome sequences and corresponding translated sequences are available, making it feasible to test the existence of biological language models over the evolutionary tree. Results We studied whole proteome sequences of 970 microbial organisms using n-gram frequencies and cross-perplexity employing the Biological Language Modeling Toolkit and Patternix Revelio toolkit. Genus-specific signatures were observed even in a simple unigram distribution. By taking statistical n-gram model of one organism as reference and computing cross-perplexity of all other microbial proteomes with it, cross-perplexity was found to be predictive of branch distance of the phylogenetic tree. For example, a 4-gram model from proteome of Shigellae flexneri 2a, which belongs to the Gammaproteobacteria class showed a self-perplexity of 15.34 while the cross-perplexity of other organisms was in the range of 15.59 to 29.5 and was proportional to their branching distance in the evolutionary tree from S. flexneri. The organisms of this genus, which happen to be pathotypes of E.coli, also have the closest perplexity values with

  20. A zebrafish larval model reveals early tissue-specific innate immune responses to Mucor circinelloides

    Directory of Open Access Journals (Sweden)

    Kerstin Voelz

    2015-11-01

    as a live whole-animal model system will contribute greatly to the study of molecular mechanisms involved in the interaction of the host innate immune system with fungal spores during mucormycosis.

  1. Physiological modeling reveals novel pharmacokinetic behavior for inhaled octamethylcyclotetrasiloxane in rats.

    Science.gov (United States)

    Andersen, M E; Sarangapani, R; Reitz, R H; Gallavan, R H; Dobrev, I D; Plotzke, K P

    2001-04-01

    Octamethylcyclotetrasiloxane (D4) is an ingredient in selected consumer and precision cleaning products. Workplace inhalation exposures may occur in some D4 production operations. In this study, we analyzed tissue, plasma, and excreta time-course data following D4 inhalation in Fischer 344 rats (K. Plotzke et al., 2000, Drug Metab. Dispos. 28, 192-204) to assess the degree to which the disposition of D4 is similar to or different from that of volatile hydrocarbons that lack silicone substitution. We first applied a basic physiologically based pharmacokinetic (PBPK) model (J. C. Ramsey and M. E. Andersen, 1984, Toxicol. Appl. Pharmacol. 73, 159-175) to characterize the biological determinants of D4 kinetics. Parameter estimation techniques indicated an unusual set of characteristics, i.e., a low blood:air (P(b:a) congruent with 0.9) and a high fat:blood partition coefficient (P(f:b) congruent with 550). These parameters were then determined experimentally by equilibrating tissue or liquid samples with saturated atmospheres of D4. Consistent with the estimates from the time-course data, blood:air partition coefficients were small, ranging from 1.9 to 6.9 in six samples. Perirenal fat:air partition coefficients were large, from 1400 to 2500. The average P(f:b) was determined to be 485. This combination of partitioning characteristics leads to rapid exhalation of free D4 at the cessation of the inhalation exposure followed by a much slower redistribution of D4 from fat and tissue storage compartments. The basic PK model failed to describe D4 tissue kinetics in the postexposure period and had to be expanded by adding deep-tissue compartments in liver and lung, a mobile chylomicron-like lipid transport pool in blood, and a second fat compartment. Model parameters for the refined model were optimized using single-exposure data in male and female rats exposed at three concentrations: 7, 70, and 700 ppm. With inclusion of induction of D4 metabolism at 700 ppm (3-fold in

  2. Integrating Kinetic Model of E. coli with Genome Scale Metabolic Fluxes Overcomes Its Open System Problem and Reveals Bistability in Central Metabolism.

    Directory of Open Access Journals (Sweden)

    Ahmad A Mannan

    Full Text Available An understanding of the dynamics of the metabolic profile of a bacterial cell is sought from a dynamical systems analysis of kinetic models. This modelling formalism relies on a deterministic mathematical description of enzyme kinetics and their metabolite regulation. However, it is severely impeded by the lack of available kinetic information, limiting the size of the system that can be modelled. Furthermore, the subsystem of the metabolic network whose dynamics can be modelled is faced with three problems: how to parameterize the model with mostly incomplete steady state data, how to close what is now an inherently open system, and how to account for the impact on growth. In this study we address these challenges of kinetic modelling by capitalizing on multi-'omics' steady state data and a genome-scale metabolic network model. We use these to generate parameters that integrate knowledge embedded in the genome-scale metabolic network model, into the most comprehensive kinetic model of the central carbon metabolism of E. coli realized to date. As an application, we performed a dynamical systems analysis of the resulting enriched model. This revealed bistability of the central carbon metabolism and thus its potential to express two distinct metabolic states. Furthermore, since our model-informing technique ensures both stable states are constrained by the same thermodynamically feasible steady state growth rate, the ensuing bistability represents a temporal coexistence of the two states, and by extension, reveals the emergence of a phenotypically heterogeneous population.

  3. Dynamic Modelling Reveals 'Hotspots' on the Pathway to Enzyme-Substrate Complex Formation.

    Directory of Open Access Journals (Sweden)

    Shane E Gordon

    2016-03-01

    Full Text Available Dihydrodipicolinate synthase (DHDPS catalyzes the first committed step in the diaminopimelate pathway of bacteria, yielding amino acids required for cell wall and protein biosyntheses. The essentiality of the enzyme to bacteria, coupled with its absence in humans, validates DHDPS as an antibacterial drug target. Conventional drug design efforts have thus far been unsuccessful in identifying potent DHDPS inhibitors. Here, we make use of contemporary molecular dynamics simulation and Markov state models to explore the interactions between DHDPS from the human pathogen Staphylococcus aureus and its cognate substrate, pyruvate. Our simulations recover the crystallographic DHDPS-pyruvate complex without a priori knowledge of the final bound structure. The highly conserved residue Arg140 was found to have a pivotal role in coordinating the entry of pyruvate into the active site from bulk solvent, consistent with previous kinetic reports, indicating an indirect role for the residue in DHDPS catalysis. A metastable binding intermediate characterized by multiple points of intermolecular interaction between pyruvate and key DHDPS residue Arg140 was found to be a highly conserved feature of the binding trajectory when comparing alternative binding pathways. By means of umbrella sampling we show that these binding intermediates are thermodynamically metastable, consistent with both the available experimental data and the substrate binding model presented in this study. Our results provide insight into an important enzyme-substrate interaction in atomistic detail that offers the potential to be exploited for the discovery of more effective DHDPS inhibitors and, in a broader sense, dynamic protein-drug interactions.

  4. Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen-induced toxicity in humans.

    Science.gov (United States)

    Thiel, C; Cordes, H; Baier, V; Blank, L M; Kuepfer, L

    2017-02-01

    Acetaminophen (APAP) is a widely used analgesic drug that is frequently co-administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP-induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co-medication with CAF. Therefore, drug-drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug-specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP-induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  5. Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

    Science.gov (United States)

    Thiel, C; Cordes, H; Baier, V; Blank, LM

    2017-01-01

    Acetaminophen (APAP) is a widely used analgesic drug that is frequently co‐administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP‐induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co‐medication with CAF. Therefore, drug‐drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug‐specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP‐induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice. PMID:28130915

  6. Mammary-Stem-Cell-Based Somatic Mouse Models Reveal Breast Cancer Drivers Causing Cell Fate Dysregulation

    Directory of Open Access Journals (Sweden)

    Zheng Zhang

    2016-09-01

    Full Text Available Cancer genomics has provided an unprecedented opportunity for understanding genetic causes of human cancer. However, distinguishing which mutations are functionally relevant to cancer pathogenesis remains a major challenge. We describe here a mammary stem cell (MaSC organoid-based approach for rapid generation of somatic genetically engineered mouse models (GEMMs. By using RNAi and CRISPR-mediated genome engineering in MaSC-GEMMs, we have discovered that inactivation of Ptpn22 or Mll3, two genes mutated in human breast cancer, greatly accelerated PI3K-driven mammary tumorigenesis. Using these tumor models, we have also identified genetic alterations promoting tumor metastasis and causing resistance to PI3K-targeted therapy. Both Ptpn22 and Mll3 inactivation resulted in disruption of mammary gland differentiation and an increase in stem cell activity. Mechanistically, Mll3 deletion enhanced stem cell activity through activation of the HIF pathway. Thus, our study has established a robust in vivo platform for functional cancer genomics and has discovered functional breast cancer mutations.

  7. Ambiguity revealed

    OpenAIRE

    Bayer, Ralph-C; Bose, Subir; Polisson, Matthew; Renou, Ludovic

    2013-01-01

    We derive necessary and sufficient conditions for data sets composed of state-contingent prices and consumption to be consistent with two prominent models of decision making under uncertainty: variational preferences and smooth ambiguity. The revealed preference conditions for subjective expected utility, maxmin expected utility, and multiplier preferences are characterised as special cases. We implement our tests on data from a portfolio choice experiment.

  8. Mechanics of the IL2RA gene activation revealed by modeling and atomic force microscopy.

    Science.gov (United States)

    Milani, Pascale; Marilley, Monique; Sanchez-Sevilla, Albert; Imbert, Jean; Vaillant, Cédric; Argoul, Françoise; Egly, Jean-Marc; Rocca-Serra, José; Arneodo, Alain

    2011-04-13

    Transcription implies recruitment of RNA polymerase II and transcription factors (TFs) by DNA melting near transcription start site (TSS). Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites), located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studies, result in the progressive positioning of curvature apex towards the TSS, likely facilitating local DNA melting. In vitro assays confirm specific binding of the General Transcription Factors (GTFs) TBP and TFIIB over TATA-TSS position, where an inhibitory nucleosome prevented preinitiation complex (PIC) formation and uncontrolled DNA melting. These findings represent a substantial advance showing, first, that the structural properties of the IL2RA promoter are encoded in the DNA sequence and second, that during the initiation process DNA conformation is dynamic and not static.

  9. Study design in causal models

    OpenAIRE

    2012-01-01

    The causal assumptions, the study design and the data are the elements required for scientific inference in empirical research. The research is adequately communicated only if all of these elements and their relations are described precisely. Causal models with design describe the study design and the missing data mechanism together with the causal structure and allow the direct application of causal calculus in the estimation of the causal effects. The flow of the study is visualized by orde...

  10. Phylogenetic and Molecular Variability Studies Reveal a New Genetic Clade of Citrus leprosis virus C.

    Science.gov (United States)

    Ramos-González, Pedro Luis; Chabi-Jesus, Camila; Guerra-Peraza, Orlene; Breton, Michèle Claire; Arena, Gabriella Dias; Nunes, Maria Andreia; Kitajima, Elliot Watanabe; Machado, Marcos Antonio; Freitas-Astúa, Juliana

    2016-06-06

    Citrus leprosis virus C (CiLV-C) causes a severe disease affecting citrus orchards in the Western hemisphere. This study reveals the molecular variability of the virus by analyzing four genomic regions (p29, p15, MP and RNA2-intergenic region) distributed over its two RNAs. Nucleotide diversity (π) values were relatively low but statistically different over the analyzed genes and subpopulations, indicating their distinct evolutionary history. Values of πp29 and πMP were higher than those of πp15 and πRNA2-IR, whereas πMP was increased due to novel discovered isolates phylogenetically clustered in a divergent clade that we called SJP. Isolate BR_SP_SJP_01 RNA1 and RNA2 sequences, clade SJP, showed an identity of 85.6% and 88.4%, respectively, with those corresponding to CiLV-C, the type member of the genus Cilevirus, and its RNA2 5'-proximal region was revealed as a minor donor in a putative inter-clade recombination event. In addition to citrus, BR_SP_SJP_01 naturally infects the weed Commelina benghalensis and is efficiently transmitted by Brevipalpus yothersi mites. Our data demonstrated that negative selection was the major force operating in the evaluated viral coding regions and defined amino acids putatively relevant for the biological function of cilevirus proteins. This work provides molecular tools and sets up a framework for further epidemiological studies.

  11. Study of integrated heterogeneous data reveals prognostic power of gene expression for breast cancer survival.

    Directory of Open Access Journals (Sweden)

    Richard E Neapolitan

    Full Text Available Studies show that thousands of genes are associated with prognosis of breast cancer. Towards utilizing available genetic data, efforts have been made to predict outcomes using gene expression data, and a number of commercial products have been developed. These products have the following shortcomings: 1 They use the Cox model for prediction. However, the RSF model has been shown to significantly outperform the Cox model. 2 Testing was not done to see if a complete set of clinical predictors could predict as well as the gene expression signatures.We address these shortcomings. The METABRIC data set concerns 1981 breast cancer tumors. Features include 21 clinical features, expression levels for 16,384 genes, and survival. We compare the survival prediction performance of the Cox model and the RSF model using the clinical data and the gene expression data to their performance using only the clinical data. We obtain significantly better results when we used both clinical data and gene expression data for 5 year, 10 year, and 15 year survival prediction. When we replace the gene expression data by PAM50 subtype, our results are significant only for 5 year and 15 year prediction. We obtain significantly better results using the RSF model over the Cox model. Finally, our results indicate that gene expression data alone may predict long-term survival.Our results indicate that we can obtain improved survival prediction using clinical data and gene expression data compared to prediction using only clinical data. We further conclude that we can obtain improved survival prediction using the RSF model instead of the Cox model. These results are significant because by incorporating more gene expression data with clinical features and using the RSF model, we could develop decision support systems that better utilize heterogeneous information to improve outcome prediction and decision making.

  12. Range wide molecular data and niche modeling revealed the Pleistocene history of a global invader (Halyomorpha halys)

    Science.gov (United States)

    Zhu, Geng-Ping; Ye, Zhen; Du, Juan; Zhang, Dan-Li; Zhen, Ya-hui; Zheng, Chen-guang; Zhao, Li; Li, Min; Bu, Wen-Jun

    2016-01-01

    Invasive species’ Pleistocene history contains much information on its present population structure, dispersability and adaptability. In this study, the Pleistocene history of a global invasive pest (Brown Marmorated Stink Bug BMSB, Halyomorpha halys) was unveiled using the coupled approach of phylogeography and ecological niche modelling. Rangewide molecular data suggests that the Taiwan and other native populations had diverged in mid-Pleistocene. In mainland China, the native BMSB did not experience population contraction and divergence during last glacial, but persisted in interconnected populations. Combined Bayesian Skyline Plot (BSP) and niche modelling revealed a rapid expansion occurred during the transition of Last Inter Glacial (LIG) to Last Glacial Maximum (LGM). High genetic diversity and multi-reticular haplotypes network exist in the original sources populations of BMSB invasion in northern China. They were speculated to be colonized from the central China, with many derived haplotypes evolved to adapt the novel environment. The ENM future prediction suggest that BMSB may expand northward to higher latitudes in the US and Europe, because of its high invasive ability, together with the available suitable climate space there. PMID:26996353

  13. Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

    Directory of Open Access Journals (Sweden)

    Insa Bultmann-Mellin

    2015-04-01

    Full Text Available Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C, which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S−/−, the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S−/− and Ltbp4-null (Ltbp4−/− mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM. Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.

  14. Bioenergetic modeling reveals that Chinese green tree vipers select postprandial temperatures in laboratory thermal gradients that maximize net energy intake.

    Science.gov (United States)

    Tsai, Tein-Shun; Lee, How-Jing; Tu, Ming-Chung

    2009-11-01

    With bioenergetic modeling, we tested the hypothesis that reptiles maximize net energy gain by postprandial thermal selection. Previous studies have shown that Chinese green tree vipers (Trimeresurus s. stejnegeri) have postprandial thermophily (mean preferred temperature T(p) for males =27.8 degrees C) in a linear thigmothermal gradient when seclusion sites and water existed. With some published empirical models of digestion associated factors for this snake, we calculated the average rate (E(net)) and efficiency (K(net)) of net energy gain from possible combinations of meal size, activity level, and feeding frequency at each temperature. The simulations consistently revealed that E(net) maximizes at the T(p) of these snakes. Although the K(net) peaks at a lower temperature than E(net), the value of K(net) remains high (>=0.85 in ratio to maximum) at the peak temperature of E(net). This suggested that the demands of both E(net) and K(net) can be attained by postprandial thermal selection in this snake. In conclusion, the data support our prediction that postprandial thermal selection may maximize net energy gain.

  15. Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment.

    Science.gov (United States)

    Biezonski, D; Shah, R; Krivko, A; Cha, J; Guilfoyle, D N; Hrabe, J; Gerum, S; Xie, S; Duan, Y; Bansal, R; Leventhal, B L; Peterson, B S; Kellendonk, C; Posner, J

    2016-09-06

    Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, 'Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy.

  16. Longitudinal magnetic resonance imaging reveals striatal hypertrophy in a rat model of long-term stimulant treatment

    Science.gov (United States)

    Biezonski, D; Shah, R; Krivko, A; Cha, J; Guilfoyle, D N; Hrabe, J; Gerum, S; Xie, S; Duan, Y; Bansal, R; Leventhal, B L; Peterson, B S; Kellendonk, C; Posner, J

    2016-01-01

    Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, ‘Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy. PMID:27598968

  17. Revealing pathologies in the liquid crystalline structures of the brain by polarimetric studies (Presentation Recording)

    Science.gov (United States)

    Bakhshetyan, Karen; Melkonyan, Gurgen G.; Galstian, Tigran V.; Saghatelyan, Armen

    2015-10-01

    Natural or "self" alignment of molecular complexes in living tissue represents many similarities with liquid crystals (LC), which are anisotropic liquids. The orientational characteristics of those complexes may be related to many important functional parameters and their study may reveal important pathologies. The know-how, accumulated thanks to the study of LC materials, may thus be used to this end. One of the traditionally used methods, to characterize those materials, is the polarized light imaging (PLI) that allows for label-free analysis of anisotropic structures in the brain tissue and can be used, for example, for the analysis of myelinated fiber bundles. In the current work, we first attempted to apply the PLI on the mouse histological brain sections to create a map of anisotropic structures using cross-polarizer transmission light. Then we implemented the PLI for comparative study of histological sections of human postmortem brain samples under normal and pathological conditions, such as Parkinson's disease (PD). Imaging the coronal, sagittal and horizontal sections of mouse brain allowed us to create a false color-coded fiber orientation map under polarized light. In human brain datasets for both control and PD groups we measured the pixel intensities in myelin-rich subregions of internal capsule and normalized these to non-myelinated background signal from putamen and caudate nucleus. Quantification of intensities revealed a statistically significant reduction of fiber intensity of PD compared to control subjects (2.801 +/- 0.303 and 3.724 +/- 0.07 respectively; *p < 0.05). Our study confirms the validity of PLI method for visualizing myelinated axonal fibers. This relatively simple technique can become a promising tool for study of neurodegenerative diseases where labeling-free imaging is an important benefit.

  18. Revealing characteristics of mixed consortia for azo dye decolorization: Lotka-Volterra model and game theory.

    Science.gov (United States)

    Chen, Bor-Yann

    2007-10-22

    This study provides a novel explanation to put forward, in Lotka-Volterra competition model and game theory, interspecific competition in bioaugmentation using constructed mixed consortia for azo dye decolorization. As mixed cultures are regularly used in industrial dye-laden wastewater treatment, understanding species competition of mixed consortia is apparently of great importance to azo dye decolorization. In aerobic growth conditions, Escherichia coli DH5alpha owned a growth advantage to out-compete Pseudomonas luteola due to preferential growth rate of DH5alpha. However, in static decolorization conditions DH5alpha surrendered some proportion of its advantage (i.e., a decrease in its competitive power for metabolite stimulation) to enhance color removal of P. luteola for total coexistence. In aerobic growth, DH5alpha had its growth advantage to exclude P. luteola for dominance (i.e, conflict strategy) according to competitive exclusion principle. In static decolorization conditions, as the removal of a common dye threat was crucial to both species for survival, both species selected cooperation strategy through metabolite stimulation of DH5alpha to enhance effective decolorization of P. luteola for long-term sustainable management. This analysis of game theory clearly unlocked unsolved mysteries in previous studies.

  19. Molecular tools and bumble bees: revealing hidden details of ecology and evolution in a model system.

    Science.gov (United States)

    Woodard, S Hollis; Lozier, Jeffrey D; Goulson, David; Williams, Paul H; Strange, James P; Jha, Shalene

    2015-06-01

    Bumble bees are a longstanding model system for studies on behaviour, ecology and evolution, due to their well-studied social lifestyle, invaluable role as wild and managed pollinators, and ubiquity and diversity across temperate ecosystems. Yet despite their importance, many aspects of bumble bee biology have remained enigmatic until the rise of the genetic and, more recently, genomic eras. Here, we review and synthesize new insights into the ecology, evolution and behaviour of bumble bees that have been gained using modern genetic and genomic techniques. Special emphasis is placed on four areas of bumble bee biology: the evolution of eusociality in this group, population-level processes, large-scale evolutionary relationships and patterns, and immunity and resistance to pesticides. We close with a prospective on the future of bumble bee genomics research, as this rapidly advancing field has the potential to further revolutionize our understanding of bumble bees, particularly in regard to adaptation and resilience. Worldwide, many bumble bee populations are in decline. As such, throughout the review, connections are drawn between new molecular insights into bumble bees and our understanding of the causal factors involved in their decline. Ongoing and potential applications to bumble bee management and conservation are also included to demonstrate how genetics- and genomics-enabled research aids in the preservation of this threatened group. © 2015 John Wiley & Sons Ltd.

  20. A spastic paraplegia mouse model reveals REEP1-dependent ER shaping.

    Science.gov (United States)

    Beetz, Christian; Koch, Nicole; Khundadze, Mukhran; Zimmer, Geraldine; Nietzsche, Sandor; Hertel, Nicole; Huebner, Antje-Kathrin; Mumtaz, Rizwan; Schweizer, Michaela; Dirren, Elisabeth; Karle, Kathrin N; Irintchev, Andrey; Alvarez, Victoria; Redies, Christoph; Westermann, Martin; Kurth, Ingo; Deufel, Thomas; Kessels, Michael M; Qualmann, Britta; Hübner, Christian A

    2013-10-01

    Axonopathies are a group of clinically diverse disorders characterized by the progressive degeneration of the axons of specific neurons. In hereditary spastic paraplegia (HSP), the axons of cortical motor neurons degenerate and cause a spastic movement disorder. HSP is linked to mutations in several loci known collectively as the spastic paraplegia genes (SPGs). We identified a heterozygous receptor accessory protein 1 (REEP1) exon 2 deletion in a patient suffering from the autosomal dominantly inherited HSP variant SPG31. We generated the corresponding mouse model to study the underlying cellular pathology. Mice with heterozygous deletion of exon 2 in Reep1 displayed a gait disorder closely resembling SPG31 in humans. Homozygous exon 2 deletion resulted in the complete loss of REEP1 and a more severe phenotype with earlier onset. At the molecular level, we demonstrated that REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the ER. We further show that Reep1 expression was prominent in cortical motor neurons. In REEP1-deficient mice, these neurons showed reduced complexity of the peripheral ER upon ultrastructural analysis. Our study connects proper neuronal ER architecture to long-term axon survival.

  1. Revealing the mystery of metabolic adaptations using a genome scale model of Leishmania infantum.

    Science.gov (United States)

    Subramanian, Abhishek; Sarkar, Ram Rup

    2017-08-31

    Human macrophage phagolysosome and sandfly midgut provide antagonistic ecological niches for Leishmania parasites to survive and proliferate. Parasites optimize their metabolism to utilize the available inadequate resources by adapting to those environments. Lately, a number of metabolomics studies have revived the interest to understand metabolic strategies utilized by the Leishmania parasite for optimal survival within its hosts. For the first time, we propose a reconstructed genome-scale metabolic model for Leishmania infantum JPCM5, the analyses of which not only captures observations reported by metabolomics studies in other Leishmania species but also divulges novel features of the L. infantum metabolome. Our results indicate that Leishmania metabolism is organized in such a way that the parasite can select appropriate alternatives to compensate for limited external substrates. A dynamic non-essential amino acid motif exists within the network that promotes a restricted redistribution of resources to yield required essential metabolites. Further, subcellular compartments regulate this metabolic re-routing by reinforcing the physiological coupling of specific reactions. This unique metabolic organization is robust against accidental errors and provides a wide array of choices for the parasite to achieve optimal survival.

  2. Competing mechanisms for perfluoroalkyl acid accumulation in plants revealed using an Arabidopsis model system.

    Science.gov (United States)

    Müller, Claudia E; LeFevre, Gregory H; Timofte, Anca E; Hussain, Fatima A; Sattely, Elizabeth S; Luthy, Richard G

    2016-05-01

    Perfluoroalkyl acids (PFAAs) bioaccumulate in plants, presenting a human exposure route if present in irrigation water. Curiously, accumulation of PFAAs in plant tissues is greatest for both the short-chain and long-chain PFAAs, generating a U-shaped relationship with chain length. In the present study, the authors decouple competing mechanisms of PFAA accumulation using a hydroponic model plant system (Arabidopsis thaliana) exposed to a suite of 10 PFAAs to determine uptake, depuration, and translocation kinetics. Rapid saturation of root concentrations occurred for all PFAAs except perfluorobutanoate, the least-sorptive (shortest-chain) PFAA. Shoot concentrations increased continuously, indicating that PFAAs are efficiently transported and accumulate in shoots. Tissue concentrations of PFAAs during depuration rapidly declined in roots but remained constant in shoots, demonstrating irreversibility of the translocation process. Root and shoot concentration factors followed the U-shaped trend with perfluoroalkyl chain length; however, when normalized to dead-tissue sorption, this relationship linearized. The authors therefore introduce a novel term, the "sorption normalized concentration factor," to describe PFAA accumulation in plants; because of their hydrophobicity, sorption is the determining factor for long-chain PFAAs, whereas the shortest-chain PFAAs are most effectively transported in the plant. The present study provides a mechanistic explanation for previously unexplained PFAA accumulation trends in plants and suggests that shorter-chained PFAAs may bioaccumulate more readily in edible portions.

  3. Isotope studies reveal a complete Himalayan section in the Nanga Parbat syntaxis

    Science.gov (United States)

    Argles, Tom; Foster, Gavin; Whittington, Alan; Harris, Nigel; George, Mark

    2003-12-01

    Many models of orogenesis invoke simple anatomies for mountain belts, comprising a small number of major tectonic provinces separated by major faults. In the Himalayan arc, three main tectonic provinces (the Lesser Himalayan, High Himalayan and Tethyan Series) have been recognized over 2500 km along strike from Bhutan to Kashmir. However, their extension westward to the Nanga Parbat syntaxis remains equivocal. We have supplemented detailed field work in the area with isotopic analysis aimed at revealing distinct signatures for each of the three main provinces. Using Sr isotopic data to refine previous Nd-based discrimination, we demonstrate that the three main tectonic provinces of the central Himalaya also occur in the western syntaxis of northern Pakistan. These three units are thus continuous along the entire orogenic arc. However, their metamorphic grade is generally higher in the syntaxis than in the central Himalaya, challenging the validity of distinctions commonly drawn on this basis elsewhere in the mountain belt. The corollary is that these high-grade units probably continue beyond the syntaxis into northwestern Pakistan, which suggests that, although the precollisional materials may be identical, the western syntaxis marks a change in tectonic style from the main orogen. This conclusion in turn requires that the burial and exhumation history in the western Himalaya be radically different from that in the central Himalaya and thus necessitates a reexamination of models for India-Asia collision.

  4. Potential Role of the Last Half Repeat in TAL Effectors Revealed by a Molecular Simulation Study

    Directory of Open Access Journals (Sweden)

    Hua Wan

    2016-01-01

    Full Text Available TAL effectors (TALEs contain a modular DNA-binding domain that is composed of tandem repeats. In all naturally occurring TALEs, the end of tandem repeats is invariantly a truncated half repeat. To investigate the potential role of the last half repeat in TALEs, we performed comparative molecular dynamics simulations for the crystal structure of DNA-bound TALE AvrBs3 lacking the last half repeat and its modeled structure having the last half repeat. The structural stability analysis indicates that the modeled system is more stable than the nonmodeled system. Based on the principle component analysis, it is found that the AvrBs3 increases its structural compactness in the presence of the last half repeat. The comparison of DNA groove parameters of the two systems implies that the last half repeat also causes the change of DNA major groove binding efficiency. The following calculation of hydrogen bond reveals that, by stabilizing the phosphate binding with DNA at the C-terminus, the last half repeat helps to adopt a compact conformation at the protein-DNA interface. It further mediates more contacts between TAL repeats and DNA nucleotide bases. Finally, we suggest that the last half repeat is required for the high-efficient recognition of DNA by TALE.

  5. Potential Role of the Last Half Repeat in TAL Effectors Revealed by a Molecular Simulation Study

    Science.gov (United States)

    Wan, Hua; Chang, Shan; Hu, Jian-ping; Tian, Xu-hong

    2016-01-01

    TAL effectors (TALEs) contain a modular DNA-binding domain that is composed of tandem repeats. In all naturally occurring TALEs, the end of tandem repeats is invariantly a truncated half repeat. To investigate the potential role of the last half repeat in TALEs, we performed comparative molecular dynamics simulations for the crystal structure of DNA-bound TALE AvrBs3 lacking the last half repeat and its modeled structure having the last half repeat. The structural stability analysis indicates that the modeled system is more stable than the nonmodeled system. Based on the principle component analysis, it is found that the AvrBs3 increases its structural compactness in the presence of the last half repeat. The comparison of DNA groove parameters of the two systems implies that the last half repeat also causes the change of DNA major groove binding efficiency. The following calculation of hydrogen bond reveals that, by stabilizing the phosphate binding with DNA at the C-terminus, the last half repeat helps to adopt a compact conformation at the protein-DNA interface. It further mediates more contacts between TAL repeats and DNA nucleotide bases. Finally, we suggest that the last half repeat is required for the high-efficient recognition of DNA by TALE. PMID:27803930

  6. Multi-Analytical Approach Reveals Potential Microbial Indicators in Soil for Sugarcane Model Systems.

    Directory of Open Access Journals (Sweden)

    Acacio Aparecido Navarrete

    Full Text Available This study focused on the effects of organic and inorganic amendments and straw retention on the microbial biomass (MB and taxonomic groups of bacteria in sugarcane-cultivated soils in a greenhouse mesocosm experiment monitored for gas emissions and chemical factors. The experiment consisted of combinations of synthetic nitrogen (N, vinasse (V; a liquid waste from ethanol production, and sugarcane-straw blankets. Increases in CO2-C and N2O-N emissions were identified shortly after the addition of both N and V to the soils, thus increasing MB nitrogen (MB-N and decreasing MB carbon (MB-C in the N+V-amended soils and altering soil chemical factors that were correlated with the MB. Across 57 soil metagenomic datasets, Actinobacteria (31.5%, Planctomycetes (12.3%, Deltaproteobacteria (12.3%, Alphaproteobacteria (12.0% and Betaproteobacteria (11.1% were the most dominant bacterial groups during the experiment. Differences in relative abundance of metagenomic sequences were mainly revealed for Acidobacteria, Actinobacteria, Gammaproteobacteria and Verrucomicrobia with regard to N+V fertilization and straw retention. Differential abundances in bacterial groups were confirmed using 16S rRNA gene-targeted phylum-specific primers for real-time PCR analysis in all soil samples, whose results were in accordance with sequence data, except for Gammaproteobacteria. Actinobacteria were more responsive to straw retention with Rubrobacterales, Bifidobacteriales and Actinomycetales related to the chemical factors of N+V-amended soils. Acidobacteria subgroup 7 and Opitutae, a verrucomicrobial class, were related to the chemical factors of soils without straw retention as a surface blanket. Taken together, the results showed that MB-C and MB-N responded to changes in soil chemical factors and CO2-C and N2O-N emissions, especially for N+V-amended soils. The results also indicated that several taxonomic groups of bacteria, such as Acidobacteria, Actinobacteria and

  7. Genetic models reveal historical patterns of sea lamprey population fluctuations within Lake Champlain

    Directory of Open Access Journals (Sweden)

    Cassidy C. D’Aloia

    2015-10-01

    Full Text Available The origin of sea lamprey (Petromyzon marinus in Lake Champlain has been heavily debated over the past decade. Given the lack of historical documentation, two competing hypotheses have emerged in the literature. First, it has been argued that the relatively recent population size increase and concomitant rise in wounding rates on prey populations are indicative of an invasive population that entered the lake through the Champlain Canal. Second, recent genetic evidence suggests a post-glacial colonization at the end of the Pleistocene, approximately 11,000 years ago. One limitation to resolving the origin of sea lamprey in Lake Champlain is a lack of historical and current measures of population size. In this study, the issue of population size was explicitly addressed using nuclear (nDNA and mitochondrial DNA (mtDNA markers to estimate historical demography with genetic models. Haplotype network analysis, mismatch analysis, and summary statistics based on mtDNA noncoding sequences for NCI (479 bp and NCII (173 bp all indicate a recent population expansion. Coalescent models based on mtDNA and nDNA identified two potential demographic events: a population decline followed by a very recent population expansion. The decline in effective population size may correlate with land-use and fishing pressure changes post-European settlement, while the recent expansion may be associated with the implementation of the salmonid stocking program in the 1970s. These results are most consistent with the hypothesis that sea lamprey are native to Lake Champlain; however, the credibility intervals around parameter estimates demonstrate that there is uncertainty regarding the magnitude and timing of past demographic events.

  8. A zebrafish model of manganism reveals reversible and treatable symptoms that are independent of neurotoxicity

    Science.gov (United States)

    Bakthavatsalam, Subha; Das Sharma, Shreya; Sonawane, Mahendra; Thirumalai, Vatsala; Datta, Ankona

    2014-01-01

    Manganese (manganese ion; referred to as Mn) is essential for neuronal function, yet it is toxic at high concentrations. Environmental and occupational exposure to high concentrations of Mn causes manganism, a well-defined movement disorder in humans, with symptoms resembling Parkinson’s disease (PD). However, manganism is distinct from PD and the neural basis of its pathology is poorly understood. To address this issue, we generated a zebrafish model of manganism by incubating larvae in rearing medium containing Mn. We find that Mn-treated zebrafish larvae exhibit specific postural and locomotor defects. Larvae begin to float on their sides, show a curved spine and swim in circles. We discovered that treatment with Mn causes postural defects by interfering with mechanotransduction at the neuromasts. Furthermore, we find that the circling locomotion could be caused by long-duration bursting in the motor neurons, which can lead to long-duration tail bends in the Mn-treated larvae. Mn-treated larvae also exhibited fewer startle movements. Additionally, we show that the intensity of tyrosine hydroxylase immunoreactivity is reversibly reduced after Mn-treatment. This led us to propose that reduced dopamine neuromodulation drives the changes in startle movements. To test this, when we supplied an external source of dopamine to Mn-treated larvae, the larvae exhibited a normal number of startle swims. Taken together, these results indicate that Mn interferes with neuronal function at the sensory, motor and modulatory levels, and open avenues for therapeutically targeted studies on the zebrafish model of manganism. PMID:25261567

  9. Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function.

    Science.gov (United States)

    Sztal, Tamar E; Zhao, Mo; Williams, Caitlin; Oorschot, Viola; Parslow, Adam C; Giousoh, Aminah; Yuen, Michaela; Hall, Thomas E; Costin, Adam; Ramm, Georg; Bird, Phillip I; Busch-Nentwich, Elisabeth M; Stemple, Derek L; Currie, Peter D; Cooper, Sandra T; Laing, Nigel G; Nowak, Kristen J; Bryson-Richardson, Robert J

    2015-09-01

    Nemaline myopathy is characterized by muscle weakness and the presence of rod-like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle α-actin (ACTA1) and nebulin (NEB). We identify three distinct types of nemaline bodies and visualize their formation in vivo, demonstrating these nemaline bodies not only exhibit different subcellular origins, but also have distinct pathological consequences within the skeletal muscle. One subtype is highly dynamic and upon breakdown leads to the accumulation of cytoplasmic actin contributing to muscle weakness. Examination of a Neb-deficient model suggests this mechanism may be common in nemaline myopathy. Another subtype results from a reduction of actin and forms a more stable cytoplasmic body. In contrast, the final type originates at the Z-disk and is associated with myofibrillar disorganization. Analysis of zebrafish and muscle biopsies from ACTA1 nemaline myopathy patients demonstrates that nemaline bodies also possess a different protein signature. In addition, we show that the ACTA1(D286G) mutation causes impaired actin incorporation and localization in the sarcomere. Together these data provide a novel examination of nemaline body origins and dynamics in vivo and identifies pathological changes that correlate with muscle weakness.

  10. Children with dyslexia reveal abnormal native language representations: evidence from a study of mismatch negativity.

    Science.gov (United States)

    Bruder, Jennifer; Leppänen, Paavo H T; Bartling, Jürgen; Csépe, Valéria; Démonet, Jean-Francois; Schulte-Körne, Gerd

    2011-08-01

    Although a deficit perceiving phonemes, as indexed by the mismatch negativity (MMN), is apparent in developmental dyslexia (DD), studies have not yet addressed whether this deficit might be a result of deficient native language speech representations. The present study examines how a native-vowel prototype and an atypical vowel are discriminated by 9-year-old children with (n = 14) and without (n = 12) DD. MMN was elicited in all conditions in both groups. The control group revealed enhanced MMN to the native-vowel prototype in comparison to the atypical vowel. Children with DD did not show enhanced MMN amplitude to the native-vowel prototype, suggesting impaired tuning to native language speech representations. Furthermore, higher MMN amplitudes to the native-vowel prototype correlated with more advanced reading (r = - .47) and spelling skills (r = - .52). Copyright © 2011 Society for Psychophysiological Research.

  11. Changes in southern hemispheric polar amplification over the past 5 million years revealed by climate modelling

    Science.gov (United States)

    Hoencamp, Jori; Stap, Lennert; Tuenter, Erik; Lourens, Luc; van de Wal, Roderik

    2016-04-01

    Knowledge on polar amplification is important to relate high latitude climate records to global mean temperature changes. Several studies have pointed out that the strength of polar amplification in the Northern Hemisphere varies considerably due to the presence of large ice sheets and more sea ice during colder climate conditions. As a result, the polar amplification in the Northern Hemisphere decreases for warmer climates. In this study, we address the fact that these changes in the Northern Hemisphere also affect the polar amplification in the Southern Hemisphere. We study the Southern and Northern Hemisphere amplification together over the past 5 million years with the CLIMBER-2 intermediate complexity model. Radiation, land ice extent and height, and greenhouse gases are prescribed as forcing. We find that in contrast to the reduction in polar amplification in the Northern Hemisphere, polar amplification in the Southern Hemisphere increases for warmer climates. The amplification decreases in the Northern Hemisphere from 2.7 during glacial conditions to 1.6 for a pre-industrial climate, which is line with other climate simulations. Over the same CO2 range the southern hemispheric polar amplification increases from 1 to 1.6. This is caused by the fact that the atmospheric transport needed to balance the radiation surplus in the equatorial region needs to be compensated by relatively stronger transport of energy in Southern direction while the transport in Northern direction reduces. This reduction in Northern direction is driven by less (land and sea) ice resulting in a smaller meridional gradient in Northern direction and hence a smaller atmospheric transport. As a consequence, the traditional scaled (with LGM temperature) Dome C record needs to be corrected with a maximum of 0.6 degrees half-way glacial and interglacial conditions, if it is to be interpreted as global mean temperature change indicator. While this changes the amplitude, the phasing of

  12. Four studies of economic behavior : integrating revealed and stated preferences data

    NARCIS (Netherlands)

    de Ree, J.J.

    2010-01-01

    This thesis estimates equivalence scales for Indonesia, proposes a new type of test of the life-cycle model, shows how important economic and demographic characteristics of Dutch households evolve over age, cohorts and time, and studies the decision problem to when and how much to work, save and con

  13. Sparse Modeling Reveals miRNA Signatures for Diagnostics of Inflammatory Bowel Disease.

    Science.gov (United States)

    Hübenthal, Matthias; Hemmrich-Stanisak, Georg; Degenhardt, Frauke; Szymczak, Silke; Du, Zhipei; Elsharawy, Abdou; Keller, Andreas; Schreiber, Stefan; Franke, Andre

    2015-01-01

    The diagnosis of inflammatory bowel disease (IBD) still remains a clinical challenge and the most accurate diagnostic procedure is a combination of clinical tests including invasive endoscopy. In this study we evaluated whether systematic miRNA expression profiling, in conjunction with machine learning techniques, is suitable as a non-invasive test for the major IBD phenotypes (Crohn's disease (CD) and ulcerative colitis (UC)). Based on microarray technology, expression levels of 863 miRNAs were determined for whole blood samples from 40 CD and 36 UC patients and compared to data from 38 healthy controls (HC). To further discriminate between disease-specific and general inflammation we included miRNA expression data from other inflammatory diseases (inflammation controls (IC): 24 chronic obstructive pulmonary disease (COPD), 23 multiple sclerosis, 38 pancreatitis and 45 sarcoidosis cases) as well as 70 healthy controls from previous studies. Classification problems considering 2, 3 or 4 groups were solved using different types of penalized support vector machines (SVMs). The resulting models were assessed regarding sparsity and performance and a subset was selected for further investigation. Measured by the area under the ROC curve (AUC) the corresponding median holdout-validated accuracy was estimated as ranging from 0.75 to 1.00 (including IC) and 0.89 to 0.98 (excluding IC), respectively. In combination, the corresponding models provide tools for the distinction of CD and UC as well as CD, UC and HC with expected classification error rates of 3.1 and 3.3%, respectively. These results were obtained by incorporating not more than 16 distinct miRNAs. Validated target genes of these miRNAs have been previously described as being related to IBD. For others we observed significant enrichment for IBD susceptibility loci identified in earlier GWAS. These results suggest that the proposed miRNA signature is of relevance for the etiology of IBD. Its diagnostic value

  14. Transcription closed and open complex dynamics studies reveal balance between genetic determinants and co-factors.

    Science.gov (United States)

    Sala, Adrien; Shoaib, Muhammad; Anufrieva, Olga; Mutharasu, Gnanavel; Jahan Hoque, Rawnak; Yli-Harja, Olli; Kandhavelu, Meenakshisundaram

    2015-05-19

    In E. coli, promoter closed and open complexes are key steps in transcription initiation, where magnesium-dependent RNA polymerase catalyzes RNA synthesis. However, the exact mechanism of initiation remains to be fully elucidated. Here, using single mRNA detection and dual reporter studies, we show that increased intracellular magnesium concentration affects Plac initiation complex formation resulting in a highly dynamic process over the cell growth phases. Mg2+ regulates transcription transition, which modulates bimodality of mRNA distribution in the exponential phase. We reveal that Mg2+ regulates the size and frequency of the mRNA burst by changing the open complex duration. Moreover, increasing magnesium concentration leads to higher intrinsic and extrinsic noise in the exponential phase. RNAP-Mg2+ interaction simulation reveals critical movements creating a shorter contact distance between aspartic acid residues and Nucleotide Triphosphate residues and increasing electrostatic charges in the active site. Our findings provide unique biophysical insights into the balanced mechanism of genetic determinants and magnesium ion in transcription initiation regulation during cell growth.

  15. Talaromyces marneffei Genomic, Transcriptomic, Proteomic and Metabolomic Studies Reveal Mechanisms for Environmental Adaptations and Virulence

    Directory of Open Access Journals (Sweden)

    Susanna K. P. Lau

    2017-06-01

    Full Text Available Talaromyces marneffei is a thermally dimorphic fungus causing systemic infections in patients positive for HIV or other immunocompromised statuses. Analysis of its ~28.9 Mb draft genome and additional transcriptomic, proteomic and metabolomic studies revealed mechanisms for environmental adaptations and virulence. Meiotic genes and genes for pheromone receptors, enzymes which process pheromones, and proteins involved in pheromone response pathway are present, indicating its possibility as a heterothallic fungus. Among the 14 Mp1p homologs, only Mp1p is a virulence factor binding a variety of host proteins, fatty acids and lipids. There are 23 polyketide synthase genes, one for melanin and two for mitorubrinic acid/mitorubrinol biosynthesis, which are virulence factors. Another polyketide synthase is for biogenesis of the diffusible red pigment, which consists of amino acid conjugates of monascorubin and rubropunctatin. Novel microRNA-like RNAs (milRNAs and processing proteins are present. The dicer protein, dcl-2, is required for biogenesis of two milRNAs, PM-milR-M1 and PM-milR-M2, which are more highly expressed in hyphal cells. Comparative transcriptomics showed that tandem repeat-containing genes were overexpressed in yeast phase, generating protein polymorphism among cells, evading host’s immunity. Comparative proteomics between yeast and hyphal cells revealed that glyceraldehyde-3-phosphate dehydrogenase, up-regulated in hyphal cells, is an adhesion factor for conidial attachment.

  16. Comparative study of the human ficolins reveals unique features of Ficolin-3 (Hakata antigen).

    Science.gov (United States)

    Hummelshoj, Tina; Fog, Lea Munthe; Madsen, Hans O; Sim, Robert B; Garred, Peter

    2008-03-01

    The ficolins and mannose-binding lectin (MBL) are collagen-like defence proteins that serve as recognition molecules in lectin complement pathway. Differential features that may indicate diverse functions of these proteins are poorly understood. In this study we compared important biological features of the ficolins and MBL. We investigated the tissue distribution of the FCN1-3 and the MBL2 genes encoding the ficolins and MBL by quantitative PCR. Recombinant proteins were produced and structural and biological characteristics were investigated and compared. Our main findings were that FCN3 mRNA was highly expressed in the liver and lung compared with the other genes revealing the lung as the tissue with the highest FCN3 expression pattern. Ficolin-3 revealed higher complement activating capacity compared with Ficolin-2, MBL and Ficolin-1 and was highly resistant to bacterial collagenase treatment, which is different from the other ficolins and MBL. We discovered several unique properties of Ficolin-3 showing that FCN3 is the most highly expressed gene in liver and lung among the lectin complement pathway initiators. Moreover, Ficolin-3 has a high complement activating potential and is the only collagenase proteolytic resistant molecule among the lectin complement pathway initiators.

  17. Campus network security model study

    Science.gov (United States)

    Zhang, Yong-ku; Song, Li-ren

    2011-12-01

    Campus network security is growing importance, Design a very effective defense hacker attacks, viruses, data theft, and internal defense system, is the focus of the study in this paper. This paper compared the firewall; IDS based on the integrated, then design of a campus network security model, and detail the specific implementation principle.

  18. Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation.

    Science.gov (United States)

    Maier, Ezekiel J; Haynes, Brian C; Gish, Stacey R; Wang, Zhuo A; Skowyra, Michael L; Marulli, Alyssa L; Doering, Tamara L; Brent, Michael R

    2015-05-01

    Key steps in understanding a biological process include identifying genes that are involved and determining how they are regulated. We developed a novel method for identifying transcription factors (TFs) involved in a specific process and used it to map regulation of the key virulence factor of a deadly fungus-its capsule. The map, built from expression profiles of 41 TF mutants, includes 20 TFs not previously known to regulate virulence attributes. It also reveals a hierarchy comprising executive, midlevel, and "foreman" TFs. When grouped by temporal expression pattern, these TFs explain much of the transcriptional dynamics of capsule induction. Phenotypic analysis of TF deletion mutants revealed complex relationships among virulence factors and virulence in mice. These resources and analyses provide the first integrated, systems-level view of capsule regulation and biosynthesis. Our methods dramatically improve the efficiency with which transcriptional networks can be analyzed, making genomic approaches accessible to laboratories focused on specific physiological processes.

  19. Principles of proteome allocation are revealed using proteomic data and genome-scale models

    DEFF Research Database (Denmark)

    Yang, Laurence; Yurkovich, James T.; Lloyd, Colton J.

    2016-01-01

    , prediction errors for growth rate and metabolic fluxes were 69% and 14% lower, respectively. The sector-constrained ME model thus represents a generalist ME model reflecting both growth rate maximization and "hedging" against uncertain environments and stresses, as indicated by significant enrichment...... of these sectors for the general stress response sigma factor sigma(S). Finally, the sector constraints represent a general formalism for integrating omics data from any experimental condition into constraint-based ME models. The constraints can be fine-grained (individual proteins) or coarse-grained (functionally......Integrating omics data to refine or make context-specific models is an active field of constraint-based modeling. Proteomics now cover over 95% of the Escherichia coli proteome by mass. Genome-scale models of Metabolism and macromolecular Expression (ME) compute proteome allocation linked...

  20. Mechanics of the IL2RA gene activation revealed by modeling and atomic force microscopy.

    Directory of Open Access Journals (Sweden)

    Pascale Milani

    Full Text Available Transcription implies recruitment of RNA polymerase II and transcription factors (TFs by DNA melting near transcription start site (TSS. Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites, located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studies, result in the progressive positioning of curvature apex towards the TSS, likely facilitating local DNA melting. In vitro assays confirm specific binding of the General Transcription Factors (GTFs TBP and TFIIB over TATA-TSS position, where an inhibitory nucleosome prevented preinitiation complex (PIC formation and uncontrolled DNA melting. These findings represent a substantial advance showing, first, that the structural properties of the IL2RA promoter are encoded in the DNA sequence and second, that during the initiation process DNA conformation is dynamic and not static.

  1. New insight into motor adaptation to pain revealed by a combination of modelling and empirical approaches.

    Science.gov (United States)

    Hodges, P W; Coppieters, M W; MacDonald, D; Cholewicki, J

    2013-09-01

    Movement changes in pain. Unlike the somewhat stereotypical response of limb muscles to pain, trunk muscle responses are highly variable when challenged by pain in that region. This has led many to question the existence of a common underlying theory to explain the adaptation. Here, we tested the hypotheses that (1) adaptation in muscle activation in acute pain leads to enhanced spine stability, despite variation in the pattern of muscle activation changes; and (2) individuals would use a similar 'signature' pattern for tasks with different mechanical demands. In 17 healthy individuals, electromyography recordings were made from a broad array of anterior and posterior trunk muscles while participants moved slowly between trunk flexion and extension with and without experimentally induced back pain. Hypotheses were tested by estimating spine stability (Stability Index) with an electromyography-driven spine model and analysis of individual and overall (net) adaptations in muscle activation. The Stability Index (P muscle activity (P muscle activity. For most, the adaptation was similar between movement directions despite opposite movement demands. These data provide the first empirical confirmation that, in most individuals, acute back pain leads to increased spinal stability and that the pattern of muscle activity is not stereotypical, but instead involves an individual-specific response to pain. This adaptation is likely to provide short-term benefit to enhance spinal protection, but could have long-term consequences for spinal health. © 2013 European Federation of International Association for the Study of Pain Chapters.

  2. The Intrinsic Dynamics and Unfolding Process of an Antibody Fab Fragment Revealed by Elastic Network Model

    Directory of Open Access Journals (Sweden)

    Ji-Guo Su

    2015-12-01

    Full Text Available Antibodies have been increasingly used as pharmaceuticals in clinical treatment. Thermal stability and unfolding process are important properties that must be considered in antibody design. In this paper, the structure-encoded dynamical properties and the unfolding process of the Fab fragment of the phosphocholine-binding antibody McPC603 are investigated by use of the normal mode analysis of Gaussian network model (GNM. Firstly, the temperature factors for the residues of the protein were calculated with GNM and then compared with the experimental measurements. A good result was obtained, which provides the validity for the use of GNM to study the dynamical properties of the protein. Then, with this approach, the mean-square fluctuation (MSF of the residues, as well as the MSF in the internal distance (MSFID between all pairwise residues, was calculated to investigate the mobility and flexibility of the protein, respectively. It is found that the mobility and flexibility of the constant regions are higher than those of the variable regions, and the six complementarity-determining regions (CDRs in the variable regions also exhibit relative large mobility and flexibility. The large amplitude motions of the CDRs are considered to be associated with the immune function of the antibody. In addition, the unfolding process of the protein was simulated by iterative use of the GNM. In our method, only the topology of protein native structure is taken into account, and the protein unfolding process is simulated through breaking the native contacts one by one according to the MSFID values between the residues. It is found that the flexible regions tend to unfold earlier. The sequence of the unfolding events obtained by our method is consistent with the hydrogen-deuterium exchange experimental results. Our studies imply that the unfolding behavior of the Fab fragment of antibody McPc603 is largely determined by the intrinsic dynamics of the protein.

  3. Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets.

    Science.gov (United States)

    Lu, Junyan; Zeng, Hanlin; Liang, Zhongjie; Chen, Limin; Zhang, Liyi; Zhang, Hao; Liu, Hong; Jiang, Hualiang; Shen, Bairong; Huang, Ming; Geng, Meiyu; Spiegel, Sarah; Luo, Cheng

    2015-10-08

    The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment. Furthermore, in silico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects. Overall, our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner.

  4. Different human gut models reveal the distinct fermentation patterns of arabinoxylan versus inulin

    NARCIS (Netherlands)

    Abbeele, P. van den; Venema, K.; Wiele, T. van de; Verstraete, W.; Possemiers, S.

    2013-01-01

    Different in vitro models have been developed to assess how food compounds affect the human gut microbiota. Using two such models (SHIME(R) and TIM-2), we compared how long-chain arabinoxylan (LC-AX), a wheat-derived potentially prebiotic fiber, and inulin (IN), a well-established prebiotic compound

  5. The cellular and molecular mechanisms of tissue repair and regeneration as revealed by studies in Xenopus

    Science.gov (United States)

    Li, Jingjing; Zhang, Siwei

    2016-01-01

    Abstract Survival of any living organism critically depends on its ability to repair and regenerate damaged tissues and/or organs during its lifetime following injury, disease, or aging. Various animal models from invertebrates to vertebrates have been used to investigate the molecular and cellular mechanisms of wound healing and tissue regeneration. It is hoped that such studies will form the framework for identifying novel clinical treatments that will improve the healing and regenerative capacity of humans. Amongst these models, Xenopus stands out as a particularly versatile and powerful system. This review summarizes recent findings using this model, which have provided fundamental knowledge of the mechanisms responsible for efficient and perfect tissue repair and regeneration.

  6. Seed metabolomic study reveals significant metabolite variations and correlations among different soybean cultivars

    Institute of Scientific and Technical Information of China (English)

    Hong Lin; Jun Rao; Jianxin Shi; Chaoyang Hu; Fang Cheng; Zoe AWilson; Dabing Zhang; Sheng Quan

    2014-01-01

    Soybean [Glycine max (L.) Merr.] is one of the world’s major crops, and soybean seeds are a rich and important resource for proteins and oils. While “omics”studies, such as genomics, transcriptomics, and proteomics, have been widely applied in soybean molecular research, fewer metabolomic studies have been conducted for large-scale detection of low molecular weight metabolites, especial y in soybean seeds. In this study, we investigated the seed metabolomes of 29 common soybean cultivars through combined gas chromatography-mass spectrometry and ultra-performance liquid chromatography-tandem mass spectrometry. One hundred sixty-nine named metabolites were identified and subsequently used to construct a metabolic network of mature soybean seed. Among the 169 detected metabolites, 104 were found to be significantly variable in their levels across tested cultivars. Metabolite markers that could be used to distinguish genetical y related soybean cultivars were also identified, and metabolite-metabolite correlation analysis revealed some significant associations within the same or among different metabolite groups. Findings from this work may potentially provide the basis for further studies on both soybean seed metabolism and metabolic engineering to improve soybean seed quality and yield.

  7. Pore water chemistry reveals gradients in mineral transformation across a model basaltic hillslope

    Science.gov (United States)

    Pohlmann, Michael; Dontsova, Katerina; Root, Robert; Ruiz, Joaquin; Troch, Peter; Chorover, Jon

    2016-06-01

    The extent of weathering incongruency during soil formation from rock controls local carbon and nutrient cycling in ecosystems, as well as the evolution of hydrologic flow paths. Prior studies of basalt weathering, including those that have quantified the dynamics of well-mixed, bench-scale laboratory reactors or characterized the structure and integrated response of field systems, indicate a strong influence of system scale on weathering rate and trajectory. For example, integrated catchment response tends to produce lower weathering rates than do well mixed reactors, but the mechanisms underlying these disparities remain unclear. Here we present pore water geochemistry and physical sensor data gathered during two controlled rainfall-runoff events on a large-scale convergent model hillslope mantled with 1 m uniform depth of granular basaltic porous media. The dense sampler and sensor array (1488 samplers and sensors embedded in 330 m3 of basalt) showed that rainfall-induced dissolution of basaltic glass produced supersaturation of pore waters with respect to multiple secondary solids including allophane, gibbsite, ferrihydrite, birnessite and calcite. The spatial distribution of saturation state was heterogeneous, suggesting an accumulation of solutes leading to precipitation of secondary solids along hydrologic flow paths. Rapid dissolution of primary silicates was widespread throughout the entire hillslope, irrespective of up-gradient flowpath length. However, coherent spatial variations in solution chemistry and saturation indices were observed in depth profiles and between distinct topographic regions of the hillslope. Colloids (110-2000 nm) enriched in iron (Fe), aluminum (Al), and phosphorus (P) were mobile in soil pore waters.

  8. Using higher-order Markov models to reveal flow-based communities in networks

    CERN Document Server

    Salnikov, Vsevolod; Lambiotte, Renaud

    2016-01-01

    Complex systems made of interacting elements are commonly abstracted as networks, in which nodes are associated with dynamic state variables, whose evolution is driven by interactions mediated by the edges. Markov processes have been the prevailing paradigm to model such a network-based dynamics, for instance in the form of random walks or other types of diffusions. Despite the success of this modelling perspective for numerous applications, it represents an over-simplification of several real-world systems. Importantly, simple Markov models lack memory in their dynamics, an assumption often not realistic in practice. Here, we explore possibilities to enrich the system description by means of second-order Markov models, exploiting empirical pathway information. We focus on the problem of community detection and show that standard network algorithms can be generalized in order to extract novel temporal information about the system under investigation. We also apply our methodology to temporal networks, where w...

  9. Feasibility study of spectral pattern recognition reveals distinct classes of volcanic tremor

    Science.gov (United States)

    Unglert, K.; Jellinek, A. M.

    2017-04-01

    Systematic investigations of the similarities and differences among volcanic tremor at a range of volcano types may hold crucial information about the plausibility of inferred source mechanisms, which, in turn, may be important for eruption forecasting. However, such studies are rare, in part because of an intrinsic difficulty with identifying tremor signals within very long time series of volcano seismic data. Accordingly, we develop an efficient tremor detection algorithm and identify over 12,000h of volcanic tremor on 24 stations at Kīlauea, Okmok, Pavlof, and Redoubt volcanoes. We estimate spectral content over 5-minute tremor windows, and apply a novel combination of Principal Component Analysis (PCA) and hierarchical clustering to identify patterns in the tremor spectra. Analyzing several stations from a given volcano together reveals different styles of tremor within individual volcanic settings. In addition to identifying tremor properties common to all stations in a given network, we find localized tremor signals including those related to processes such as lahars or dike intrusions that are only observed on some of the stations within a network. Subsequent application of our analysis to a combination of stations from the different volcanoes reveals that at least three main tremor classes can be detected across all settings. Whereas a regime with a ridge of high power distributed over 1-2Hz and a gradual decay of spectral power towards higher frequencies is observed dominantly at three volcanoes (Kīlauea, Okmok, Redoubt) with magma reservoirs centered at less than 5km below sea level (b.s.l.), a spectrum with a steeper slope and a narrower peak at 1-2Hz is observed only in association with open vents (Kīlauea and Pavlof). A third regime with a peak at approximately 3Hz is confined to two stratovolcanoes (Pavlof and Redoubt). These observations suggest generic relationships between the spectral character of the observed signals and volcano

  10. A study revealing the key aroma compounds of steamed bread made by Chinese traditional sourdough.

    Science.gov (United States)

    Zhang, Guo-Hua; Wu, Tao; Sadiq, Faizan A; Yang, Huan-Yi; Liu, Tong-Jie; Ruan, Hui; He, Guo-Qing

    Aroma of Chinese steamed bread (CSB) is one of the important parameters that determines the overall quality attributes and consumer acceptance. However, the aroma profile of CSB still remains poorly understood, mainly because of relying on only a single method for aroma extraction in previous studies. Therefore, the objective of this study was to determine the volatile aroma compounds of five different samples of CSB using three different aroma extraction methods, namely solid-phase microextraction (SPME), simultaneous distillation-extraction (SDE), and purge and trap (P&T). All samples showed a unique aroma profile, which could be attributed to their unique microbial consortia. (E)-2-Nonenal and (E,E)-2,4-decadienal were the most prevalent aromatic compounds revealed by SDE, which have not been reported previously, while ethanol and acetic acid proved to be the most dominant compounds by both SPME and P&T. Our approach of combining three different aroma extraction methods provided better insights into the aroma profile of CSB, which had remained largely unknown in previous studies.

  11. A study revealing the key aroma compounds of steamed bread made by Chinese traditional sourdough*

    Science.gov (United States)

    Zhang, Guo-hua; Wu, Tao; Sadiq, Faizan A.; Yang, Huan-yi; Liu, Tong-jie; Ruan, Hui; He, Guo-qing

    2016-01-01

    Aroma of Chinese steamed bread (CSB) is one of the important parameters that determines the overall quality attributes and consumer acceptance. However, the aroma profile of CSB still remains poorly understood, mainly because of relying on only a single method for aroma extraction in previous studies. Therefore, the objective of this study was to determine the volatile aroma compounds of five different samples of CSB using three different aroma extraction methods, namely solid-phase microextraction (SPME), simultaneous distillation–extraction (SDE), and purge and trap (P&T). All samples showed a unique aroma profile, which could be attributed to their unique microbial consortia. (E)-2-Nonenal and (E,E)-2,4-decadienal were the most prevalent aromatic compounds revealed by SDE, which have not been reported previously, while ethanol and acetic acid proved to be the most dominant compounds by both SPME and P&T. Our approach of combining three different aroma extraction methods provided better insights into the aroma profile of CSB, which had remained largely unknown in previous studies. PMID:27704748

  12. Study on sickle cell disease haplotypes reveals the African origin of Amapá's population

    Directory of Open Access Journals (Sweden)

    Natália de Morais Castelo

    2014-04-01

    Full Text Available Introduction:Sickle cell disease (SCD is a hereditary, hematologic, multifactorial disease, with high prevalence worldwide; its cause is a mutation in the sixth codon of the beta globin gene (βs.Objective:To identify the haplotypes present in people with SCD in Amapá, and relate them to African descent.Methods:We analyzed, by molecular techniques, 46 blood samples from people with SCD in Macapá, the capital of Amapá, with the purpose of obtaining information about haplotype frequency distribution, which helps understand the ethnic background of Amapá's population.Results:Our study revealed that the most frequent haplotype is Bantu (61.2%, followed by Benin (26.6% and Senegal (12.2%. Results showed statistical differences from studies conducted in other regions. A high frequency of the Senegal haplotype stands out, in comparison with some Brazilian studies.Conclusion:Amapá's results exhibit unique characteristics when compared to haplotypes in other regions, with high frequency of Senegal and Benin haplotypes, absence of atypical, Cameroon and Saudi, confirming that Brazil shows ethnic background diversity, as well as different haplotype frequencies.

  13. Thirty-day rat toxicity study reveals reversible liver toxicity of mifepristone (RU486) and metapristone.

    Science.gov (United States)

    Xiao, Yingying; Zhu, Yewei; Yu, Suhong; Yan, Cuicui; Ho, Rodney J Y; Liu, Jian; Li, Tao; Wang, Jie; Wan, Liyuan; Yang, Xingtian; Xu, Huo; Wang, Jichuang; Tu, Xiaohuang; Jia, Lee

    2016-01-01

    Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs. The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses. Oral mifepristone (3000 mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200 mg/kg/day) caused reversible hepatotoxicity that only occurred at 200 mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight. The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses.

  14. Paleodata-model integration reveals uncertain boreal forest carbon balance due to rapid recent fire regime change

    Science.gov (United States)

    Kelly, R.; Genet, H.; McGuire, D.; Hu, F.

    2013-12-01

    estimate future boreal C dynamics. The central role of fire frequency in driving boreal C balance has practical implications for the use of models to understand present and future C dynamics. Biogeochemical models are typically initialized (or 'spun up') to achieve approximately stationary conditions at the start of simulations. For lack of fire data prior to the beginning of observational records (ca. 1950 AD in most boreal systems), many studies have assumed a fire regime similar to modern for the spin-up period. However, this assumption is grossly challenged by our paleodata, which indicate that fire frequency has increased rapidly over recent decades to a level (18.5 fires/kyr) more than double the past-millennium mean (8.4 fires/kyr). If this dramatic shift was unknown from the sediment record, simulations would suggest that our study region was a net C sink since 1950 AD. In fact, our results that incorporate past fire regime change reveal rapid losses of >1 kg C/m2. Thus, current estimates of the boreal C sink may be biased in this era of rapid change.

  15. Environmental enrichment reveals effects of genotype on hippocampal spine morphologies in the mouse model of Fragile X Syndrome.

    Science.gov (United States)

    Lauterborn, Julie C; Jafari, Matiar; Babayan, Alex H; Gall, Christine M

    2015-02-01

    Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were ∼ 40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS.

  16. Metabolite Profiling Reveals the Effect of Dietary Rubus coreanus Vinegar on Ovariectomy-Induced Osteoporosis in a Rat Model

    Directory of Open Access Journals (Sweden)

    Mee Youn Lee

    2016-01-01

    Full Text Available The study was aimed at exploring the curative effects of Rubus coreanus (RC vinegar against postmenopausal osteoporosis by using ovariectomized rats as a model. The investigations were performed in five groups: sham, ovariectomized (OVX rats without treatment, low-dose RC vinegar (LRV-treated OVX rats, high-dose RC vinegar (HRV-treated OVX rats and alendronate (ALEN-treated OVX rats. The efficacy of RC vinegar was evaluated using physical, biochemical, histological and metabolomic parameters. Compared to the OVX rats, the LRV and HRV groups showed positive effects on the aforementioned parameters, indicating estrogen regulation. Plasma metabolome analysis of the groups using gas chromatography-time of flight mass spectrometry (GC-TOF-MS and ultra-performance liquid chromatography quadrupole-TOF-MS (UPLC-Q-TOF-MS with multivariate analysis revealed 19 and 16 metabolites, respectively. Notably, the levels of butyric acid, phenylalanine, glucose, tryptophan and some lysophosphatidylcholines were marginally increased in RC vinegar-treated groups compared to OVX. However, the pattern of metabolite levels in RC vinegar-treated groups was found similar to ALEN, but differed significantly from that in sham group. The results highlight the prophylactic and curative potential of dietary vinegar against postmenopausal osteoporosis. RC vinegar could be an effective natural alternative for the prevention of postmenopausal osteoporosis.

  17. Metabolite Profiling Reveals the Effect of Dietary Rubus coreanus Vinegar on Ovariectomy-Induced Osteoporosis in a Rat Model.

    Science.gov (United States)

    Lee, Mee Youn; Kim, Hyang Yeon; Singh, Digar; Yeo, Soo Hwan; Baek, Seong Yeol; Park, Yoo Kyoung; Lee, Choong Hwan

    2016-01-26

    The study was aimed at exploring the curative effects of Rubus coreanus (RC) vinegar against postmenopausal osteoporosis by using ovariectomized rats as a model. The investigations were performed in five groups: sham, ovariectomized (OVX) rats without treatment, low-dose RC vinegar (LRV)-treated OVX rats, high-dose RC vinegar (HRV)-treated OVX rats and alendronate (ALEN)-treated OVX rats. The efficacy of RC vinegar was evaluated using physical, biochemical, histological and metabolomic parameters. Compared to the OVX rats, the LRV and HRV groups showed positive effects on the aforementioned parameters, indicating estrogen regulation. Plasma metabolome analysis of the groups using gas chromatography-time of flight mass spectrometry (GC-TOF-MS) and ultra-performance liquid chromatography quadrupole-TOF-MS (UPLC-Q-TOF-MS) with multivariate analysis revealed 19 and 16 metabolites, respectively. Notably, the levels of butyric acid, phenylalanine, glucose, tryptophan and some lysophosphatidylcholines were marginally increased in RC vinegar-treated groups compared to OVX. However, the pattern of metabolite levels in RC vinegar-treated groups was found similar to ALEN, but differed significantly from that in sham group. The results highlight the prophylactic and curative potential of dietary vinegar against postmenopausal osteoporosis. RC vinegar could be an effective natural alternative for the prevention of postmenopausal osteoporosis.

  18. Understanding the complexities of Salmonella-host crosstalk as revealed by in vivo model organisms.

    Science.gov (United States)

    Verma, Smriti; Srikanth, Chittur V

    2015-07-01

    Foodborne infections caused by non-typhoidal Salmonellae, such as Salmonella enterica serovar Typhimurium (ST), pose a major challenge in the developed and developing world. With constant rise of drug-resistant strains, understanding the epidemiology, microbiology, pathogenesis and host-pathogen interactions biology is a mandatory requirement to enable health systems to be ready to combat these illnesses. Patient data from hospitals, at least from some parts of the world, have aided in epidemiological understanding of ST-mediated disease. Most of the other aspects connected to Salmonella-host crosstalk have come from model systems that offer convenience, genetic tractability and low maintenance costs that make them extremely valuable tools. Complex model systems such as the bovine model have helped in understanding key virulence factors needed for infection. Simple systems such as fruit flies and Caenorhabditis elegans have aided in identification of novel virulence factors, host pathways and mechanistic details of interactions. Some of the path-breaking concepts of the field have come from mice model of ST colitis, which allows genetic manipulations as well as high degree of similarity to human counterpart. Together, they are invaluable for correlating in vitro findings of ST-induced disease progression in vivo. The current review is a compilation of various advances of ST-host interactions at cellular and molecular levels that has come from investigations involving model organisms. © 2015 International Union of Biochemistry and Molecular Biology.

  19. A mouse model of visual perceptual learning reveals alterations in neuronal coding and dendritic spine density in the visual cortex

    Directory of Open Access Journals (Sweden)

    Yan eWang

    2016-03-01

    Full Text Available Visual perceptual learning (VPL can improve spatial vision in normally sighted and visually impaired individuals. Although previous studies of humans and large animals have explored the neural basis of VPL, elucidation of the underlying cellular and molecular mechanisms remains a challenge. Owing to the advantages of molecular genetic and optogenetic manipulations, the mouse is a promising model for providing a mechanistic understanding of VPL. Here, we thoroughly evaluated the effects and properties of VPL on spatial vision in C57BL/6J mice using a two-alternative, forced-choice visual water task. Briefly, the mice underwent prolonged training at near the individual threshold of contrast or spatial frequency (SF for pattern discrimination or visual detection for 35 consecutive days. Following training, the contrast-threshold trained mice showed an 87% improvement in contrast sensitivity (CS and a 55% gain in visual acuity (VA. Similarly, the SF-threshold trained mice exhibited comparable and long-lasting improvements in VA and significant gains in CS over a wide range of SFs. Furthermore, learning largely transferred across eyes and stimulus orientations. Interestingly, learning could transfer from a pattern discrimination task to a visual detection task, but not vice versa. We validated that this VPL fully restored VA in adult amblyopic mice and old mice. Taken together, these data indicate that mice, as a species, exhibit reliable VPL. Intrinsic signal optical imaging revealed that mice with perceptual training had higher cut-off SFs in primary visual cortex (V1 than those without perceptual training. Moreover, perceptual training induced an increase in the dendritic spine density in layer 2/3 pyramidal neurons of V1. These results indicated functional and structural alterations in V1 during VPL. Overall, our VPL mouse model will provide a platform for investigating the neurobiological basis of VPL.

  20. Mutual information reveals multiple structural relaxation mechanisms in a model glass former.

    Science.gov (United States)

    Dunleavy, Andrew J; Wiesner, Karoline; Yamamoto, Ryoichi; Royall, C Patrick

    2015-01-22

    Among the key challenges to our understanding of solidification in the glass transition is that it is accompanied by little apparent change in structure. Recently, geometric motifs have been identified in glassy liquids, but a causal link between these motifs and solidification remains elusive. One 'smoking gun' for such a link would be identical scaling of structural and dynamic lengthscales on approaching the glass transition, but this is highly controversial. Here we introduce an information theoretic approach to determine correlations in displacement for particle relaxation encoded in the initial configuration of a glass-forming liquid. We uncover two populations of particles, one inclined to relax quickly, the other slowly. Each population is correlated with local density and geometric motifs. Our analysis further reveals a dynamic lengthscale similar to that associated with structural properties, which may resolve the discrepancy between structural and dynamic lengthscales.

  1. Computational EEG modelling of decision making under ambiguity reveals spatio-temporal dynamics of outcome evaluation.

    Science.gov (United States)

    Jollans, Lee; Whelan, Robert; Venables, Louise; Turnbull, Oliver H; Cella, Matteo; Dymond, Simon

    2017-03-15

    Complex human cognition, such as decision-making under ambiguity, is reflected in dynamic spatio-temporal activity in the brain. Here, we combined event-related potentials with computational modelling of the time course of decision-making and outcome evaluation during the Iowa Gambling Task. Measures of choice probability generated using the Prospect Valence Learning Delta (PVL-Delta) model, in addition to objective trial outcomes (outcome magnitude and valence), were applied as regressors in a general linear model of the EEG signal. The resulting three-dimensional spatio-temporal characterization of task-related neural dynamics demonstrated that outcome valence, outcome magnitude, and PVL-Delta choice probability were expressed in distinctly separate event related potentials. Our findings showed that the P3 component was associated with an experience-based measure of outcome expectancy. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Mental Lexicon Growth Modelling Reveals the Multiplexity of the English Language

    CERN Document Server

    Stella, Massimo

    2016-01-01

    In this work we extend previous analyses of linguistic networks by adopting a multi-layer network framework for modelling the human mental lexicon, i.e. an abstract mental repository where words and concepts are stored together with their linguistic patterns. Across a three-layer linguistic multiplex, we model English words as nodes and connect them according to (i) phonological similarities, (ii) synonym relationships and (iii) free word associations. Our main aim is to exploit this multi-layered structure to explore the influence of phonological and semantic relationships on lexicon assembly over time. We propose a model of lexicon growth which is driven by the phonological layer: words are suggested according to different orderings of insertion (e.g. shorter word length, highest frequency, semantic multiplex features) and accepted or rejected subject to constraints. We then measure times of network assembly and compare these to empirical data about the age of acquisition of words. In agreement with empiric...

  3. New insights into sulfur metabolism in yeasts as revealed by studies of Yarrowia lipolytica.

    Science.gov (United States)

    Hébert, Agnès; Forquin-Gomez, Marie-Pierre; Roux, Aurélie; Aubert, Julie; Junot, Christophe; Heilier, Jean-François; Landaud, Sophie; Bonnarme, Pascal; Beckerich, Jean-Marie

    2013-02-01

    Yarrowia lipolytica, located at the frontier of hemiascomycetous yeasts and fungi, is an excellent candidate for studies of metabolism evolution. This yeast, widely recognized for its technological applications, in particular produces volatile sulfur compounds (VSCs) that fully contribute to the flavor of smear cheese. We report here a relevant global vision of sulfur metabolism in Y. lipolytica based on a comparison between high- and low-sulfur source supplies (sulfate, methionine, or cystine) by combined approaches (transcriptomics, metabolite profiling, and VSC analysis). The strongest repression of the sulfate assimilation pathway was observed in the case of high methionine supply, together with a large accumulation of sulfur intermediates. A high sulfate supply seems to provoke considerable cellular stress via sulfite production, resulting in a decrease of the availability of the glutathione pathway's sulfur intermediates. The most limited effect was observed for the cystine supply, suggesting that the intracellular cysteine level is more controlled than that of methionine and sulfate. Using a combination of metabolomic profiling and genetic experiments, we revealed taurine and hypotaurine metabolism in yeast for the first time. On the basis of a phylogenetic study, we then demonstrated that this pathway was lost by some of the hemiascomycetous yeasts during evolution.

  4. Fish gut-liver immunity during homeostasis or inflammation revealed by integrative transcriptome and proteome studies

    Science.gov (United States)

    Wu, Nan; Song, Yu-Long; Wang, Bei; Zhang, Xiang-Yang; Zhang, Xu-Jie; Wang, Ya-Li; Cheng, Ying-Yin; Chen, Dan-Dan; Xia, Xiao-Qin; Lu, Yi-Shan; Zhang, Yong-An

    2016-11-01

    The gut-associated lymphoid tissue, connected with liver via bile and blood, constructs a local immune environment of both defense and tolerance. The gut-liver immunity has been well-studied in mammals, yet in fish remains largely unknown, even though enteritis as well as liver and gallbladder syndrome emerged as a limitation in aquaculture. In this study, we performed integrative bioinformatic analysis for both transcriptomic (gut and liver) and proteomic (intestinal mucus and bile) data, in both healthy and infected tilapias. We found more categories of immune transcripts in gut than liver, as well as more adaptive immune in gut meanwhile more innate in liver. Interestingly reduced differential immune transcripts between gut and liver upon inflammation were also revealed. In addition, more immune proteins in bile than intestinal mucus were identified. And bile probably providing immune effectors to intestinal mucus upon inflammation was deduced. Specifically, many key immune transcripts in gut or liver as well as key immune proteins in mucus or bile were demonstrated. Accordingly, we proposed a hypothesized profile of fish gut-liver immunity, during either homeostasis or inflammation. Current data suggested that fish gut and liver may collaborate immunologically while keep homeostasis using own strategies, including potential unique mechanisms.

  5. THREE-DIMENSIONAL RADIO AND X-RAY MODELING AND DATA ANALYSIS SOFTWARE: REVEALING FLARE COMPLEXITY

    Energy Technology Data Exchange (ETDEWEB)

    Nita, Gelu M.; Fleishman, Gregory D.; Gary, Dale E. [Center For Solar-Terrestrial Research, New Jersey Institute of Technology, Newark, NJ 07102 (United States); Kuznetsov, Alexey A. [Institute of Solar-Terrestrial Physics, Irkutsk 664033 (Russian Federation); Kontar, Eduard P. [School of Physics and Astronomy, The University of Glasgow, Glasgow G12 8QQ (United Kingdom)

    2015-02-01

    Many problems in solar physics require analysis of imaging data obtained in multiple wavelength domains with differing spatial resolution in a framework supplied by advanced three-dimensional (3D) physical models. To facilitate this goal, we have undertaken a major enhancement of our IDL-based simulation tools developed earlier for modeling microwave and X-ray emission. The enhanced software architecture allows the user to (1) import photospheric magnetic field maps and perform magnetic field extrapolations to generate 3D magnetic field models; (2) investigate the magnetic topology by interactively creating field lines and associated flux tubes; (3) populate the flux tubes with user-defined nonuniform thermal plasma and anisotropic, nonuniform, nonthermal electron distributions; (4) investigate the spatial and spectral properties of radio and X-ray emission calculated from the model; and (5) compare the model-derived images and spectra with observational data. The package integrates shared-object libraries containing fast gyrosynchrotron emission codes, IDL-based soft and hard X-ray codes, and potential and linear force-free field extrapolation routines. The package accepts user-defined radiation and magnetic field extrapolation plug-ins. We use this tool to analyze a relatively simple single-loop flare and use the model to constrain the magnetic 3D structure and spatial distribution of the fast electrons inside this loop. We iteratively compute multi-frequency microwave and multi-energy X-ray images from realistic magnetic flux tubes obtained from pre-flare extrapolations, and compare them with imaging data obtained by SDO, NoRH, and RHESSI. We use this event to illustrate the tool's use for the general interpretation of solar flares to address disparate problems in solar physics.

  6. An evolutionary-network model reveals stratified interactions in the V3 loop of the HIV-1 envelope.

    Directory of Open Access Journals (Sweden)

    Art F Y Poon

    2007-11-01

    Full Text Available The third variable loop (V3 of the human immunodeficiency virus type 1 (HIV-1 envelope is a principal determinant of antibody neutralization and progression to AIDS. Although it is undoubtedly an important target for vaccine research, extensive genetic variation in V3 remains an obstacle to the development of an effective vaccine. Comparative methods that exploit the abundance of sequence data can detect interactions between residues of rapidly evolving proteins such as the HIV-1 envelope, revealing biological constraints on their variability. However, previous studies have relied implicitly on two biologically unrealistic assumptions: (1 that founder effects in the evolutionary history of the sequences can be ignored, and; (2 that statistical associations between residues occur exclusively in pairs. We show that comparative methods that neglect the evolutionary history of extant sequences are susceptible to a high rate of false positives (20%-40%. Therefore, we propose a new method to detect interactions that relaxes both of these assumptions. First, we reconstruct the evolutionary history of extant sequences by maximum likelihood, shifting focus from extant sequence variation to the underlying substitution events. Second, we analyze the joint distribution of substitution events among positions in the sequence as a Bayesian graphical model, in which each branch in the phylogeny is a unit of observation. We perform extensive validation of our models using both simulations and a control case of known interactions in HIV-1 protease, and apply this method to detect interactions within V3 from a sample of 1,154 HIV-1 envelope sequences. Our method greatly reduces the number of false positives due to founder effects, while capturing several higher-order interactions among V3 residues. By mapping these interactions to a structural model of the V3 loop, we find that the loop is stratified into distinct evolutionary clusters. We extend our model to

  7. Unifying model of shoot gravitropism reveals proprioception as a central feature of posture control in plants

    DEFF Research Database (Denmark)

    Bastien, Renaud; Bohr, Tomas; Moulia, Bruno

    2012-01-01

    auxin to the lower side is then enhanced, resulting in differential gene expression and cell elongation causing the organ to bend. However, little is known about the dynamics, regulation, and diversity of the entire bending and straightening process. Here, we modeled the bending and straightening...

  8. How can macroscopic models reveal self-organization in traffic flow?

    CERN Document Server

    Cristiani, Emiliano; Tosin, Andrea

    2012-01-01

    In this paper we propose a new modeling technique for vehicular traffic flow, designed for capturing at a macroscopic level some effects, due to the microscopic granularity of the flow of cars, which would be lost with a purely continuous approach. The starting point is a multiscale method for pedestrian modeling, recently introduced in Cristiani et al., Multiscale Model. Simul., 2011, in which measure-theoretic tools are used to manage the microscopic and the macroscopic scales under a unique framework. In the resulting coupled model the two scales coexist and share information, in the sense that the same system is simultaneously described from both a discrete (microscopic) and a continuous (macroscopic) perspective. This way it is possible to perform numerical simulations in which the single trajectories and the average density of the moving agents affect each other. Such a method is here revisited in order to deal with multi-population traffic flow on networks. For illustrative purposes, we focus on the si...

  9. Gray box modeling of MSW degradation: Revealing its dominant (bio)chemical mechanism

    NARCIS (Netherlands)

    Van Turnhout, A.G.; Heimovaara, T.J.; Kleerebezem, R.

    2013-01-01

    In this paper we present an approach to describe organic degradation within immobile water regions of Municipal Solid Waste (MSW) landfills which is best described by the term “gray box” model. We use a simplified set of dominant (bio)chemical and physical reactions and realistic environmental condi

  10. The centre of mass of a ‘flying’ body revealed by a computational model

    Science.gov (United States)

    Simeão Carvalho, Paulo; José Rodrigues, Marcelo

    2017-01-01

    The interpretation of complex trajectories of rigid bodies by the identification of their centre of mass (CM), has a large potential for improving the understanding of the concept of CM at college and university level. Therefore, it is not surprising that there are several techniques described in the literature concerning how to identify the CM of rigid bodies. However, these techniques fail when the CM’s position in the body’s frame of reference changes when the body is at motion. In this work we present a computational model that allows the identification of the CM with very good accuracy, either when the CM’s position changes or is fixed in the body’s frame of reference. This model can be used for a system of bodies moving in a plane, for which the CM of each body coincides with its geometric centre. The effectiveness of this model is tested with experiments using video acquisition and numerical analysis, and can be done in experimental classes under controlled conditions. Students are then able to compare the computed CM with the experimental CM, and investigate why the bodies sometimes present weird trajectories. This property applies in particular to sports, so the model can be also very useful as an educational resource for the explanation of the motion of athletes, namely as a tool for optimizing their performance.

  11. Using fuzzy logic models to reveal farmers' motives to integrate livestock, fish, and crops

    NARCIS (Netherlands)

    Bosma, R.H.

    2007-01-01

    Rural extension services have changed paradigm and shifted to more participatory approaches, whereas in common mathematical models of farming systems, farmers’ motivation is solely represented by ‘utility maximisation’. While globally, farmers specialise, in Vietnam the rice-based systems have diver

  12. 3D Geodynamic Modelling Reveals Stress and Strain Partitioning within Continental Rifting

    Science.gov (United States)

    Rey, P. F.; Mondy, L. S.; Duclaux, G.; Moresi, L. N.

    2014-12-01

    The relative movement between two divergent rigid plates on a sphere can be described using a Euler pole and an angular velocity. On Earth, this typically results in extensional velocities increasing linearly as a function of the distance from the pole (for example in the South Atlantic, North Atlantic, Woodlark Basin, Red Sea Basin, etc.). This property has strong implications for continental rifting and the formation of passive margins, given the role that extensional velocity plays on both rift style (wide or narrow), fault pattern, subsidence histories, and magmatism. Until now, this scissor-style opening has been approached via suites of 2D numerical models of contrasting extensional velocities, complimenting field geology and geophysics. New advances in numerical modelling tools and computational hardware have enabled us to investigate the geodynamics of this problem in a 3D self-consistent high-resolution context. Using Underworld at a grid resolution of 2 km over a domain of 500 km x 500 km x 180 km, we have explored the role of the velocity gradient on the strain pattern, style of rifting, and decompression melting, along the margin. We find that the three dimensionality of this problem is important. The rise of the asthenosphere is enhanced in 2D models compared to 3D numerical solutions, due to the limited volume of material available in 2D. This leads to oceanisation occurring significantly sooner in 2D models. The 3D model shows that there is a significant time and space dependent flows parallel to the rift-axis. A similar picture emerges from the stress field, showing time and space partitioning, including regions of compression separating areas dominated by extension. The strain pattern shows strong zonation along the rift axis, with increasingly localised deformation with extension velocity and though time.

  13. Inclusion of the glucocorticoid receptor in a hypothalamic pituitary adrenal axis model reveals bistability

    Directory of Open Access Journals (Sweden)

    Vernon Suzanne D

    2007-02-01

    Full Text Available Abstract Background The body's primary stress management system is the hypothalamic pituitary adrenal (HPA axis. The HPA axis responds to physical and mental challenge to maintain homeostasis in part by controlling the body's cortisol level. Dysregulation of the HPA axis is implicated in numerous stress-related diseases. Results We developed a structured model of the HPA axis that includes the glucocorticoid receptor (GR. This model incorporates nonlinear kinetics of pituitary GR synthesis. The nonlinear effect arises from the fact that GR homodimerizes after cortisol activation and induces its own synthesis in the pituitary. This homodimerization makes possible two stable steady states (low and high and one unstable state of cortisol production resulting in bistability of the HPA axis. In this model, low GR concentration represents the normal steady state, and high GR concentration represents a dysregulated steady state. A short stress in the normal steady state produces a small perturbation in the GR concentration that quickly returns to normal levels. Long, repeated stress produces persistent and high GR concentration that does not return to baseline forcing the HPA axis to an alternate steady state. One consequence of increased steady state GR is reduced steady state cortisol, which has been observed in some stress related disorders such as Chronic Fatigue Syndrome (CFS. Conclusion Inclusion of pituitary GR expression resulted in a biologically plausible model of HPA axis bistability and hypocortisolism. High GR concentration enhanced cortisol negative feedback on the hypothalamus and forced the HPA axis into an alternative, low cortisol state. This model can be used to explore mechanisms underlying disorders of the HPA axis.

  14. Study on Alzheimer's disease model

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    It is well known that the main brain lesion in Alzheimer's disease (AD) brain is neurofibrillary tangles (NFT) and senile plaques (SP). The amount of NFT is positively correlated with clinical degree of dementia in AD. It is also well studied that the major component of NFT is abnormally hyperphosphorylated microtubule associated protein tau that is caused by an imbalance of protein kinase and protein phosphatase (PP). To reconstitute a specific AD model based on the above hypothesis, we have injected separately calcium calmodulin dependent protein kinase (CaMKKII) activator, bradykinin and PP-2B inhibitor, cyclosporin A into rat hippocampus in the present study. The results showed that the injection of bradykinin caused learning and memory deficient in rats as well as Alzheimer-like tau phosphorylation, including Ser-262/356, Thr-231/235 and Ser-396/404. On the other hand, the injection of cyclosporin A induced the same phosphorylation sites as above except Ser-262/356, however, it did not mimic rat behavior abnormality as bradykinin injection did. The data suggested that activating of CaMKII and the phosphorylation of Ser-262/356 at tau might responsible for the lesion of learning and memory in our model rats. We also incubated PP-2A and PP-1 inhibitor, okadaic acid with human neuroblastoma cell line (SH-SY5Y), and found that (1) inhibition of above PPs induced Alzheimer-like phosphorylation and accumulation of neurofilaments, and Alzheimer-like microtubule disruption, (2) melatonin showed certain protection of the cell from okadaic acid toxicity. The data obtained from this study is significant in AD specific model study.

  15. Conserved intergenic sequences revealed by CTAG-profiling in Salmonella: thermodynamic modeling for function prediction

    Science.gov (United States)

    Tang, Le; Zhu, Songling; Mastriani, Emilio; Fang, Xin; Zhou, Yu-Jie; Li, Yong-Guo; Johnston, Randal N.; Guo, Zheng; Liu, Gui-Rong; Liu, Shu-Lin

    2017-01-01

    Highly conserved short sequences help identify functional genomic regions and facilitate genomic annotation. We used Salmonella as the model to search the genome for evolutionarily conserved regions and focused on the tetranucleotide sequence CTAG for its potentially important functions. In Salmonella, CTAG is highly conserved across the lineages and large numbers of CTAG-containing short sequences fall in intergenic regions, strongly indicating their biological importance. Computer modeling demonstrated stable stem-loop structures in some of the CTAG-containing intergenic regions, and substitution of a nucleotide of the CTAG sequence would radically rearrange the free energy and disrupt the structure. The postulated degeneration of CTAG takes distinct patterns among Salmonella lineages and provides novel information about genomic divergence and evolution of these bacterial pathogens. Comparison of the vertically and horizontally transmitted genomic segments showed different CTAG distribution landscapes, with the genome amelioration process to remove CTAG taking place inward from both terminals of the horizontally acquired segment. PMID:28262684

  16. Computer simulations reveal complex distribution of haemodynamic forces in a mouse retina model of angiogenesis

    CERN Document Server

    Bernabeu, Miguel O; Jones, Martin; Nielsen, Jens H; Krüger, Timm; Nash, Rupert W; Groen, Derek; Hetherington, James; Gerhardt, Holger; Coveney, Peter V

    2013-01-01

    There is currently limited understanding of the role played by haemodynamic forces on the processes governing vascular development. One of many obstacles to be overcome is being able to measure those forces, at the required resolution level, on vessels only a few micrometres thick. In the current paper, we present an in silico method for the computation of the haemodynamic forces experienced by murine retinal vasculature (a widely used vascular development animal model) beyond what is measurable experimentally. Our results show that it is possible to reconstruct high-resolution three-dimensional geometrical models directly from samples of retinal vasculature and that the lattice-Boltzmann algorithm can be used to obtain accurate estimates of the haemodynamics in these domains. Our findings show that the flow patterns recovered are complex, that branches of predominant flow exist from early development stages, and that the pruning process tends to make the wall shear stress experienced by the capillaries incre...

  17. Conserved intergenic sequences revealed by CTAG-profiling in Salmonella: thermodynamic modeling for function prediction

    Science.gov (United States)

    Tang, Le; Zhu, Songling; Mastriani, Emilio; Fang, Xin; Zhou, Yu-Jie; Li, Yong-Guo; Johnston, Randal N.; Guo, Zheng; Liu, Gui-Rong; Liu, Shu-Lin

    2017-03-01

    Highly conserved short sequences help identify functional genomic regions and facilitate genomic annotation. We used Salmonella as the model to search the genome for evolutionarily conserved regions and focused on the tetranucleotide sequence CTAG for its potentially important functions. In Salmonella, CTAG is highly conserved across the lineages and large numbers of CTAG-containing short sequences fall in intergenic regions, strongly indicating their biological importance. Computer modeling demonstrated stable stem-loop structures in some of the CTAG-containing intergenic regions, and substitution of a nucleotide of the CTAG sequence would radically rearrange the free energy and disrupt the structure. The postulated degeneration of CTAG takes distinct patterns among Salmonella lineages and provides novel information about genomic divergence and evolution of these bacterial pathogens. Comparison of the vertically and horizontally transmitted genomic segments showed different CTAG distribution landscapes, with the genome amelioration process to remove CTAG taking place inward from both terminals of the horizontally acquired segment.

  18. Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

    Science.gov (United States)

    Howell, Kristen; Chien, Chun; Bell, Rebecca; Laudier, Damien; Tufa, Sara F.; Keene, Douglas R.; Andarawis-Puri, Nelly; Huang, Alice H.

    2017-01-01

    To date, the cell and molecular mechanisms regulating tendon healing are poorly understood. Here, we establish a novel model of tendon regeneration using neonatal mice and show that neonates heal via formation of a ‘neo-tendon’ that differentiates along the tendon specific lineage with functional restoration of gait and mechanical properties. In contrast, adults heal via fibrovascular scar, aberrant differentiation toward cartilage and bone, with persistently impaired function. Lineage tracing identified intrinsic recruitment of Scx-lineage cells as a key cellular mechanism of neonatal healing that is absent in adults. Instead, adult Scx-lineage tenocytes are not recruited into the defect but transdifferentiate into ectopic cartilage; in the absence of tenogenic cells, extrinsic αSMA-expressing cells persist to form a permanent scar. Collectively, these results establish an exciting model of tendon regeneration and uncover a novel cellular mechanism underlying regenerative vs non-regenerative tendon healing. PMID:28332620

  19. Autonomy and Non-autonomy of Angiogenic Cell Movements Revealed by Experiment-Driven Mathematical Modeling

    Directory of Open Access Journals (Sweden)

    Kei Sugihara

    2015-12-01

    Full Text Available Angiogenesis is a multicellular phenomenon driven by morphogenetic cell movements. We recently reported morphogenetic vascular endothelial cell (EC behaviors to be dynamic and complex. However, the principal mechanisms orchestrating individual EC movements in angiogenic morphogenesis remain largely unknown. Here we present an experiment-driven mathematical model that enables us to systematically dissect cellular mechanisms in branch elongation. We found that cell-autonomous and coordinated actions governed these multicellular behaviors, and a cell-autonomous process sufficiently illustrated essential features of the morphogenetic EC dynamics at both the single-cell and cell-population levels. Through refining our model and experimental verification, we further identified a coordinated mode of tip EC behaviors regulated via a spatial relationship between tip and follower ECs, which facilitates the forward motility of tip ECs. These findings provide insights that enhance our mechanistic understanding of not only angiogenic morphogenesis, but also other types of multicellular phenomenon.

  20. In silico synchronization reveals regulators of nuclear ruptures in lamin A/C deficient model cells

    Science.gov (United States)

    Robijns, J.; Molenberghs, F.; Sieprath, T.; Corne, T. D. J.; Verschuuren, M.; de Vos, W. H.

    2016-07-01

    The nuclear lamina is a critical regulator of nuclear structure and function. Nuclei from laminopathy patient cells experience repetitive disruptions of the nuclear envelope, causing transient intermingling of nuclear and cytoplasmic components. The exact causes and consequences of these events are not fully understood, but their stochastic occurrence complicates in-depth analyses. To resolve this, we have established a method that enables quantitative investigation of spontaneous nuclear ruptures, based on co-expression of a firmly bound nuclear reference marker and a fluorescent protein that shuttles between the nucleus and cytoplasm during ruptures. Minimally invasive imaging of both reporters, combined with automated tracking and in silico synchronization of individual rupture events, allowed extracting information on rupture frequency and recovery kinetics. Using this approach, we found that rupture frequency correlates inversely with lamin A/C levels, and can be reduced in genome-edited LMNA knockout cells by blocking actomyosin contractility or inhibiting the acetyl-transferase protein NAT10. Nuclear signal recovery followed a kinetic that is co-determined by the severity of the rupture event, and could be prolonged by knockdown of the ESCRT-III complex component CHMP4B. In conclusion, our approach reveals regulators of nuclear rupture induction and repair, which may have critical roles in disease development.

  1. Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis.

    Science.gov (United States)

    Ang, Yen-Sin; Rivas, Renee N; Ribeiro, Alexandre J S; Srivas, Rohith; Rivera, Janell; Stone, Nicole R; Pratt, Karishma; Mohamed, Tamer M A; Fu, Ji-Dong; Spencer, C Ian; Tippens, Nathaniel D; Li, Molong; Narasimha, Anil; Radzinsky, Ethan; Moon-Grady, Anita J; Yu, Haiyuan; Pruitt, Beth L; Snyder, Michael P; Srivastava, Deepak

    2016-12-15

    Mutation of highly conserved residues in transcription factors may affect protein-protein or protein-DNA interactions, leading to gene network dysregulation and human disease. Human mutations in GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy. Here, iPS-derived cardiomyocytes from subjects with a heterozygous GATA4-G296S missense mutation showed impaired contractility, calcium handling, and metabolic activity. In human cardiomyocytes, GATA4 broadly co-occupied cardiac enhancers with TBX5, another transcription factor that causes septal defects when mutated. The GATA4-G296S mutation disrupted TBX5 recruitment, particularly to cardiac super-enhancers, concomitant with dysregulation of genes related to the phenotypic abnormalities, including cardiac septation. Conversely, the GATA4-G296S mutation led to failure of GATA4 and TBX5-mediated repression at non-cardiac genes and enhanced open chromatin states at endothelial/endocardial promoters. These results reveal how disease-causing missense mutations can disrupt transcriptional cooperativity, leading to aberrant chromatin states and cellular dysfunction, including those related to morphogenetic defects. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Computational modeling reveals dendritic origins of GABA(A-mediated excitation in CA1 pyramidal neurons.

    Directory of Open Access Journals (Sweden)

    Naomi Lewin

    Full Text Available GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABA(A-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABA(A receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABA(A-mediated excitation is complex. Experimentally it is difficult to determine the ionic mechanisms of depolarizing current since potassium transients are challenging to isolate pharmacologically and much GABA signaling occurs in small, difficult to measure, dendritic compartments. To address this problem and determine plausible ionic mechanisms of GABA(A-mediated excitation, we built a detailed biophysically realistic model of the CA1 pyramidal neuron that includes processes critical for ion homeostasis. Our results suggest that in dendritic compartments, but not in the somatic compartments, chloride buildup is sufficient to cause dramatic depolarization of the GABA(A reversal potential and dominating bicarbonate currents that provide a substantial current source to drive whole-cell depolarization. The model simulations predict that extracellular K(+ transients can augment GABA(A-mediated excitation, but not cause it. Our model also suggests the potential for GABA(A-mediated excitation to promote network synchrony depending on interneuron synapse location - excitatory positive-feedback can occur when interneurons synapse onto distal dendritic compartments, while interneurons projecting to the perisomatic

  3. Computational modelling of cell chain migration reveals mechanisms that sustain follow-the-leader behaviour.

    Science.gov (United States)

    Wynn, Michelle L; Kulesa, Paul M; Schnell, Santiago

    2012-07-07

    Follow-the-leader chain migration is a striking cell migratory behaviour observed during vertebrate development, adult neurogenesis and cancer metastasis. Although cell-cell contact and extracellular matrix (ECM) cues have been proposed to promote this phenomenon, mechanisms that underlie chain migration persistence remain unclear. Here, we developed a quantitative agent-based modelling framework to test mechanistic hypotheses of chain migration persistence. We defined chain migration and its persistence based on evidence from the highly migratory neural crest model system, where cells within a chain extend and retract filopodia in short-lived cell contacts and move together as a collective. In our agent-based simulations, we began with a set of agents arranged as a chain and systematically probed the influence of model parameters to identify factors critical to the maintenance of the chain migration pattern. We discovered that chain migration persistence requires a high degree of directional bias in both lead and follower cells towards the target. Chain migration persistence was also promoted when lead cells maintained cell contact with followers, but not vice-versa. Finally, providing a path of least resistance in the ECM was not sufficient alone to drive chain persistence. Our results indicate that chain migration persistence depends on the interplay of directional cell movement and biased cell-cell contact.

  4. Modeling filamentous cyanobacteria reveals the advantages of long and fast trichomes for optimizing light exposure.

    Science.gov (United States)

    Tamulonis, Carlos; Postma, Marten; Kaandorp, Jaap

    2011-01-01

    Cyanobacteria form a very large and diverse phylum of prokaryotes that perform oxygenic photosynthesis. Many species of cyanobacteria live colonially in long trichomes of hundreds to thousands of cells. Of the filamentous species, many are also motile, gliding along their long axis, and display photomovement, by which a trichome modulates its gliding according to the incident light. The latter has been found to play an important role in guiding the trichomes to optimal lighting conditions, which can either inhibit the cells if the incident light is too weak, or damage the cells if too strong. We have developed a computational model for gliding filamentous photophobic cyanobacteria that allows us to perform simulations on the scale of a Petri dish using over 10(5) individual trichomes. Using the model, we quantify the effectiveness of one commonly observed photomovement strategy--photophobic responses--in distributing large populations of trichomes optimally over a light field. The model predicts that the typical observed length and gliding speeds of filamentous cyanobacteria are optimal for the photophobic strategy. Therefore, our results suggest that not just photomovement but also the trichome shape itself improves the ability of the cyanobacteria to optimize their light exposure.

  5. The Polytrope Index Revealed: Implications for Planet, Solar and Material Models

    CERN Document Server

    Weppner, S P; Thielen, K D; Zielinski, A K

    2014-01-01

    Techniques to model the interior of planets are varied. We introduce a new approach to a century old assumption which enhances not only planetary interior calculations but also solar models and high pressure material physics. Our methodology uses the polytrope assumption which was used to model main sequence and white dwarf stars by Eddington. A polytrope is a simple structural assumption between a material's pressure and volume, $PV^n = C$, where $C$ is a constant and $n$ is the polytrope index. We derive that the polytropic index is the derivative of the bulk modulus with respect to pressure. We then augment the theory by including a variable polytrope index which produces a high quality universal equation of state, within the confines of the Lane-Emden differential equation, making it a robust tool with the potential for excellent predictive power. Unlike most previous equations of state, which have pressure as the dependent variable, the theoretical foundation of our equation of state is the same elastic ...

  6. Modeling filamentous cyanobacteria reveals the advantages of long and fast trichomes for optimizing light exposure.

    Directory of Open Access Journals (Sweden)

    Carlos Tamulonis

    Full Text Available Cyanobacteria form a very large and diverse phylum of prokaryotes that perform oxygenic photosynthesis. Many species of cyanobacteria live colonially in long trichomes of hundreds to thousands of cells. Of the filamentous species, many are also motile, gliding along their long axis, and display photomovement, by which a trichome modulates its gliding according to the incident light. The latter has been found to play an important role in guiding the trichomes to optimal lighting conditions, which can either inhibit the cells if the incident light is too weak, or damage the cells if too strong. We have developed a computational model for gliding filamentous photophobic cyanobacteria that allows us to perform simulations on the scale of a Petri dish using over 10(5 individual trichomes. Using the model, we quantify the effectiveness of one commonly observed photomovement strategy--photophobic responses--in distributing large populations of trichomes optimally over a light field. The model predicts that the typical observed length and gliding speeds of filamentous cyanobacteria are optimal for the photophobic strategy. Therefore, our results suggest that not just photomovement but also the trichome shape itself improves the ability of the cyanobacteria to optimize their light exposure.

  7. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

    Science.gov (United States)

    Lanktree, Matthew B.; Guo, Yiran; Murtaza, Muhammed; Glessner, Joseph T.; Bailey, Swneke D.; Onland-Moret, N. Charlotte; Lettre, Guillaume; Ongen, Halit; Rajagopalan, Ramakrishnan; Johnson, Toby; Shen, Haiqing; Nelson, Christopher P.; Klopp, Norman; Baumert, Jens; Padmanabhan, Sandosh; Pankratz, Nathan; Pankow, James S.; Shah, Sonia; Taylor, Kira; Barnard, John; Peters, Bas J.; M. Maloney, Cliona; Lobmeyer, Maximilian T.; Stanton, Alice; Zafarmand, M. Hadi; Romaine, Simon P.R.; Mehta, Amar; van Iperen, Erik P.A.; Gong, Yan; Price, Tom S.; Smith, Erin N.; Kim, Cecilia E.; Li, Yun R.; Asselbergs, Folkert W.; Atwood, Larry D.; Bailey, Kristian M.; Bhatt, Deepak; Bauer, Florianne; Behr, Elijah R.; Bhangale, Tushar; Boer, Jolanda M.A.; Boehm, Bernhard O.; Bradfield, Jonathan P.; Brown, Morris; Braund, Peter S.; Burton, Paul R.; Carty, Cara; Chandrupatla, Hareesh R.; Chen, Wei; Connell, John; Dalgeorgou, Chrysoula; Boer, Anthonius de; Drenos, Fotios; Elbers, Clara C.; Fang, James C.; Fox, Caroline S.; Frackelton, Edward C.; Fuchs, Barry; Furlong, Clement E.; Gibson, Quince; Gieger, Christian; Goel, Anuj; Grobbee, Diederik E.; Hastie, Claire; Howard, Philip J.; Huang, Guan-Hua; Johnson, W. Craig; Li, Qing; Kleber, Marcus E.; Klein, Barbara E.K.; Klein, Ronald; Kooperberg, Charles; Ky, Bonnie; LaCroix, Andrea; Lanken, Paul; Lathrop, Mark; Li, Mingyao; Marshall, Vanessa; Melander, Olle; Mentch, Frank D.; J. Meyer, Nuala; Monda, Keri L.; Montpetit, Alexandre; Murugesan, Gurunathan; Nakayama, Karen; Nondahl, Dave; Onipinla, Abiodun; Rafelt, Suzanne; Newhouse, Stephen J.; Otieno, F. George; Patel, Sanjey R.; Putt, Mary E.; Rodriguez, Santiago; Safa, Radwan N.; Sawyer, Douglas B.; Schreiner, Pamela J.; Simpson, Claire; Sivapalaratnam, Suthesh; Srinivasan, Sathanur R.; Suver, Christine; Swergold, Gary; Sweitzer, Nancy K.; Thomas, Kelly A.; Thorand, Barbara; Timpson, Nicholas J.; Tischfield, Sam; Tobin, Martin; Tomaszweski, Maciej; Verschuren, W.M. Monique; Wallace, Chris; Winkelmann, Bernhard; Zhang, Haitao; Zheng, Dongling; Zhang, Li; Zmuda, Joseph M.; Clarke, Robert; Balmforth, Anthony J.; Danesh, John; Day, Ian N.; Schork, Nicholas J.; de Bakker, Paul I.W.; Delles, Christian; Duggan, David; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofker, Marten H.; Humphries, Steve E.; Kivimaki, Mika; Lawlor, Debbie A.; Kottke-Marchant, Kandice; Mega, Jessica L.; Mitchell, Braxton D.; Morrow, David A.; Palmen, Jutta; Redline, Susan; Shields, Denis C.; Shuldiner, Alan R.; Sleiman, Patrick M.; Smith, George Davey; Farrall, Martin; Jamshidi, Yalda; Christiani, David C.; Casas, Juan P.; Hall, Alistair S.; Doevendans, Pieter A.; D. Christie, Jason; Berenson, Gerald S.; Murray, Sarah S.; Illig, Thomas; Dorn, Gerald W.; Cappola, Thomas P.; Boerwinkle, Eric; Sever, Peter; Rader, Daniel J.; Reilly, Muredach P.; Caulfield, Mark; Talmud, Philippa J.; Topol, Eric; Engert, James C.; Wang, Kai; Dominiczak, Anna; Hamsten, Anders; Curtis, Sean P.; Silverstein, Roy L.; Lange, Leslie A.; Sabatine, Marc S.; Trip, Mieke; Saleheen, Danish; Peden, John F.; Cruickshanks, Karen J.; März, Winfried; O'Connell, Jeffrey R.; Klungel, Olaf H.; Wijmenga, Cisca; Maitland-van der Zee, Anke Hilse; Schadt, Eric E.; Johnson, Julie A.; Jarvik, Gail P.; Papanicolaou, George J.; Grant, Struan F.A.; Munroe, Patricia B.; North, Kari E.; Samani, Nilesh J.; Koenig, Wolfgang; Gaunt, Tom R.; Anand, Sonia S.; van der Schouw, Yvonne T.; Soranzo, Nicole; FitzGerald, Garret A.; Reiner, Alex; Hegele, Robert A.; Hakonarson, Hakon; Keating, Brendan J.

    2011-01-01

    Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10−6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10−8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10−11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait. PMID:21194676

  8. Structural Studies Reveal the Functional Modularity of the Scc2-Scc4 Cohesin Loader

    Directory of Open Access Journals (Sweden)

    William C.H. Chao

    2015-08-01

    Full Text Available The remarkable accuracy of eukaryotic cell division is partly maintained by the cohesin complex acting as a molecular glue to prevent premature sister chromatid separation. The loading of cohesin onto chromosomes is catalyzed by the Scc2-Scc4 loader complex. Here, we report the crystal structure of Scc4 bound to the N terminus of Scc2 and show that Scc4 is a tetratricopeptide repeat (TPR superhelix. The Scc2 N terminus adopts an extended conformation and is entrapped by the core of the Scc4 superhelix. Electron microscopy (EM analysis reveals that the Scc2-Scc4 loader complex comprises three domains: a head, body, and hook. Deletion studies unambiguously assign the Scc2N-Scc4 as the globular head domain, whereas in vitro cohesin loading assays show that the central body and the hook domains are sufficient to catalyze cohesin loading onto circular DNA, but not chromatinized DNA in vivo, suggesting a possible role for Scc4 as a chromatin adaptor.

  9. A resurrection study reveals rapid adaptive evolution within populations of an invasive plant.

    Science.gov (United States)

    Sultan, Sonia E; Horgan-Kobelski, Tim; Nichols, Lauren M; Riggs, Charlotte E; Waples, Ryan K

    2013-02-01

    The future spread and impact of an introduced species will depend on how it adapts to the abiotic and biotic conditions encountered in its new range, so the potential for rapid evolution subsequent to species introduction is a critical, evolutionary dimension of invasion biology. Using a resurrection approach, we provide a direct test for change over time within populations in a species' introduced range, in the Asian shade annual Polygonum cespitosum. We document, over an 11-year period, the evolution of increased reproductive output as well as greater physiological and root-allocational plasticity in response to the more open, sunny conditions found in the North American range in which the species has become invasive. These findings show that extremely rapid adaptive modifications to ecologically-important traits and plastic expression patterns can evolve subsequent to a species' introduction, within populations established in its introduced range. This study is one of the first to directly document evolutionary change in adaptive plasticity. Such rapid evolutionary changes can facilitate the spread of introduced species into novel habitats and hence contribute to their invasive success in a new range. The data also reveal how evolutionary trajectories can differ among populations in ways that can influence invasion dynamics.

  10. Whole brain white matter changes revealed by multiple diffusion metrics in multiple sclerosis: A TBSS study

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yaou, E-mail: asiaeurope80@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Duan, Yunyun, E-mail: xiaoyun81.love@163.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); He, Yong, E-mail: yong.h.he@gmail.com [State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875 (China); Yu, Chunshui, E-mail: csyuster@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Wang, Jun, E-mail: jun_wang@bnu.edu.cn [State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875 (China); Huang, Jing, E-mail: sainthj@126.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Ye, Jing, E-mail: jingye.2007@yahoo.com.cn [Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Parizel, Paul M., E-mail: paul.parizel@ua.ac.be [Department of Radiology, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Edegem, 8 Belgium (Belgium); Li, Kuncheng, E-mail: kunchengli55@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Shu, Ni, E-mail: nshu55@gmail.com [State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875 (China)

    2012-10-15

    Objective: To investigate whole brain white matter changes in multiple sclerosis (MS) by multiple diffusion indices, we examined patients with diffusion tensor imaging and utilized tract-based spatial statistics (TBSS) method to analyze the data. Methods: Forty-one relapsing-remitting multiple sclerosis (RRMS) patients and 41 age- and gender-matched normal controls were included in this study. Diffusion weighted images were acquired by employing a single-shot echo planar imaging sequence on a 1.5 T MR scanner. Voxel-wise analyses of multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were performed with TBSS. Results: The MS patients had significantly decreased FA (9.11%), increased MD (8.26%), AD (3.48%) and RD (13.17%) in their white matter skeletons compared with the controls. Through TBSS analyses, we found abnormal diffusion changes in widespread white matter regions in MS patients. Specifically, decreased FA, increased MD and increased RD were involved in whole-brain white matter, while several regions exhibited increased AD. Furthermore, white matter regions with significant correlations between the diffusion metrics and the clinical variables (the EDSS scores, disease durations and white matter lesion loads) in MS patients were identified. Conclusion: Widespread white matter abnormalities were observed in MS patients revealed by multiple diffusion metrics. The diffusion changes and correlations with clinical variables were mainly attributed to increased RD, implying the predominant role of RD in reflecting the subtle pathological changes in MS.

  11. Integrating fossils, phylogenies, and niche models into biogeography to reveal ancient evolutionary history: the case of Hypericum (hypericaceae).

    Science.gov (United States)

    Meseguer, Andrea S; Lobo, Jorge M; Ree, Richard; Beerling, David J; Sanmartín, Isabel

    2015-03-01

    In disciplines such as macroevolution that are not amenable to experimentation, scientists usually rely on current observations to test hypotheses about historical events, assuming that "the present is the key to the past." Biogeographers, for example, used this assumption to reconstruct ancestral ranges from the distribution of extant species. Yet, under scenarios of high extinction rates, the biodiversity we observe today might not be representative of the historical diversity and this could result in incorrect biogeographic reconstructions. Here, we introduce a new approach to incorporate into biogeographic inference the temporal, spatial, and environmental information provided by the fossil record, as a direct evidence of the extinct biodiversity fraction. First, inferences of ancestral ranges for those nodes in the phylogeny calibrated with the fossil record are constrained to include the geographic distribution of the fossil. Second, we use fossil distribution and past climate data to reconstruct the climatic preferences and potential distribution of ancestral lineages over time, and use this information to build a biogeographic model that takes into account "ecological connectivity" through time. To show the power of this approach, we reconstruct the biogeographic history of the large angiosperm genus Hypericum, which has a fossil record extending back to the Early Cenozoic. Unlike previous reconstructions based on extant species distributions, our results reveal that Hypericum stem lineages were already distributed in the Holarctic before diversification of its crown-group, and that the geographic distribution of the genus has been relatively stable throughout the climatic oscillations of the Cenozoic. Geographical movement was mediated by the existence of climatic corridors, like Beringia, whereas the equatorial tropical belt acted as a climatic barrier, preventing Hypericum lineages to reach the southern temperate regions. Our study shows that an

  12. Boolean Modeling Reveals the Necessity of Transcriptional Regulation for Bistability in PC12 Cell Differentiation.

    Science.gov (United States)

    Offermann, Barbara; Knauer, Steffen; Singh, Amit; Fernández-Cachón, María L; Klose, Martin; Kowar, Silke; Busch, Hauke; Boerries, Melanie

    2016-01-01

    The nerve growth factor NGF has been shown to cause cell fate decisions toward either differentiation or proliferation depending on the relative activity of downstream pERK, pAKT, or pJNK signaling. However, how these protein signals are translated into and fed back from transcriptional activity to complete cellular differentiation over a time span of hours to days is still an open question. Comparing the time-resolved transcriptome response of NGF- or EGF-stimulated PC12 cells over 24 h in combination with protein and phenotype data we inferred a dynamic Boolean model capturing the temporal sequence of protein signaling, transcriptional response and subsequent autocrine feedback. Network topology was optimized by fitting the model to time-resolved transcriptome data under MEK, PI3K, or JNK inhibition. The integrated model confirmed the parallel use of MAPK/ERK, PI3K/AKT, and JNK/JUN for PC12 cell differentiation. Redundancy of cell signaling is demonstrated from the inhibition of the different MAPK pathways. As suggested in silico and confirmed in vitro, differentiation was substantially suppressed under JNK inhibition, yet delayed only under MEK/ERK inhibition. Most importantly, we found that positive transcriptional feedback induces bistability in the cell fate switch. De novo gene expression was necessary to activate autocrine feedback that caused Urokinase-Type Plasminogen Activator (uPA) Receptor signaling to perpetuate the MAPK activity, finally resulting in the expression of late, differentiation related genes. Thus, the cellular decision toward differentiation depends on the establishment of a transcriptome-induced positive feedback between protein signaling and gene expression thereby constituting a robust control between proliferation and differentiation.

  13. Large-scale Models Reveal the Two-component Mechanics of Striated Muscle

    Directory of Open Access Journals (Sweden)

    Robert Jarosch

    2008-12-01

    Full Text Available This paper provides a comprehensive explanation of striated muscle mechanics and contraction on the basis of filament rotations. Helical proteins, particularly the coiled-coils of tropomyosin, myosin and α-actinin, shorten their H-bonds cooperatively and produce torque and filament rotations when the Coulombic net-charge repulsion of their highly charged side-chains is diminished by interaction with ions. The classical “two-component model” of active muscle differentiated a “contractile component” which stretches the “series elastic component” during force production. The contractile components are the helically shaped thin filaments of muscle that shorten the sarcomeres by clockwise drilling into the myosin cross-bridges with torque decrease (= force-deficit. Muscle stretch means drawing out the thin filament helices off the cross-bridges under passive counterclockwise rotation with torque increase (= stretch activation. Since each thin filament is anchored by four elastic α-actinin Z-filaments (provided with forceregulating sites for Ca2+ binding, the thin filament rotations change the torsional twist of the four Z-filaments as the “series elastic components”. Large scale models simulate the changes of structure and force in the Z-band by the different Z-filament twisting stages A, B, C, D, E, F and G. Stage D corresponds to the isometric state. The basic phenomena of muscle physiology, i. e. latency relaxation, Fenn-effect, the force-velocity relation, the length-tension relation, unexplained energy, shortening heat, the Huxley-Simmons phases, etc. are explained and interpreted with the help of the model experiments.

  14. Sediment Yields Revealed and Fluid Modelling by Twice LiDAR Surveys in Active Tectonics Area

    Science.gov (United States)

    Hsieh, Y.; Chan, Y.; Hu, J.; Lin, C.

    2010-12-01

    LiDAR technique allows rapid acquisition of high resolution and high precision topographic data. The technique has found considerable use in the earth sciences, for example for fluvial morphology and flood modelling. These developments have offered new opportunities for investigating spatial and temporal patterns of morphological change in gravel-bed river and have contributed to develop in two points: (1)morphometric estimates of sediment transport and sediment yields ;(2)boundary conditions for numerical models, including computational fluid dynamics and modelling. This topographic research funded by the Taiwan Central Geological Survey, surveyed the terrain of the Lanyang River before and after the typhoon season using Airborne LiDAR technique, and computed the terrain variations. The Lanyang River is one of main rivers in Taiwan and often suffers the influence of typhoon during summer. Most of sediments generated from slump and soil erosion into river were transported from the upstream watershed and resulted in the riverbed changes during the typhoon season. In 2008, there are four significant typhoon events influencing this area, including the Kalmaegi, Fung-wong, Sinlaku, and Jangmi typhoons. At present, sediment yield calculation often used empirical or theoretical formula as well as data collected at hydrological stations, and rarely had the actual measured value through high-resolution topography. The variations of the terrain on the riverbed may be regarded as the sediment yield of the bed load transported during the typhoon season. This research used high-resolution terrain models to compute sediment yield of the bed load, and further discussed volumes of sediment yield in watershed during the typhoon season. In the Lanyang River we discovered that the upstream and midstream channel still had the characteristics of erosion and transportation during the typhoon season. The results imply significant sediment yield and transportation from the upstream

  15. Network Modeling Reveals Cross Talk of MAP Kinases during Adaptation to Caspofungin Stress in Aspergillus fumigatus.

    Science.gov (United States)

    Altwasser, Robert; Baldin, Clara; Weber, Jakob; Guthke, Reinhard; Kniemeyer, Olaf; Brakhage, Axel A; Linde, Jörg; Valiante, Vito

    2015-01-01

    Mitogen activated protein kinases (MAPKs) are highly conserved in eukaryotic organisms. In pathogenic fungi, their activities were assigned to different physiological functions including drug adaptation and resistance. Aspergillus fumigatus is a human pathogenic fungus, which causes life-threatening invasive infections. Therapeutic options against invasive mycoses are still limited. One of the clinically used drugs is caspofungin, which specifically targets the fungal cell wall biosynthesis. A systems biology approach, based on comprehensive transcriptome data sets and mathematical modeling, was employed to infer a regulatory network and identify key interactions during adaptation to caspofungin stress in A. fumigatus. Mathematical modeling and experimental validations confirmed an intimate cross talk occurring between the cell wall-integrity and the high osmolarity-glycerol signaling pathways. Specifically, increased concentrations of caspofungin promoted activation of these signalings. Moreover, caspofungin affected the intracellular transport, which caused an additional osmotic stress that is independent of glucan inhibition. High concentrations of caspofungin reduced this osmotic stress, and thus decreased its toxic activity. Our results demonstrated that MAPK signaling pathways play a key role during caspofungin adaptation and are contributing to the paradoxical effect exerted by this drug.

  16. Aiptasia sp. larvae as a model to reveal mechanisms of symbiont selection in cnidarians

    KAUST Repository

    Wolfowicz, Iliona

    2016-09-01

    Symbiosis, defined as the persistent association between two distinct species, is an evolutionary and ecologically critical phenomenon facilitating survival of both partners in diverse habitats. The biodiversity of coral reef ecosystems depends on a functional symbiosis with photosynthetic dinoflagellates of the highly diverse genus Symbiodinium, which reside in coral host cells and continuously support their nutrition. The mechanisms underlying symbiont selection to establish a stable endosymbiosis in non-symbiotic juvenile corals are unclear. Here we show for the first time that symbiont selection patterns for larvae of two Acropora coral species and the model anemone Aiptasia are similar under controlled conditions. We find that Aiptasia larvae distinguish between compatible and incompatible symbionts during uptake into the gastric cavity and phagocytosis. Using RNA-Seq, we identify a set of candidate genes potentially involved in symbiosis establishment. Together, our data complement existing molecular resources to mechanistically dissect symbiont phagocytosis in cnidarians under controlled conditions, thereby strengthening the role of Aiptasia larvae as a powerful model for cnidarian endosymbiosis establishment.

  17. Computational models reveal a passive mechanism for cell migration in the crypt.

    Directory of Open Access Journals (Sweden)

    Sara-Jane Dunn

    Full Text Available Cell migration in the intestinal crypt is essential for the regular renewal of the epithelium, and the continued upward movement of cells is a key characteristic of healthy crypt dynamics. However, the driving force behind this migration is unknown. Possibilities include mitotic pressure, active movement driven by motility cues, or negative pressure arising from cell loss at the crypt collar. It is possible that a combination of factors together coordinate migration. Here, three different computational models are used to provide insight into the mechanisms that underpin cell movement in the crypt, by examining the consequence of eliminating cell division on cell movement. Computational simulations agree with existing experimental results, confirming that migration can continue in the absence of mitosis. Importantly, however, simulations allow us to infer mechanisms that are sufficient to generate cell movement, which is not possible through experimental observation alone. The results produced by the three models agree and suggest that cell loss due to apoptosis and extrusion at the crypt collar relieves cell compression below, allowing cells to expand and move upwards. This finding suggests that future experiments should focus on the role of apoptosis and cell extrusion in controlling cell migration in the crypt.

  18. Proteomics-Based Metabolic Modeling Reveals That Fatty Acid Oxidation (FAO) Controls Endothelial Cell (EC) Permeability*

    Science.gov (United States)

    Patella, Francesca; Schug, Zachary T.; Persi, Erez; Neilson, Lisa J.; Erami, Zahra; Avanzato, Daniele; Maione, Federica; Hernandez-Fernaud, Juan R.; Mackay, Gillian; Zheng, Liang; Reid, Steven; Frezza, Christian; Giraudo, Enrico; Fiorio Pla, Alessandra; Anderson, Kurt; Ruppin, Eytan; Gottlieb, Eyal; Zanivan, Sara

    2015-01-01

    Endothelial cells (ECs) play a key role to maintain the functionality of blood vessels. Altered EC permeability causes severe impairment in vessel stability and is a hallmark of pathologies such as cancer and thrombosis. Integrating label-free quantitative proteomics data into genome-wide metabolic modeling, we built up a model that predicts the metabolic fluxes in ECs when cultured on a tridimensional matrix and organize into a vascular-like network. We discovered how fatty acid oxidation increases when ECs are assembled into a fully formed network that can be disrupted by inhibiting CPT1A, the fatty acid oxidation rate-limiting enzyme. Acute CPT1A inhibition reduces cellular ATP levels and oxygen consumption, which are restored by replenishing the tricarboxylic acid cycle. Remarkably, global phosphoproteomic changes measured upon acute CPT1A inhibition pinpointed altered calcium signaling. Indeed, CPT1A inhibition increases intracellular calcium oscillations. Finally, inhibiting CPT1A induces hyperpermeability in vitro and leakage of blood vessel in vivo, which were restored blocking calcium influx or replenishing the tricarboxylic acid cycle. Fatty acid oxidation emerges as central regulator of endothelial functions and blood vessel stability and druggable pathway to control pathological vascular permeability. PMID:25573745

  19. Modeling chemotaxis reveals the role of reversed phosphotransfer and a bi-functional kinase-phosphatase.

    Directory of Open Access Journals (Sweden)

    Marcus J Tindall

    2010-08-01

    Full Text Available Understanding how multiple signals are integrated in living cells to produce a balanced response is a major challenge in biology. Two-component signal transduction pathways, such as bacterial chemotaxis, comprise histidine protein kinases (HPKs and response regulators (RRs. These are used to sense and respond to changes in the environment. Rhodobacter sphaeroides has a complex chemosensory network with two signaling clusters, each containing a HPK, CheA. Here we demonstrate, using a mathematical model, how the outputs of the two signaling clusters may be integrated. We use our mathematical model supported by experimental data to predict that: (1 the main RR controlling flagellar rotation, CheY(6, aided by its specific phosphatase, the bifunctional kinase CheA(3, acts as a phosphate sink for the other RRs; and (2 a phosphorelay pathway involving CheB(2 connects the cytoplasmic cluster kinase CheA(3 with the polar localised kinase CheA(2, and allows CheA(3-P to phosphorylate non-cognate chemotaxis RRs. These two mechanisms enable the bifunctional kinase/phosphatase activity of CheA(3 to integrate and tune the sensory output of each signaling cluster to produce a balanced response. The signal integration mechanisms identified here may be widely used by other bacteria, since like R. sphaeroides, over 50% of chemotactic bacteria have multiple cheA homologues and need to integrate signals from different sources.

  20. Hidden Markov models reveal complexity in the diving behaviour of short-finned pilot whales.

    Science.gov (United States)

    Quick, Nicola J; Isojunno, Saana; Sadykova, Dina; Bowers, Matthew; Nowacek, Douglas P; Read, Andrew J

    2017-03-31

    Diving behaviour of short-finned pilot whales is often described by two states; deep foraging and shallow, non-foraging dives. However, this simple classification system ignores much of the variation that occurs during subsurface periods. We used multi-state hidden Markov models (HMM) to characterize states of diving behaviour and the transitions between states in short-finned pilot whales. We used three parameters (number of buzzes, maximum dive depth and duration) measured in 259 dives by digital acoustic recording tags (DTAGs) deployed on 20 individual whales off Cape Hatteras, North Carolina, USA. The HMM identified a four-state model as the best descriptor of diving behaviour. The state-dependent distributions for the diving parameters showed variation between states, indicative of different diving behaviours. Transition probabilities were considerably higher for state persistence than state switching, indicating that dive types occurred in bouts. Our results indicate that subsurface behaviour in short-finned pilot whales is more complex than a simple dichotomy of deep and shallow diving states, and labelling all subsurface behaviour as deep dives or shallow dives discounts a significant amount of important variation. We discuss potential drivers of these patterns, including variation in foraging success, prey availability and selection, bathymetry, physiological constraints and socially mediated behaviour.

  1. Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma.

    Science.gov (United States)

    Kling, Teresia; Ferrarese, Roberto; Ó hAilín, Darren; Johansson, Patrik; Heiland, Dieter Henrik; Dai, Fangping; Vasilikos, Ioannis; Weyerbrock, Astrid; Jörnsten, Rebecka; Carro, Maria Stella; Nelander, Sven

    2016-10-01

    Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and transcriptional regulators of glioblastoma subtypes. Our model identified Annexin A2 (ANXA2) as a novel methylation-controlled positive regulator of the mesenchymal subtype. Subsequent evaluation in two independent cohorts established ANXA2 expression as a prognostic factor that is dependent on ANXA2 promoter methylation. ANXA2 knockdown in primary glioblastoma stem cell-like cultures suppressed known mesenchymal master regulators, and abrogated cell proliferation and invasion. Our results place ANXA2 at the apex of a regulatory cascade that determines glioblastoma mesenchymal transformation and validate aSICS as a general methodology to uncover regulators of cancer subtypes.

  2. Proteomics-based metabolic modeling reveals that fatty acid oxidation (FAO) controls endothelial cell (EC) permeability.

    Science.gov (United States)

    Patella, Francesca; Schug, Zachary T; Persi, Erez; Neilson, Lisa J; Erami, Zahra; Avanzato, Daniele; Maione, Federica; Hernandez-Fernaud, Juan R; Mackay, Gillian; Zheng, Liang; Reid, Steven; Frezza, Christian; Giraudo, Enrico; Fiorio Pla, Alessandra; Anderson, Kurt; Ruppin, Eytan; Gottlieb, Eyal; Zanivan, Sara

    2015-03-01

    Endothelial cells (ECs) play a key role to maintain the functionality of blood vessels. Altered EC permeability causes severe impairment in vessel stability and is a hallmark of pathologies such as cancer and thrombosis. Integrating label-free quantitative proteomics data into genome-wide metabolic modeling, we built up a model that predicts the metabolic fluxes in ECs when cultured on a tridimensional matrix and organize into a vascular-like network. We discovered how fatty acid oxidation increases when ECs are assembled into a fully formed network that can be disrupted by inhibiting CPT1A, the fatty acid oxidation rate-limiting enzyme. Acute CPT1A inhibition reduces cellular ATP levels and oxygen consumption, which are restored by replenishing the tricarboxylic acid cycle. Remarkably, global phosphoproteomic changes measured upon acute CPT1A inhibition pinpointed altered calcium signaling. Indeed, CPT1A inhibition increases intracellular calcium oscillations. Finally, inhibiting CPT1A induces hyperpermeability in vitro and leakage of blood vessel in vivo, which were restored blocking calcium influx or replenishing the tricarboxylic acid cycle. Fatty acid oxidation emerges as central regulator of endothelial functions and blood vessel stability and druggable pathway to control pathological vascular permeability.

  3. Hidden Markov models reveal complexity in the diving behaviour of short-finned pilot whales

    Science.gov (United States)

    Quick, Nicola J.; Isojunno, Saana; Sadykova, Dina; Bowers, Matthew; Nowacek, Douglas P.; Read, Andrew J.

    2017-01-01

    Diving behaviour of short-finned pilot whales is often described by two states; deep foraging and shallow, non-foraging dives. However, this simple classification system ignores much of the variation that occurs during subsurface periods. We used multi-state hidden Markov models (HMM) to characterize states of diving behaviour and the transitions between states in short-finned pilot whales. We used three parameters (number of buzzes, maximum dive depth and duration) measured in 259 dives by digital acoustic recording tags (DTAGs) deployed on 20 individual whales off Cape Hatteras, North Carolina, USA. The HMM identified a four-state model as the best descriptor of diving behaviour. The state-dependent distributions for the diving parameters showed variation between states, indicative of different diving behaviours. Transition probabilities were considerably higher for state persistence than state switching, indicating that dive types occurred in bouts. Our results indicate that subsurface behaviour in short-finned pilot whales is more complex than a simple dichotomy of deep and shallow diving states, and labelling all subsurface behaviour as deep dives or shallow dives discounts a significant amount of important variation. We discuss potential drivers of these patterns, including variation in foraging success, prey availability and selection, bathymetry, physiological constraints and socially mediated behaviour. PMID:28361954

  4. Generalized additive models reveal the intrinsic complexity of wood formation dynamics.

    Science.gov (United States)

    Cuny, Henri E; Rathgeber, Cyrille B K; Kiessé, Tristan Senga; Hartmann, Felix P; Barbeito, Ignacio; Fournier, Meriem

    2013-04-01

    The intra-annual dynamics of wood formation, which involves the passage of newly produced cells through three successive differentiation phases (division, enlargement, and wall thickening) to reach the final functional mature state, has traditionally been described in conifers as three delayed bell-shaped curves followed by an S-shaped curve. Here the classical view represented by the 'Gompertz function (GF) approach' was challenged using two novel approaches based on parametric generalized linear models (GLMs) and 'data-driven' generalized additive models (GAMs). These three approaches (GFs, GLMs, and GAMs) were used to describe seasonal changes in cell numbers in each of the xylem differentiation phases and to calculate the timing of cell development in three conifer species [Picea abies (L.), Pinus sylvestris L., and Abies alba Mill.]. GAMs outperformed GFs and GLMs in describing intra-annual wood formation dynamics, showing two left-skewed bell-shaped curves for division and enlargement, and a right-skewed bimodal curve for thickening. Cell residence times progressively decreased through the season for enlargement, whilst increasing late but rapidly for thickening. These patterns match changes in cell anatomical features within a tree ring, which allows the separation of earlywood and latewood into two distinct cell populations. A novel statistical approach is presented which renews our understanding of xylogenesis, a dynamic biological process in which the rate of cell production interplays with cell residence times in each developmental phase to create complex seasonal patterns.

  5. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression.

    Science.gov (United States)

    Airan, Raag D; Meltzer, Leslie A; Roy, Madhuri; Gong, Yuqing; Chen, Han; Deisseroth, Karl

    2007-08-10

    The hippocampus is one of several brain areas thought to play a central role in affective behaviors, but the underlying local network dynamics are not understood. We used quantitative voltage-sensitive dye imaging to probe hippocampal dynamics with millisecond resolution in brain slices after bidirectional modulation of affective state in rat models of depression. We found that a simple measure of real-time activity-stimulus-evoked percolation of activity through the dentate gyrus relative to the hippocampal output subfield-accounted for induced changes in animal behavior independent of the underlying mechanism of action of the treatments. Our results define a circuit-level neurophysiological endophenotype for affective behavior and suggest an approach to understanding circuit-level substrates underlying psychiatric disease symptoms.

  6. Model-based traction force microscopy reveals differential tension in cellular actin bundles.

    Science.gov (United States)

    Soiné, Jérôme R D; Brand, Christoph A; Stricker, Jonathan; Oakes, Patrick W; Gardel, Margaret L; Schwarz, Ulrich S

    2015-03-01

    Adherent cells use forces at the cell-substrate interface to sense and respond to the physical properties of their environment. These cell forces can be measured with traction force microscopy which inverts the equations of elasticity theory to calculate them from the deformations of soft polymer substrates. We introduce a new type of traction force microscopy that in contrast to traditional methods uses additional image data for cytoskeleton and adhesion structures and a biophysical model to improve the robustness of the inverse procedure and abolishes the need for regularization. We use this method to demonstrate that ventral stress fibers of U2OS-cells are typically under higher mechanical tension than dorsal stress fibers or transverse arcs.

  7. Model-based traction force microscopy reveals differential tension in cellular actin bundles.

    Directory of Open Access Journals (Sweden)

    Jérôme R D Soiné

    2015-03-01

    Full Text Available Adherent cells use forces at the cell-substrate interface to sense and respond to the physical properties of their environment. These cell forces can be measured with traction force microscopy which inverts the equations of elasticity theory to calculate them from the deformations of soft polymer substrates. We introduce a new type of traction force microscopy that in contrast to traditional methods uses additional image data for cytoskeleton and adhesion structures and a biophysical model to improve the robustness of the inverse procedure and abolishes the need for regularization. We use this method to demonstrate that ventral stress fibers of U2OS-cells are typically under higher mechanical tension than dorsal stress fibers or transverse arcs.

  8. Mixture model of pottery decorations from Lake Chad Basin archaeological sites reveals ancient segregation patterns.

    Science.gov (United States)

    O'Brien, John D; Lin, Kathryn; MacEachern, Scott

    2016-03-30

    We present a new statistical approach to analysing an extremely common archaeological data type--potsherds--that infers the structure of cultural relationships across a set of excavation units (EUs). This method, applied to data from a set of complex, culturally heterogeneous sites around the Mandara mountains in the Lake Chad Basin, helps elucidate cultural succession through the Neolithic and Iron Age. We show how the approach can be integrated with radiocarbon dates to provide detailed portraits of cultural dynamics and deposition patterns within single EUs. In this context, the analysis supports ancient cultural segregation analogous to historical ethnolinguistic patterning in the region. We conclude with a discussion of the many possible model extensions using other archaeological data types.

  9. The study of fkbp and ubiquitin reveals interesting aspects of Artemia stress history.

    Science.gov (United States)

    Maniatsi, Stefania; Farmaki, Theodora; Abatzopoulos, Theodore J

    2015-08-01

    Research on stress responses in animals has increased greatly during the last decades. Though most studies focus on the cellular and molecular bases of the stress response mechanisms, the ecological and evolutionary aspects of stress responses gain more and more interest. Here, we use species and parthenogenetic strains of the genus Artemia, an extremophile model organism, to study, for the first time, a protein well known for its chaperone activity and its involvement in stress responses. More specifically, transcription and protein accumulation of an FK506-Binding Protein (FKBP) homologue were investigated under heat and salt stresses. Additionally, the mRNA levels of ubiquitin, a heat-inducible protein related to the proteasomal pathway, were quantitated under these conditions. Biochemical and phylogenetic analyses showed that the studied FKBP orthologue is a typical representative of the family that clusters with other crustacean sequences. The expression was increased in both fkbp and ubiquitin genes after salt and heat stresses. However, our results in combination with the fact that Artemia species and parthenogenetic strains, selected for this study, exhibit different heat or salt tolerance provide useful hints about the evolutionary significance of FKBP and ubiquitin. Regarding FKBP, mRNA expression and protein accumulation seem to depend on the environmental conditions and the evolutionary history of each Artemia population while ubiquitin has a clear and more conserved role under heat shock.

  10. Immunogold labeling reveals subcellular localisation of silica nanoparticles in a human blood-brain barrier model

    Science.gov (United States)

    Ye, Dong; Anguissola, Sergio; O'Neill, Tiina; Dawson, Kenneth A.

    2015-05-01

    Subcellular location of nanoparticles has been widely investigated with fluorescence microscopy, via fluorescently labeled antibodies to visualise target antigens in cells. However, fluorescence microscopy, such as confocal or live cell imaging, has generally limited 3D spatial resolution. Conventional electron microscopy can be useful in bridging resolution gap, but still not ideal in resolving subcellular organelle identities. Using the pre-embedding immunogold electron microscopic imaging, we performed accurate examination of the intracellular trafficking and gathered further evidence of transport mechanisms of silica nanoparticles across a human in vitro blood-brain barrier model. Our approach can effectively immunolocalise a variety of intracellular compartments and provide new insights into the uptake and subcellular transport of nanoparticles.Subcellular location of nanoparticles has been widely investigated with fluorescence microscopy, via fluorescently labeled antibodies to visualise target antigens in cells. However, fluorescence microscopy, such as confocal or live cell imaging, has generally limited 3D spatial resolution. Conventional electron microscopy can be useful in bridging resolution gap, but still not ideal in resolving subcellular organelle identities. Using the pre-embedding immunogold electron microscopic imaging, we performed accurate examination of the intracellular trafficking and gathered further evidence of transport mechanisms of silica nanoparticles across a human in vitro blood-brain barrier model. Our approach can effectively immunolocalise a variety of intracellular compartments and provide new insights into the uptake and subcellular transport of nanoparticles. Electronic supplementary information (ESI) available: Nanoparticle characterisation data, preservation of cellular structures, staining controls, optimisation of size amplification via the silver enhancement, and more imaging results from anti-clathrin and anti-caveolin 1

  11. Action potential processing in a detailed Purkinje cell model reveals a critical role for axonal compartmentalization

    Directory of Open Access Journals (Sweden)

    Stefano eMasoli

    2015-02-01

    Full Text Available The Purkinje cell (PC is among the most complex neurons in the brain and plays a critical role for cerebellar functioning. PCs operate as fast pacemakers modulated by synaptic inputs but can switch from simple spikes to complex bursts and, in some conditions, show bistability. In contrast to original works emphasizing dendritic Ca-dependent mechanisms, recent experiments have supported a primary role for axonal Na-dependent processing, which could effectively regulate spike generation and transmission to deep cerebellar nuclei (DCN. In order to account for the numerous ionic mechanisms involved (at present including Nav1.6, Cav2.1, Cav3.1, Cav3.2, Cav3.3, Kv1.1, Kv1.5, Kv3.3, Kv3.4, Kv4.3, KCa1.1, KCa2.2, KCa3.1, Kir2.x, HCN1, we have elaborated a multicompartmental model incorporating available knowledge on localization and gating of PC ionic channels. The axon, including initial segment (AIS and Ranvier nodes (RNs, proved critical to obtain appropriate pacemaking and firing frequency modulation. Simple spikes initiated in the AIS and protracted discharges were stabilized in the soma through Na-dependent mechanisms, while somato-dendritic Ca channels contributed to sustain pacemaking and to generate complex bursting at high discharge regimes. Bistability occurred only following Na and Ca channel down-regulation. In addition, specific properties in RNs K currents were required to limit spike transmission frequency along the axon. The model showed how organized electroresponsive functions could emerge from the molecular complexity of PCs and showed that the axon is fundamental to complement ionic channel compartmentalization enabling action potential processing and transmission of specific spike patterns to DCN.

  12. Ascl3 knockout and cell ablation models reveal complexity of salivary gland maintenance and regeneration.

    Science.gov (United States)

    Arany, Szilvia; Catalán, Marcelo A; Roztocil, Elisa; Ovitt, Catherine E

    2011-05-15

    Expression of the transcription factor, Ascl3, marks a population of adult progenitor cells, which can give rise to both acinar and duct cell types in the murine salivary glands. Using a previously reported Ascl3(EGFP-Cre/+) knock-in strain, we demonstrate that Ascl3-expressing cells represent a molecularly distinct, and proliferating population of progenitor cells located in salivary gland ducts. To investigate both the role of the Ascl3 transcription factor, and the role of the cells in which it is expressed, we generated knockout and cell-specific ablation models. Ascl3 knockout mice develop smaller salivary glands than wild type littermates, but secrete saliva normally. They display a lower level of cell proliferation, consistent with their smaller size. In the absence of Ascl3, the cells maintain their progenitor function and continue to generate both acinar and duct cells. To directly test the role of the progenitor cells, themselves, in salivary gland development and regeneration, we used Cre-activated expression of diphtheria toxin (DTA) in the Ascl3-expressing (Ascl3+) cell population, resulting in specific cell ablation of Ascl3+ cells. In the absence of the Ascl3+ progenitor cells, the mice developed morphologically normal, albeit smaller, salivary glands able to secrete saliva. Furthermore, in a ductal ligation model of salivary gland injury, the glands of these mice were able to regenerate acinar cells. Our results indicate that Ascl3+ cells are active proliferating progenitors, but they are not the only precursors for salivary gland development or regeneration. We conclude that maintenance of tissue homeostasis in the salivary gland must involve more than one progenitor cell population.

  13. Anatase (101)-like Structural Model Revealed for Metastable Rutile TiO2(011) Surface.

    Science.gov (United States)

    Xu, Meiling; Shao, Sen; Gao, Bo; Lv, Jian; Li, Quan; Wang, Yanchao; Wang, Hui; Zhang, Lijun; Ma, Yanming

    2017-03-08

    Titanium dioxide has been widely used as an efficient transition metal oxide photocatalyst. However, its photocatalytic activity is limited to the ultraviolet spectrum range due to the large bandgap beyond 3 eV. Efforts to reduce the bandgap to achieve a broader spectrum range of light absorption have been successfully attempted via the experimental synthesis of dopant-free metastable surface structures of rutile-type TiO2 (011) 2 × 1. This new surface phase possesses a reduced bandgap of ∼2.1 eV, showing great potential for an excellent photocatalyst covering a wide range of visible light. There is a need to establish the atomistic structure of this metastable surface to understand the physical cause for the bandgap reduction and to improve the future design of photocatalysts. Here, we report computational investigations in an effort to unravel this surface structure via swarm structure-searching simulations. The established structure adopts the anatase (101)-like structure model, where the topmost 2-fold O atoms form a quasi-hexagonal surface pattern and bond with the unsaturated 5-fold and 4-fold Ti atoms in the next layer. The predicted anatase (101)-like surface model can naturally explain the experimental observation of the STM images, the electronic bandgap, and the oxidation state of Ti(4+). Dangling bonds on the anatase (101)-like surface are abundant making it a superior photocatalyst. First-principles molecular dynamics simulations have supported the high photocatalytic activity by showing that water and formic acid molecules dissociate spontaneously on the anatase (101)-like surface.

  14. A Proposed Theoretical Model for Exploring the Ecological Ideologies Re-vealed in the Online Chinese Resort Profiles

    Institute of Scientific and Technical Information of China (English)

    肖瑟

    2013-01-01

      Responding to the increasingly heated discussion of environmental issues and the mounting concern about ecological degradation, the present thesis is to try formulating a comprehensive and specific theoretical model for exploring the ecological ideologies revealed in the online Chinese resort profiles. In this model, Fairclough’s three-dimensional model draws upon the Subsystem of Appraisal Theory—Attitude as the specific analytical framework and the ecological philosophy in the scope of ecocriticism as the specific explanatory tool for the exploration of ecological ideologies in these texts. Thus, the present thesis finds a point where CDA, Appraisal Theory and Ecocriticism work together to conduct a discourse analysis, which not only broadens the theoretical scope of each, but makes these theories better serve the practical course of environment protection.

  15. Complete protein-protein association kinetics in atomic detail revealed by molecular dynamics simulations and Markov modelling

    Science.gov (United States)

    Plattner, Nuria; Doerr, Stefan; de Fabritiis, Gianni; Noé, Frank

    2017-10-01

    Protein-protein association is fundamental to many life processes. However, a microscopic model describing the structures and kinetics during association and dissociation is lacking on account of the long lifetimes of associated states, which have prevented efficient sampling by direct molecular dynamics (MD) simulations. Here we demonstrate protein-protein association and dissociation in atomistic resolution for the ribonuclease barnase and its inhibitor barstar by combining adaptive high-throughput MD simulations and hidden Markov modelling. The model reveals experimentally consistent intermediate structures, energetics and kinetics on timescales from microseconds to hours. A variety of flexibly attached intermediates and misbound states funnel down to a transition state and a native basin consisting of the loosely bound near-native state and the tightly bound crystallographic state. These results offer a deeper level of insight into macromolecular recognition and our approach opens the door for understanding and manipulating a wide range of macromolecular association processes.

  16. Metabolomics in psoriatic disease: pilot study reveals metabolite differences in psoriasis and psoriatic arthritis

    Science.gov (United States)

    Armstrong, April W.; Wu, Julie; Johnson, Mary Ann; Grapov, Dmitry; Azizi, Baktazh; Dhillon, Jaskaran; Fiehn, Oliver

    2014-01-01

    Importance: While “omics” studies have advanced our understanding of inflammatory skin diseases, metabolomics is mostly an unexplored field in dermatology. Objective: We sought to elucidate the pathogenesis of psoriatic diseases by determining the differences in metabolomic profiles among psoriasis patients with or without psoriatic arthritis and healthy controls. Design: We employed a global metabolomics approach to compare circulating metabolites from patients with psoriasis, psoriasis and psoriatic arthritis, and healthy controls. Setting: Study participants were recruited from the general community and from the Psoriasis Clinic at the University of California Davis in United States. Participants: We examined metabolomic profiles using blood serum samples from 30 patients age and gender matched into three groups: 10 patients with psoriasis, 10 patients with psoriasis and psoriatic arthritis and 10 control participants. Main outcome(s) and measures(s): Metabolite levels were measured calculating the mean peak intensities from gas chromatography time-of-flight mass spectrometry. Results: Multivariate analyses of metabolomics profiles revealed altered serum metabolites among the study population. Compared to control patients, psoriasis patients had a higher level of alpha ketoglutaric acid (Pso: 288 ± 88; Control: 209 ± 69; p=0.03), a lower level of asparagine (Pso: 5460 ± 980; Control: 7260 ± 2100; p=0.02), and a lower level of glutamine (Pso: 86000 ± 20000; Control: 111000 ± 27000; p=0.02). Compared to control patients, patients with psoriasis and psoriatic arthritis had increased levels of glucuronic acid (Pso + PsA: 638 ± 250; Control: 347 ± 61; p=0.001). Compared to patients with psoriasis alone, patients with both psoriasis and psoriatic arthritis had a decreased level of alpha ketoglutaric acid (Pso + PsA: 186 ± 80; Pso: 288 ± 88; p=0.02) and an increased level of lignoceric acid (Pso + PsA: 442 ± 280; Pso: 214 ± 64; p=0.02). Conclusions and

  17. Impact of community-acquired paediatric rotavirus gastroenteritis on family life: data from the REVEAL study

    Directory of Open Access Journals (Sweden)

    Talayero José MP

    2010-03-01

    Full Text Available Abstract Background Rotavirus is the leading cause of acute gastroenteritis (AGE and the most frequent cause of severe diarrhoea in children aged less than 5 years. Although the epidemiology of rotavirus gastroenteritis (RVGE is well documented, there are few data on the impact of RVGE on the families of affected children. Methods Data associated with the burden of RVGE, including number of working days lost, levels of parental stress, the need for alternative childcare arrangements and additional nappies used, were extracted from questionnaires completed by parents of children participating in a prospective, multicentre, observational study (Rotavirus gastroenteritis Epidemiology and Viral types in Europe Accounting for Losses in public health and society, REVEAL, conducted during 2004-2005 in selected areas of Belgium, France, Germany, Italy, Spain, Sweden, and the United Kingdom to estimate the incidence of RVGE in children aged less than 5 years seeking medical care as a result of AGE. Results 1102 children with RVGE were included in the present analysis. The proportion of RVGE cases that required at least one parent or other person to be absent from work was 39%-91% in the hospital setting, 44%-64% in the emergency department, and 20%-64% in primary care. Self-reported levels of parental stress were generally high (mean stress levels, ≥ 5 on a 10-point visual analogue scale. Additional childcare arrangements were required in up to 21% of RVGE episodes. The mean number of nappies used per day during RVGE episodes was approximately double that used when the child was not ill. Conclusions Paediatric RVGE cases cause disruption to families and parental stress. The burden of RVGE on children and their families could be substantially reduced by routine rotavirus vaccination of infants.

  18. Genome-wide association study of toxic metals and trace elements reveals novel associations.

    Science.gov (United States)

    Ng, Esther; Lind, P Monica; Lindgren, Cecilia; Ingelsson, Erik; Mahajan, Anubha; Morris, Andrew; Lind, Lars

    2015-08-15

    The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals. Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray and imputed up to reference panels from the 1000 Genomes Project. Analyses revealed two regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q41. The lead single nucleotide polymorphism (SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 × 10(-11), β = -0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (P-value = 2.2 × 10(-14), β = -0.46). The SNP lies within the intronic region of SLC30A10, another transporter protein. Among other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (P = 1.4 × 10(-10), β = -1.2 and P = 1.8 × 10(-9), β = -1.8, respectively). Whole blood measurements of toxic metals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity. © The Author 2015. Published by Oxford University Press.

  19. Comparative study of human mitochondrial proteome reveals extensive protein subcellular relocalization after gene duplications

    Directory of Open Access Journals (Sweden)

    Huang Yong

    2009-11-01

    Full Text Available Abstract Background Gene and genome duplication is the principle creative force in evolution. Recently, protein subcellular relocalization, or neolocalization was proposed as one of the mechanisms responsible for the retention of duplicated genes. This hypothesis received support from the analysis of yeast genomes, but has not been tested thoroughly on animal genomes. In order to evaluate the importance of subcellular relocalizations for retention of duplicated genes in animal genomes, we systematically analyzed nuclear encoded mitochondrial proteins in the human genome by reconstructing phylogenies of mitochondrial multigene families. Results The 456 human mitochondrial proteins selected for this study were clustered into 305 gene families including 92 multigene families. Among the multigene families, 59 (64% consisted of both mitochondrial and cytosolic (non-mitochondrial proteins (mt-cy families while the remaining 33 (36% were composed of mitochondrial proteins (mt-mt families. Phylogenetic analyses of mt-cy families revealed three different scenarios of their neolocalization following gene duplication: 1 relocalization from mitochondria to cytosol, 2 from cytosol to mitochondria and 3 multiple subcellular relocalizations. The neolocalizations were most commonly enabled by the gain or loss of N-terminal mitochondrial targeting signals. The majority of detected subcellular relocalization events occurred early in animal evolution, preceding the evolution of tetrapods. Mt-mt protein families showed a somewhat different pattern, where gene duplication occurred more evenly in time. However, for both types of protein families, most duplication events appear to roughly coincide with two rounds of genome duplications early in vertebrate evolution. Finally, we evaluated the effects of inaccurate and incomplete annotation of mitochondrial proteins and found that our conclusion of the importance of subcellular relocalization after gene duplication on

  20. Revealing fibrinogen monolayer conformations at different pHs: electrokinetic and colloid deposition studies.

    Science.gov (United States)

    Nattich-Rak, Małgorzata; Adamczyk, Zbigniew; Wasilewska, Monika; Sadowska, Marta

    2015-07-01

    Adsorption mechanism of human fibrinogen on mica at different pHs is studied using the streaming potential and colloid deposition measurements. The fibrinogen monolayers are produced by a controlled adsorption under diffusion transport at pH of 3.5 and 7.4. Initially, the electrokinetic properties of these monolayers and their stability for various ionic strength are determined. It is shown that at pH 3.5 fibrinogen adsorbs irreversibly on mica for ionic strength range of 4×10(-4) to 0.15 M. At pH 7.4, a partial desorption is observed for ionic strength below 10(-2) M. This is attributed to the desorption of the end-on oriented molecules whereas the side-on adsorbed molecules remain irreversibly bound at all ionic strengths. The orientation of molecules and monolayer structure is evaluated by the colloid deposition measurements involving negatively charged polystyrene latex microspheres, 820 nm in diameter. An anomalous deposition of negative latex particles on substrates exhibiting a negative zeta potential is observed. At pH 3.5 measurable deposition of latex is observed even at low ionic strength where the approach distance of latex particles exceeded 70 nm. At pH 7.4 this critical distance is 23 nm. This confirms that fibrinogen monolayers formed at both pHs are characterized by the presence of the side-on and end-on oriented molecules that prevail at higher coverage range. It is also shown that positive charge is located at the end parts of the αA chains of the adsorbed fibrinogen molecules. Therefore, it is concluded that the colloid deposition method is an efficient tool for revealing protein adsorption mechanisms at solid/electrolyte interfaces.

  1. A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle.

    Directory of Open Access Journals (Sweden)

    Maren Mönnich

    Full Text Available The human developmental diseases Cornelia de Lange Syndrome (CdLS and Roberts Syndrome (RBS are both caused by mutations in proteins responsible for sister chromatid cohesion. Cohesion is mediated by a multi-subunit complex called cohesin, which is loaded onto chromosomes by NIPBL. Once on chromosomes, cohesin binding is stabilized in S phase upon acetylation by ESCO2. CdLS is caused by heterozygous mutations in NIPBL or cohesin subunits SMC1A and SMC3, and RBS is caused by homozygous mutations in ESCO2. The genetic cause of both CdLS and RBS reside within the chromosome cohesion apparatus, and therefore they are collectively known as "cohesinopathies". However, the two syndromes have distinct phenotypes, with differences not explained by their shared ontology. In this study, we have used the zebrafish model to distinguish between developmental pathways downstream of cohesin itself, or its acetylase ESCO2. Esco2 depleted zebrafish embryos exhibit features that resemble RBS, including mitotic defects, craniofacial abnormalities and limb truncations. A microarray analysis of Esco2-depleted embryos revealed that different subsets of genes are regulated downstream of Esco2 when compared with cohesin subunit Rad21. Genes downstream of Rad21 showed significant enrichment for transcriptional regulators, while Esco2-regulated genes were more likely to be involved the cell cycle or apoptosis. RNA in situ hybridization showed that runx1, which is spatiotemporally regulated by cohesin, is expressed normally in Esco2-depleted embryos. Furthermore, myca, which is downregulated in rad21 mutants, is upregulated in Esco2-depleted embryos. High levels of cell death contributed to the morphology of Esco2-depleted embryos without affecting specific developmental pathways. We propose that cell proliferation defects and apoptosis could be the primary cause of the features of RBS. Our results show that mutations in different elements of the cohesion apparatus have

  2. Techniques for Revealing 3d Hidden Archeological Features: Morphological Residual Models as Virtual-Polynomial Texture Maps

    Science.gov (United States)

    Pires, H.; Martínez Rubio, J.; Elorza Arana, A.

    2015-02-01

    The recent developments in 3D scanning technologies are not been accompanied by visualization interfaces. We are still using the same types of visual codes as when maps and drawings were made by hand. The available information in 3D scanning data sets is not being fully exploited by current visualization techniques. In this paper we present recent developments regarding the use of 3D scanning data sets for revealing invisible information from archaeological sites. These sites are affected by a common problem, decay processes, such as erosion, that never ceases its action and endangers the persistence of last vestiges of some peoples and cultures. Rock art engravings, or epigraphical inscriptions, are among the most affected by these processes because they are, due to their one nature, carved at the surface of rocks often exposed to climatic agents. The study and interpretation of these motifs and texts is strongly conditioned by the degree of conservation of the imprints left by our ancestors. Every single detail in the remaining carvings can make a huge difference in the conclusions taken by specialists. We have selected two case-studies severely affected by erosion to present the results of the on-going work dedicated to explore in new ways the information contained in 3D scanning data sets. A new method for depicting subtle morphological features in the surface of objects or sites has been developed. It allows to contrast human patterns still present at the surface but invisible to naked eye or by any other archaeological inspection technique. It was called Morphological Residual Model (MRM) because of its ability to contrast the shallowest morphological details, to which we refer as residuals, contained in the wider forms of the backdrop. Afterwards, we have simulated the process of building Polynomial Texture Maps - a widespread technique that as been contributing to archaeological studies for some years - in a 3D virtual environment using the results of MRM

  3. Gravity modeling reveals that the "Miocene Pyrenean peneplain" developed at high elevation

    Science.gov (United States)

    Bosch, Gemma V.; Van Den Driessche, Jean; Robert, Alexandra; Babault, Julien; Le Carlier, Christian

    2016-04-01

    Geodynamics that shaped the present morphology of the western Mediterranean are mostly linked to the African-Eurasia collision and the extension related to the Mediterranean opening. The Pyrenean chain formed by the collision between the Iberian microplate and the Eurasian plate from the Eocene to the late Oligocene. This resulted in lithosphere thickening especially below the Central Pyrenees that becomes thinner eastwards. Whether the later thinning of the lithosphere in the easternmost Pyrenees involves the removal of the lithospheric mantle or not is debated. This issue joins the problematics about the origin of the high-elevation of the "Miocene Pyrenean peneplain" remnants. Indeed the most striking feature of the Pyrenean morphology is the occurrence of high-elevation, low relief erosional surfaces that are interpreted as the remnants of a Miocene single planation surface, dissected and reworked by Quaternary fluvial and glacial erosion. Two end-member interpretations have proposed to explain the high elevation of this original surface. The first considers that the Miocene Pyrenean peneplain develops near sea-level and was later uplifted, the second claims that the planation surface developed at high elevation in response to the inhibition of erosion consecutively to the progressive rise of the base-level of the Pyrenean drainage network. The first interpretation implies the return to normal crustal thickness by erosion and later uplift by removal of the lithospheric mantle. The second interpretation considers that the mean elevation of the original planation surface matches the thickness of the lithosphere below the chain, taking into account some hundred meters of isostatic rebound due to Quaternary erosion. To test these interpretations, we first restore the Miocene original planation surface by mapping and interpolating the high-elevation, low relief surfaces across the Pyrenees. We then performed 1D and 2D gravity models that we compare with recent

  4. Functional Genomic and Advanced Genetic Studies Reveal Novel Insights into the Metabolism, Regulation, and Biology of Haloferax volcanii

    Directory of Open Access Journals (Sweden)

    Jörg Soppa

    2011-01-01

    Full Text Available The genome sequence of Haloferax volcanii is available and several comparative genomic in silico studies were performed that yielded novel insight for example into protein export, RNA modifications, small non-coding RNAs, and ubiquitin-like Small Archaeal Modifier Proteins. The full range of functional genomic methods has been established and results from transcriptomic, proteomic and metabolomic studies are discussed. Notably, Hfx. volcanii is together with Halobacterium salinarum the only prokaryotic species for which a translatome analysis has been performed. The results revealed that the fraction of translationally-regulated genes in haloarchaea is as high as in eukaryotes. A highly efficient genetic system has been established that enables the application of libraries as well as the parallel generation of genomic deletion mutants. Facile mutant generation is complemented by the possibility to culture Hfx. volcanii in microtiter plates, allowing the phenotyping of mutant collections. Genetic approaches are currently used to study diverse biological questions–from replication to posttranslational modification—and selected results are discussed. Taken together, the wealth of functional genomic and genetic tools make Hfx. volcanii a bona fide archaeal model species, which has enabled the generation of important results in recent years and will most likely generate further breakthroughs in the future.

  5. Can representational trajectory reveal the nature of an internal model of gravity?

    Science.gov (United States)

    De Sá Teixeira, Nuno; Hecht, Heiko

    2014-05-01

    The memory for the vanishing location of a horizontally moving target is usually displaced forward in the direction of motion (representational momentum) and downward in the direction of gravity (representational gravity). Moreover, this downward displacement has been shown to increase with time (representational trajectory). However, the degree to which different kinematic events change the temporal profile of these displacements remains to be determined. The present article attempts to fill this gap. In the first experiment, we replicate the finding that representational momentum for downward-moving targets is bigger than for upward motions, showing, moreover, that it increases rapidly during the first 300 ms, stabilizing afterward. This temporal profile, but not the increased error for descending targets, is shown to be disrupted when eye movements are not allowed. In the second experiment, we show that the downward drift with time emerges even for static targets. Finally, in the third experiment, we report an increased error for upward-moving targets, as compared with downward movements, when the display is compatible with a downward ego-motion by including vection cues. Thus, the errors in the direction of gravity are compatible with the perceived event and do not merely reflect a retinotopic bias. Overall, these results provide further evidence for an internal model of gravity in the visual representational system.

  6. An amoeba phagocytosis model reveals a novel developmental switch in the insect pathogen Bacillus thuringiensis.

    Science.gov (United States)

    Beeton, M L; Atkinson, D J; Waterfield, N R

    2013-02-01

    The Bacillus cereus group bacteria contain pathogens of economic and medical importance. From security and health perspectives, the lethal mammalian pathogen Bacillus anthracis remains a serious threat. In addition the potent insect pathogen Bacillus thuringiensis is extensively used as a biological control agent for insect pests. This relies upon the industrial scale induction of bacterial spore formation with the associated production of orally toxic Cry-toxins. Understanding the ecology and potential alternative developmental fates of these bacteria is therefore important. Here we describe the use of an amoeba host model to investigate the influence of environmental bactivorous protists on both spores and vegetative cells of these pathogens. We demonstrate that the bacteria can respond to different densities of amoeba by adopting different behaviours and developmental fates. We show that spores will germinate in response to factors excreted by the amoeba, and that the bacteria can grow and reproduce on these factors. We show that in low densities of amoeba, that the bacteria will seek to colonise the surface of the amoeba as micro-colonies, resisting phagocytosis. At high amoeba densities, the bacteria change morphology into long filaments and macroscopic rope-like structures which cannot be ingested due to size exclusion. We suggest these developmental fates are likely to be important both in the ecology of these bacteria and also during animal host colonisation and immune evasion.

  7. Potassium starvation in yeast: mechanisms of homeostasis revealed by mathematical modeling.

    Directory of Open Access Journals (Sweden)

    Matthias Kahm

    Full Text Available The intrinsic ability of cells to adapt to a wide range of environmental conditions is a fundamental process required for survival. Potassium is the most abundant cation in living cells and is required for essential cellular processes, including the regulation of cell volume, pH and protein synthesis. Yeast cells can grow from low micromolar to molar potassium concentrations and utilize sophisticated control mechanisms to keep the internal potassium concentration in a viable range. We developed a mathematical model for Saccharomyces cerevisiae to explore the complex interplay between biophysical forces and molecular regulation facilitating potassium homeostasis. By using a novel inference method ("the reverse tracking algorithm" we predicted and then verified experimentally that the main regulators under conditions of potassium starvation are proton fluxes responding to changes of potassium concentrations. In contrast to the prevailing view, we show that regulation of the main potassium transport systems (Trk1,2 and Nha1 in the plasma membrane is not sufficient to achieve homeostasis.

  8. Potassium starvation in yeast: mechanisms of homeostasis revealed by mathematical modeling.

    Science.gov (United States)

    Kahm, Matthias; Navarrete, Clara; Llopis-Torregrosa, Vicent; Herrera, Rito; Barreto, Lina; Yenush, Lynne; Ariño, Joaquin; Ramos, Jose; Kschischo, Maik

    2012-01-01

    The intrinsic ability of cells to adapt to a wide range of environmental conditions is a fundamental process required for survival. Potassium is the most abundant cation in living cells and is required for essential cellular processes, including the regulation of cell volume, pH and protein synthesis. Yeast cells can grow from low micromolar to molar potassium concentrations and utilize sophisticated control mechanisms to keep the internal potassium concentration in a viable range. We developed a mathematical model for Saccharomyces cerevisiae to explore the complex interplay between biophysical forces and molecular regulation facilitating potassium homeostasis. By using a novel inference method ("the reverse tracking algorithm") we predicted and then verified experimentally that the main regulators under conditions of potassium starvation are proton fluxes responding to changes of potassium concentrations. In contrast to the prevailing view, we show that regulation of the main potassium transport systems (Trk1,2 and Nha1) in the plasma membrane is not sufficient to achieve homeostasis.

  9. Detailed Physical Modeling Reveals the Magnetar Nature of a Transient Anomalous X-ray Pulsar

    Science.gov (United States)

    Guever, T.; Oezel, F.; Goegues, E.; Kouveliotou, C.

    2007-01-01

    Anomalous X-ray Pulsars (AXPs) belong to a class of neutron stars believed to harbor the strongest magnetic fields in the universe, as indicated by their energetic bursts and their rapid spindowns. However, a direct measurement of their surface field strengths has not been made to date. It is also not known whether AXP outbursts result from changes in the neutron star magnetic field or crust properties. Here we report the first, spectroscopic measurement of the surface magnetic field strength of an AXP, XTE J1810-197, and solidify its magnetar nature. The field strength obtained from detailed spectral analysis and modeling is remarkably close to the value inferred from the rate of spindown of this source and remains nearly constant during numerous observations spanning over two orders of magnitude in source flux. The surface temperature, on the other hand, declines steadily and dramatically following the 2003 outburst of this source. Our findings demonstrate that heating occurs in the upper neutron star crust during an outburst and sheds light on the transient behaviour of AXPs.

  10. Non-mammalian models reveal the role of alternative ligands for thyroid hormone receptors.

    Science.gov (United States)

    Orozco, Aurea; Lazcano, Iván; Hernández-Puga, Gabriela; Olvera, Aurora

    2017-03-04

    Thyroid hormones, or THs, are well-known regulators of a wide range of biological processes that occur throughout the lifespan of all vertebrates. THs act through genomic mechanisms mediated by thyroid hormone receptors (TRs). The main product of the thyroid gland is thyroxine or T4, which can be further transformed by different biochemical pathways to produce at least 15 active or inactive molecules. T3, a product of T4 outer-ring deiodination, has been recognized as the main bioactive TH. However, growing evidence has shown that other TH derivatives are able to bind to, and/or activate TRs, to induce thyromimetic effects. The compiled data in this review points to at least two of these TR alternative ligands: TRIAC and T2. Taking this into account, non-mammalian models have proven to be advantageous to explore new TH derivatives with potential novel actions, prompting a re-evaluation of the role and mechanism of action of TR alternative ligands that were previously believed to be inactive. The functional implications of these ligands across different vertebrates may require us to reconsider current established notions of thyroid physiology. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Role of Jnk1 in development of neural precursors revealed by iPSC modeling.

    Science.gov (United States)

    Zhang, Qian; Mao, Jian; Zhang, Xiaoxi; Fu, Haifeng; Xia, Siyuan; Yin, Zhinan; Liu, Lin

    2016-09-20

    Jnk1-deficient mice manifest disrupted anterior commissure formation and loss of axonal and dendritic microtubule integrity. However, the mechanisms and the specific stages underlying the developmental defects remain to be elucidated. Here, we report the generation of Jnk1-deficient (Jnk1 KO) iPSCs from Jnk1 KO mouse tail-tip fibroblasts (TTFs) for modeling the neural disease development. The efficiency in the early induction of iPSCs was higher from Jnk1 KO fibroblasts than that of wild-type (WT) fibroblasts. These Jnk1 KO iPSCs exhibited pluripotent stem cell properties and had the ability of differentiation into general three embryonic germ layers in vitro and in vivo. However, Jnk1 KO iPSCs showed reduced capacity in neural differentiation in the spontaneous differentiation by embryoid body (EB) formation. Notably, by directed lineage differentiation, Jnk1 KO iPSCs specifically exhibited an impaired ability to differentiate into early stage neural precursors. Furthermore, the neuroepitheliums generated from Jnk1 KO iPSCs appeared smaller, indicative of neural stem cell developmental defects, as demonstrated by teratoma tests in vivo. These data suggest that Jnk1 deficiency inhibits the development of neural stem cells/precursors and provide insights to further understanding the complex pathogenic mechanisms of JNK1-related neural diseases.

  12. Ecological niche models reveal the importance of climate variability for the biogeography of protosteloid amoebae.

    Science.gov (United States)

    Aguilar, María; Lado, Carlos

    2012-08-01

    Habitat availability and environmental preferences of species are among the most important factors in determining the success of dispersal processes and therefore in shaping the distribution of protists. We explored the differences in fundamental niches and potential distributions of an ecological guild of slime moulds-protosteloid amoebae-in the Iberian Peninsula. A large set of samples collected in a north-east to south-west transect of approximately 1000 km along the peninsula was used to test the hypothesis that, together with the existence of suitable microhabitats, climate conditions may determine the probability of survival of species. Although protosteloid amoebae share similar morphologies and life history strategies, canonical correspondence analyses showed that they have varied ecological optima, and that climate conditions have an important effect in niche differentiation. Maxent environmental niche models provided consistent predictions of the probability of presence of the species based on climate data, and they were used to generate maps of potential distribution in an 'everything is everywhere' scenario. The most important climatic factors were, in both analyses, variables that measure changes in conditions throughout the year, confirming that the alternation of fruiting bodies, cysts and amoeboid stages in the life cycles of protosteloid amoebae constitutes an advantage for surviving in a changing environment. Microhabitat affinity seems to be influenced by climatic conditions, which suggests that the micro-environment may vary at a local scale and change together with the external climate at a larger scale.

  13. Fortune Favours the Bold: An Agent-Based Model Reveals Adaptive Advantages of Overconfidence in War

    Science.gov (United States)

    Johnson, Dominic D. P.; Weidmann, Nils B.; Cederman, Lars-Erik

    2011-01-01

    Overconfidence has long been considered a cause of war. Like other decision-making biases, overconfidence seems detrimental because it increases the frequency and costs of fighting. However, evolutionary biologists have proposed that overconfidence may also confer adaptive advantages: increasing ambition, resolve, persistence, bluffing opponents, and winning net payoffs from risky opportunities despite occasional failures. We report the results of an agent-based model of inter-state conflict, which allows us to evaluate the performance of different strategies in competition with each other. Counter-intuitively, we find that overconfident states predominate in the population at the expense of unbiased or underconfident states. Overconfident states win because: (1) they are more likely to accumulate resources from frequent attempts at conquest; (2) they are more likely to gang up on weak states, forcing victims to split their defences; and (3) when the decision threshold for attacking requires an overwhelming asymmetry of power, unbiased and underconfident states shirk many conflicts they are actually likely to win. These “adaptive advantages” of overconfidence may, via selection effects, learning, or evolved psychology, have spread and become entrenched among modern states, organizations and decision-makers. This would help to explain the frequent association of overconfidence and war, even if it no longer brings benefits today. PMID:21731627

  14. Combined force spectroscopy, AFM and calorimetric studies to reveal the nanostructural organization of biomimetic membranes.

    Science.gov (United States)

    Suárez-Germà, C; Morros, A; Montero, M T; Hernández-Borrell, J; Domènech, Ò

    2014-10-01

    In this work we studied a binary lipid matrix of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG), a composition that mimics the inner membrane of Escherichia coli. More specifically, liposomes with varying fractions of POPG were analysed by differential scanning calorimetry (DSC) and a binary phase diagram of the system was created. Additionally, we performed atomic force microscopy (AFM) imaging of supported lipid bilayers (SLBs) of similar compositions at different temperatures, in order to create a pseudo-binary phase diagram specific to this membrane model. AFM study of SLBs is of particular interest, as it is conceived as the most adequate technique not only for studying lipid bilayer systems but also for imaging and even nanomanipulating inserted membrane proteins. The construction of the above-mentioned phase diagram enabled us to grasp better the thermodynamics of the thermal lipid transition from a gel-like POPE:POPG phase system to a more fluid phase system. Finally, AFM force spectroscopy (FS) was used to determine the nanomechanics of these two lipid phases at 27°C and at different POPG fractions. The resulting data correlated with the specific composition of each phase was calculated from the AFM phase diagram obtained. All the experiments were done in the presence of 10 mM of Ca(2+), as this ion is commonly used when performing AFM with negatively charged phospholipids.

  15. Denatured-state energy landscapes of a protein structural database reveal the energetic determinants of a framework model for folding.

    Science.gov (United States)

    Wang, Suwei; Gu, Jenny; Larson, Scott A; Whitten, Steven T; Hilser, Vincent J

    2008-09-19

    Position-specific denatured-state thermodynamics were determined for a database of human proteins by use of an ensemble-based model of protein structure. The results of modeling denatured protein in this manner reveal important sequence-dependent thermodynamic properties in the denatured ensembles as well as fundamental differences between the denatured and native ensembles in overall thermodynamic character. The generality and robustness of these results were validated by performing fold-recognition experiments, whereby sequences were matched with their respective folds based on amino acid propensities for the different energetic environments in the protein, as determined through cluster analysis. Correlation analysis between structure and energetic information revealed that sequence segments destined for beta-sheet in the final native fold are energetically more predisposed to a broader repertoire of states than are sequence segments destined for alpha-helix. These results suggest that within the subensemble of mostly unstructured states, the energy landscapes are dominated by states in which parts of helices adopt structure, whereas structure formation for sequences destined for beta-strand is far less probable. These results support a framework model of folding, which suggests that, in general, the denatured state has evolutionarily evolved to avoid low-energy conformations in sequences that ultimately adopt beta-strand. Instead, the denatured state evolved so that sequence segments that ultimately adopt alpha-helix and coil will have a high intrinsic structure formation capability, thus serving as potential nucleation sites.

  16. Noninvasive neutron scattering measurements reveal slower cholesterol transport in model lipid membranes.

    Science.gov (United States)

    Garg, S; Porcar, L; Woodka, A C; Butler, P D; Perez-Salas, U

    2011-07-20

    Proper cholesterol transport is essential to healthy cellular activity and any abnormality can lead to several fatal diseases. However, complete understandings of cholesterol homeostasis in the cell remains elusive, partly due to the wide variability in reported values for intra- and intermembrane cholesterol transport rates. Here, we used time-resolved small-angle neutron scattering to measure cholesterol intermembrane exchange and intramembrane flipping rates, in situ, without recourse to any external fields or compounds. We found significantly slower transport kinetics than reported by previous studies, particularly for intramembrane flipping where our measured rates are several orders of magnitude slower. We unambiguously demonstrate that the presence of chemical tags and extraneous compounds employed in traditional kinetic measurements dramatically affect the system thermodynamics, accelerating cholesterol transport rates by an order of magnitude. To our knowledge, this work provides new insights into cholesterol transport process disorders, and challenges many of the underlying assumptions used in most cholesterol transport studies to date.

  17. A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Ke Xu

    2011-12-01

    Full Text Available Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into "whole-body" contextual models that mimic in vivo conditions.

  18. Saltstone SDU6 Modeling Study

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Si Y. [Savannah River Site (SRS), Aiken, SC (United States); Hyun, Sinjae [Mercer University, Macon, GA (United States)

    2013-01-10

    A new disposal unit, designated as Saltstone Disposal Unit 6 (SDU6), is being designed for support of site accelerated closure goals and salt waste projections identified in the new Liquid Waste System Plan. The unit is a cylindrical disposal cell of 375 ft in diameter and 43 ft in height, and it has a minimum 30 million gallons of capacity. SRNL was requested to evaluate the impact of an increased grout placement height on the flow patterns radially spread on the floor and to determine whether grout quality is impacted by the height. The primary goals of the work are to develop the baseline Computational Fluid Dynamics (CFD) model and to perform the evaluations for the flow patterns of grout material in SDU6 as a function of elevation of grout discharge port and grout rheology. Two transient grout models have been developed by taking a three-dimensional multiphase CFD approach to estimate the domain size of the grout materials radially spread on the facility floor and to perform the sensitivity analysis with respect to the baseline design and operating conditions such as elevation height of the discharge port and fresh grout properties. For the CFD modeling calculations, air-grout Volume of Fluid (VOF) method combined with Bingham plastic and time-dependent grout models were used for examining the impact of fluid spread performance for the initial baseline configurations and to evaluate the impact of grout pouring height on grout quality. The grout quality was estimated in terms of the air volume fraction for the grout layer formed on the SDU6 floor, resulting in the change of grout density. The study results should be considered as preliminary scoping analyses since benchmarking analysis is not included in this task scope. Transient analyses with the Bingham plastic model were performed with the FLUENTTM code on the high performance parallel computing platform in SRNL. The analysis coupled with a transient grout aging model was performed by using ANSYS-CFX code

  19. Saltstone SDU6 Modeling Study

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Si Y. [Savannah River Site (SRS), Aiken, SC (United States); Hyun, Sinjae [Mercer University, Macon, GA (United States)

    2013-01-10

    A new disposal unit, designated as Saltstone Disposal Unit 6 (SDU6), is being designed for support of site accelerated closure goals and salt waste projections identified in the new Liquid Waste System Plan. The unit is a cylindrical disposal cell of 375 ft in diameter and 43 ft in height, and it has a minimum 30 million gallons of capacity. SRNL was requested to evaluate the impact of an increased grout placement height on the flow patterns radially spread on the floor and to determine whether grout quality is impacted by the height. The primary goals of the work are to develop the baseline Computational Fluid Dynamics (CFD) model and to perform the evaluations for the flow patterns of grout material in SDU6 as a function of elevation of grout discharge port and grout rheology. Two transient grout models have been developed by taking a three-dimensional multiphase CFD approach to estimate the domain size of the grout materials radially spread on the facility floor and to perform the sensitivity analysis with respect to the baseline design and operating conditions such as elevation height of the discharge port and fresh grout properties. For the CFD modeling calculations, air-grout Volume of Fluid (VOF) method combined with Bingham plastic and time-dependent grout models were used for examining the impact of fluid spread performance for the initial baseline configurations and to evaluate the impact of grout pouring height on grout quality. The grout quality was estimated in terms of the air volume fraction for the grout layer formed on the SDU6 floor, resulting in the change of grout density. The study results should be considered as preliminary scoping analyses since benchmarking analysis is not included in this task scope. Transient analyses with the Bingham plastic model were performed with the FLUENTTM code on the high performance parallel computing platform in SRNL. The analysis coupled with a transient grout aging model was performed by using ANSYS-CFX code

  20. Reconstructing dynamic mental models of facial expressions in prosopagnosia reveals distinct representations for identity and expression.

    Science.gov (United States)

    Richoz, Anne-Raphaëlle; Jack, Rachael E; Garrod, Oliver G B; Schyns, Philippe G; Caldara, Roberto

    2015-04-01

    The human face transmits a wealth of signals that readily provide crucial information for social interactions, such as facial identity and emotional expression. Yet, a fundamental question remains unresolved: does the face information for identity and emotional expression categorization tap into common or distinct representational systems? To address this question we tested PS, a pure case of acquired prosopagnosia with bilateral occipitotemporal lesions anatomically sparing the regions that are assumed to contribute to facial expression (de)coding (i.e., the amygdala, the insula and the posterior superior temporal sulcus--pSTS). We previously demonstrated that PS does not use information from the eye region to identify faces, but relies on the suboptimal mouth region. PS's abnormal information use for identity, coupled with her neural dissociation, provides a unique opportunity to probe the existence of a dichotomy in the face representational system. To reconstruct the mental models of the six basic facial expressions of emotion in PS and age-matched healthy observers, we used a novel reverse correlation technique tracking information use on dynamic faces. PS was comparable to controls, using all facial features to (de)code facial expressions with the exception of fear. PS's normal (de)coding of dynamic facial expressions suggests that the face system relies either on distinct representational systems for identity and expression, or dissociable cortical pathways to access them. Interestingly, PS showed a selective impairment for categorizing many static facial expressions, which could be accounted for by her lesion in the right inferior occipital gyrus. PS's advantage for dynamic facial expressions might instead relate to a functionally distinct and sufficient cortical pathway directly connecting the early visual cortex to the spared pSTS. Altogether, our data provide critical insights on the healthy and impaired face systems, question evidence of deficits

  1. 3D gravity modelling reveals off-axis crustal thickness variations along the western Gakkel Ridge (Arctic Ocean)

    Science.gov (United States)

    Schmidt-Aursch, Mechita C.; Jokat, Wilfried

    2016-11-01

    Near-orthogonal ultra-slow (13.3 mm yr- 1 to 6.5 mm yr- 1) sea floor spreading in the absence of large transform faults make the Arctic Gakkel Ridge ideally suited for the study of magmatic processes. To enable this, we generated a three-dimensional gravity model of crustal thickness over the ridge and parts of the adjacent Nansen and Amundsen basins west of 65° E. The model shows that oceanic crust accreted prior to chrons C5/C6 is generally very thin (1-3 km). Magnetic anomalies over this thin crust are highly variable both parallel and perpendicular to the ridge axis. This is the result of amagmatic or weakly volcanic spreading that started with the opening of the basins 56 Ma ago. The separation of Greenland from Svalbard at chron C5/C6 led to the inflow of North Atlantic mantle into the western Eurasia Basin leading to a change in the mantle convection system and the establishment of a magmatic dichotomy along the Gakkel Ridge. Robust magmatism was established in the Western Volcanic Zone (6° 30‧ W-3° 30‧ E), leading to creation of a 6.6 km thick igneous crust, characterized by a strong positive axial magnetic anomaly, numerous volcanic cones, and widespread thick mid-ocean ridge basalts. The transition to the neighbouring Sparsely Magmatic (3° 30‧ E-29° E) and Eastern Volcanic (29° E-85° E) zones is sharp. Peridotites cover the central valley and the inner rift flanks, the central magnetic anomaly vanishes and crustal thickness decreases to 1-4 km. Transverse basement ridges, extending for as much as 100 km into the adjacent basins, intersect the central valley. Although partly of tectonic origin, the transverse ridges are also an expression of long-living magmatic centres, as revealed by increased magnetic anomaly intensities and local thickening of the crust to values as great as 5.9 km.

  2. Opening the Big Black Box: European study reveals visitors' impressions of science laboratories

    CERN Multimedia

    2004-01-01

    "On 29 - 30 March the findings of 'Inside the Big Black Box'- a Europe-wide science and society project - will be revealed during a two-day seminar hosted by CERN*. The principle aim of Inside the Big Black Box (IN3B) is to determine whether a working scientific laboratory can capture the curiosity of the general public through visits" (1 page)

  3. Transcriptome and Proteome Studies Reveal Candidate Attachment Genes during the Development of the Barnacle Amphibalanus Amphitrite

    KAUST Repository

    Al-Aqeel, Sarah

    2016-09-21

    The acorn barnacle, Balanus amphitrite, is the main biofouling organism in marine environments. In the present study we profiled the transcriptome and proteome of B. amphitrite at different life stages (nauplius II, nauplius VI, and cyprid) from the Red Sea, where the average water surface temperature is 34°C and the salinity reaches 41%. We identified 65,784 expressed contigs, and a total of 1387 expressed proteins measured by quantitative proteomics. We found that osmotic stress, salt stress, hyperosmotic response and the Wnt signaling pathway were strongly up-regulated during the planktonic stage, while the MAPK pathway, lipid metabolism, and cuticle development genes were down-regulated. In the transition stage between the nauplius VI and the cyprid, genes that are involved in blood coagulation, cuticle development and eggshell formation were highly up-regulated, while the nitric oxide pathway, which stimulates the swimming and feeding response in marine invertebrates, was down-regulated. We are able to report for the first time that sound sensory system proteins are highly abundant in the nauplius VI stage, implying that these proteins are good targets for the development of new antifouling compounds. The results presented here together with the new genome-wide datasets for a non-model specie represent an important resource for the study of biofouling and development. Proteomics data are available via ProteomeXchange with identifier PXD004679.

  4. Transcriptome and proteome studies reveal candidate attachment genes during the development of the barnacle Amphibalanus Amphitrite

    Directory of Open Access Journals (Sweden)

    Sarah Al-Aqeel

    2016-09-01

    Full Text Available The acorn barnacle, Balanus amphitrite, is the main biofouling organism in marine environments. In the present study we profiled the transcriptome and proteome of B. amphitrite at different life stages (nauplius II, nauplius VI and cyprid from the Red Sea, where the average water surface temperature is 34°C and the salinity reaches 41‰. We identified 65,784 expressed contigs, and a total of 1,387 expressed proteins measured by quantitative proteomics. We found that osmotic stress, salt stress, hyperosmotic response and the Wnt signaling pathway were strongly up-regulated during the planktonic stage, while the MAPK pathway, lipid metabolism, and cuticle development genes were down-regulated. In the transition stage between the nauplius VI and the cyprid, genes that are involved in blood coagulation, cuticle development and eggshell formation were highly up-regulated, while the nitric oxide pathway, which stimulates the swimming and feeding response in marine invertebrates, was down-regulated. We are able to report for the first time that sound sensory system proteins are highly abundant in the nauplius VI stage, implying that these proteins are good targets for the development of new antifouling compounds. The results presented here together with the new genome-wide datasets for a non-model specie represent an important resource for the study of biofouling and development.

  5. Genomewide association study reveals a risk locus for equine metabolic syndrome in the Arabian horse.

    Science.gov (United States)

    Lewis, S L; Holl, H M; Streeter, C; Posbergh, C; Schanbacher, B J; Place, N J; Mallicote, M F; Long, M T; Brooks, S A

    2017-03-01

    Equine obesity can cause life-threatening secondary chronic conditions, similar to those in humans and other animal species. Equine metabolic syndrome (EMS), primarily characterized by hyperinsulinemia, is often present in obese horses and ponies. Due to clinical similarities to conditions such as pituitary pars intermedia dysfunction (formerly equine Cushing's disease), conclusive diagnosis of EMS often proves challenging. Aside from changes in diet and exercise, few targeted treatments are available for EMS, emphasizing the need for early identification of at-risk individuals to enable implementation of preventative measures. A genomewide association study (GWAS) using Arabian horses with a history of severe laminitis secondary to EMS revealed significant genetic markers near a single candidate gene () that may play a role in cholesterol homeostasis. The best marker, BIEC2-263524 (chr14:69276814 T > C), was correlated with elevated insulin values and increased frequency of laminitis ( = 0.0024 and = 9.663 × 10, respectively). In a second population of Arabian horses, the BIEC2-263524 marker maintained its associations with higher modified insulin-to-glucose ratio (MIRG) values ( = 0.0056) and BCS ( = 0.0063). Screening of the predicted coding regions by sequencing identified a polymorphic guanine homopolymer and 5 haplotypes in the 3' untranslated region (UTR). An 11 guanine (11-G) allele at was correlated with elevated insulin values in the GWAS population ( = 0.0008) and, in the second population, elevated MIRG and increased BCS > 6.5 ( = 0.0055 and = 0.0162, respectively). The BIEC2-263524-C and the 3' UTR -11(G) polymorphisms were correlated at a 98% frequency, indicating strong linkage disequilibrium across this 150-kb haplotype. Assays for these markers could diagnose horses with a genetic predisposition to develop obesity. Additionally, discovery of FAM174A function may improve our understanding of the etiology of this troubling illness in the horse and

  6. Monte Carlo modeling of photon propagation reveals highly scattering coral tissue

    Directory of Open Access Journals (Sweden)

    Daniel Wangpraseurt

    2016-09-01

    Full Text Available Corals are very efficient at using solar radiation, with photosynthetic quantum efficiencies approaching theoretical limits. Here, we investigated potential mechanisms underlying such outstanding photosynthetic performance through extracting inherent optical properties of the living coral tissue and skeleton in a massive faviid coral. Using Monte Carlo simulations developed for medical tissue optics it is shown that for the investigated faviid coral, the coral tissue was a strongly light scattering matrix with a reduced scattering coefficient of µs’ =10 cm-1 (at 636 nm. In contrast, the scattering coefficient of the coral skeleton was µs’ =3.4 cm-1, which facilitated the efficient propagation of light to otherwise shaded coral tissue layers, thus supporting photosynthesis in lower tissues. Our study provides a quantification of coral tissue optical properties in a massive faviid coral and suggests a novel light harvesting strategy, where tissue and skeletal optics act in concert to optimize the illumination of the photosynthesizing algal symbionts embedded within the living coral tissue.

  7. Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models

    Directory of Open Access Journals (Sweden)

    Maggie Folkesson

    2016-07-01

    Full Text Available Tobacco use is strongly associated with cardiovascular disease and the only avoidable risk factor associated with development of aortic aneurysm. While smoking is the most common form of tobacco use, snuff and other oral tobacco products are gaining popularity, but research on potentially toxic effects of oral tobacco use has not kept pace with the increase in its use. Here, we demonstrate that cigarette smoke and snuff extracts are highly toxic to developing zebrafish embryos. Exposure to such extracts led to a palette of toxic effects including early embryonic mortality, developmental delay, cerebral hemorrhages, defects in lymphatics development and ventricular function, and aneurysm development. Both cigarette smoke and snuff were more toxic than pure nicotine, indicating that other compounds in these products are also associated with toxicity. While some toxicities were found following exposure to both types of tobacco product, other toxicities, including developmental delay and aneurysm development, were specifically observed in the snuff extract group, whereas cerebral hemorrhages were only found in the group exposed to cigarette smoke extract. These findings deepen our understanding of the pathogenic effects of cigarette smoking and snuff use on the cardiovascular system and illustrate the benefits of using zebrafish to study mechanisms involved in aneurysm development.

  8. Potential antidepressant and resilience mechanism revealed by metabolomic study on peripheral blood mononuclear cells of stress resilient rats.

    Science.gov (United States)

    Li, Juan; Zhang, Shu-Xiao; Wang, Wei; Cheng, Ke; Guo, Hua; Rao, Cheng-Long; Yang, De-Yu; He, Yong; Zou, De-Zhi; Han, Yu; Zhao, Li-Bo; Li, Peng-Fei; Xie, Peng

    2017-03-01

    Resilience is an active coping response to stress, which plays a very important role in major depressive disorder study. The molecular mechanisms underlying such resilience are poorly understood. Peripheral blood mononuclear cells (PBMCs) were promising objects in unveiling the underlying pathogenesis of resilience. Hereby we carried out successive study on PBMCs metabolomics in resilient rats of chronic unpredictable mild stress (CUMS) model. A gas chromatography-mass spectrometry (GC-MS) metabolomic approach coupled with principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to detect differential metabolites in PBMCs of resilient rats. Ingenuity Pathways Analysis (IPA) was applied for pathway analysis. A set of differential metabolites including Malic acid, Ornithine, l-Lysine, Stigmasterol, Oleic acid, γ-Tocopherol, Adenosine and N-acetyl-d-glucosamine were significantly altered in resilient rats, meanwhile promoting antidepressant research. As revealed by IPA that aberrant energy metabolism, HIFα signaling, neurotransmitter, O-GlcNAcylation and cAMP signaling cascade in peripheral might be evolved in the pathogenesis of coping mechanism. The GC-MS based metabolomics may contribute to better understanding of resilience, as well as shedding light on antidepressant discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

    Directory of Open Access Journals (Sweden)

    Rico Rueedi

    2014-02-01

    Full Text Available Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8 and independent associations between single nucleotide polymorphisms (SNP and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44 and lysine (rs8101881, P = 1.2×10(-33, respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.

  10. Genome-Wide Association Study of Metabolic Traits Reveals Novel Gene-Metabolite-Disease Links

    Science.gov (United States)

    Nicholls, Andrew W.; Salek, Reza M.; Marques-Vidal, Pedro; Morya, Edgard; Sameshima, Koichi; Montoliu, Ivan; Da Silva, Laeticia; Collino, Sebastiano; Martin, François-Pierre; Rezzi, Serge; Steinbeck, Christoph; Waterworth, Dawn M.; Waeber, Gérard; Vollenweider, Peter; Beckmann, Jacques S.; Le Coutre, Johannes; Mooser, Vincent; Bergmann, Sven; Genick, Ulrich K.; Kutalik, Zoltán

    2014-01-01

    Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on 1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10−8) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10−44) and lysine (rs8101881, P = 1.2×10−33), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers. PMID:24586186

  11. A study revealing the key aroma compounds of steamed bread made by Chinese traditional sourdough

    Institute of Scientific and Technical Information of China (English)

    Guo-hua ZHANG; Tao WU; Faizan A SADIQ; Huan-yi YANG; Tong-jie LIU; Hui RUAN; Guo-qing HE

    2016-01-01

    Aroma of Chinese steamed bread (CSB) is one of the important parameters that determines the overall quality attributes and consumer acceptance. However, the aroma profile of CSB stil remains poorly understood, mainly because of relying on only a single method for aroma extraction in previous studies. Therefore, the objective of this study was to determine the volatile aroma compounds of five different samples of CSB using three different aroma extraction methods, namely solid-phase microextraction (SPME), simultaneous distilation–extraction (SDE), and purge and trap (P&T). Al samples showed a unique aroma profile, which could be attributed to their unique microbial consortia. (E)-2-Nonenal and (E,E)-2,4-decadienal were the most prevalent aromatic compounds revealed by SDE, which have not been reported previously, while ethanol and acetic acid proved to be the most dominant compounds by both SPME and P&T. Our approach of combining three different aroma extraction methods provided better insights into the aroma profile of CSB, which had remained largely unknown in previous studies.%中文概要题目:传统酸面团制备的馒头特征风味物质的研究目的:通过同时蒸馏萃取(SDE)、顶空固相微萃取(SPME)及吹扫捕集(P&T)技术结合气相色谱-嗅闻-质谱(GC-O-MS)技术对传统酸面团制备的馒头特征风味成分进行分析,并初步探讨特征风味形成机理。创新点:首次采用不同风味物质分析技术探索传统酸面团制备的馒头关键风味成分。方法:采用同时SDE、SPME及P&T方法,对不同传统酸面团制备的馒头特征风味物质进行分析。结论:SDE结果显示,反式-2-壬烯醛和反式-2,4-癸二烯醛为传统酸面团馒头中关键风味成分。SPME和P&T 方法表明乙醇和醋酸是关键风味物质。因此,需要结合不同技术方法,全面分析传统酸面团制备的馒头中特征风味成分。

  12. Spatial guilds in the Serengeti food web revealed by a Bayesian group model.

    Directory of Open Access Journals (Sweden)

    Edward B Baskerville

    2011-12-01

    Full Text Available Food webs, networks of feeding relationships in an ecosystem, provide fundamental insights into mechanisms that determine ecosystem stability and persistence. A standard approach in food-web analysis, and network analysis in general, has been to identify compartments, or modules, defined by many links within compartments and few links between them. This approach can identify large habitat boundaries in the network but may fail to identify other important structures. Empirical analyses of food webs have been further limited by low-resolution data for primary producers. In this paper, we present a Bayesian computational method for identifying group structure using a flexible definition that can describe both functional trophic roles and standard compartments. We apply this method to a newly compiled plant-mammal food web from the Serengeti ecosystem that includes high taxonomic resolution at the plant level, allowing a simultaneous examination of the signature of both habitat and trophic roles in network structure. We find that groups at the plant level reflect habitat structure, coupled at higher trophic levels by groups of herbivores, which are in turn coupled by carnivore groups. Thus the group structure of the Serengeti web represents a mixture of trophic guild structure and spatial pattern, in contrast to the standard compartments typically identified. The network topology supports recent ideas on spatial coupling and energy channels in ecosystems that have been proposed as important for persistence. Furthermore, our Bayesian approach provides a powerful, flexible framework for the study of network structure, and we believe it will prove instrumental in a variety of biological contexts.

  13. Global Proteomic Analysis Reveals an Exclusive Role of Thylakoid Membranes in Bioenergetics of a Model Cyanobacterium

    Energy Technology Data Exchange (ETDEWEB)

    Liberton, Michelle; Saha, Rajib; Jacobs, Jon M.; Nguyen, Amelia Y.; Gritsenko, Marina A.; Smith, Richard D.; Koppenaal, David W.; Pakrasi, Himadri B.

    2016-04-07

    Cyanobacteria are photosynthetic microbes with highly differentiated membrane systems. These organisms contain an outer membrane, plasma membrane, and an internal system of thylakoid membranes where the photosynthetic and respiratory machinery are found. This existence of compartmentalization and differentiation of membrane systems poses a number of challenges for cyanobacterial cells in terms of organization and distribution of proteins to the correct membrane system. Proteomics studies have long sought to identify the components of the different membrane systems, and to date about 450 different proteins have been attributed to either the plasma membrane or thylakoid membrane. Given the complexity of these membranes, many more proteins remain to be identified in these membrane systems, and a comprehensive catalog of plasma membrane and thylakoid membrane proteins is needed. Here we describe the identification of 635 proteins in Synechocystis sp. PCC 6803 by quantitative iTRAQ isobaric labeling; of these, 459 proteins were localized to the plasma membrane and 176 were localized to the thylakoid membrane. Surprisingly, we found over 2.5 times the number of unique proteins identified in the plasma membrane compared to the thylakoid membrane. This suggests that the protein composition of the thylakoid membrane is more homogeneous than the plasma membrane, consistent with the role of the plasma membrane in diverse cellular processes including protein trafficking and nutrient import, compared to a more specialized role for the thylakoid membrane in cellular energetics. Overall, the protein composition of the Synechocystis 6803 plasma membrane and thylakoid membrane is quite similar to the E.coli plasma membrane and Arabidopsis thylakoid membrane, respectively. Synechocystis 6803 can therefore be described as a gram-negative bacterium that has an additional internal membrane system that fulfils the energetic requirements of the cell.

  14. Global Proteomic Analysis Reveals an Exclusive Role of Thylakoid Membranes in Bioenergetics of a Model Cyanobacterium.

    Science.gov (United States)

    Liberton, Michelle; Saha, Rajib; Jacobs, Jon M; Nguyen, Amelia Y; Gritsenko, Marina A; Smith, Richard D; Koppenaal, David W; Pakrasi, Himadri B

    2016-06-01

    Cyanobacteria are photosynthetic microbes with highly differentiated membrane systems. These organisms contain an outer membrane, plasma membrane, and an internal system of thylakoid membranes where the photosynthetic and respiratory machinery are found. This existence of compartmentalization and differentiation of membrane systems poses a number of challenges for cyanobacterial cells in terms of organization and distribution of proteins to the correct membrane system. Proteomics studies have long sought to identify the components of the different membrane systems in cyanobacteria, and to date about 450 different proteins have been attributed to either the plasma membrane or thylakoid membrane. Given the complexity of these membranes, many more proteins remain to be identified, and a comprehensive catalogue of plasma membrane and thylakoid membrane proteins is needed. Here we describe the identification of 635 differentially localized proteins in Synechocystis sp. PCC 6803 by quantitative iTRAQ isobaric labeling; of these, 459 proteins were localized to the plasma membrane and 176 were localized to the thylakoid membrane. Surprisingly, we found over 2.5 times the number of unique proteins identified in the plasma membrane compared with the thylakoid membrane. This suggests that the protein composition of the thylakoid membrane is more homogeneous than the plasma membrane, consistent with the role of the plasma membrane in diverse cellular processes including protein trafficking and nutrient import, compared with a more specialized role for the thylakoid membrane in cellular energetics. Thus, our data clearly define the two membrane systems with distinct functions. Overall, the protein compositions of the Synechocystis 6803 plasma membrane and thylakoid membrane are quite similar to that of the plasma membrane of Escherichia coli and thylakoid membrane of Arabidopsis chloroplasts, respectively. Synechocystis 6803 can therefore be described as a Gram

  15. Drosophila host model reveals new enterococcus faecalis quorum-sensing associated virulence factors.

    Science.gov (United States)

    Teixeira, Neuza; Varahan, Sriram; Gorman, Matthew J; Palmer, Kelli L; Zaidman-Remy, Anna; Yokohata, Ryoji; Nakayama, Jiro; Hancock, Lynn E; Jacinto, António; Gilmore, Michael S; de Fátima Silva Lopes, Maria

    2013-01-01

    Enterococcus faecalis V583 is a vancomycin-resistant clinical isolate which belongs to the hospital-adapted clade, CC2. This strain harbours several factors that have been associated with virulence, including the fsr quorum-sensing regulatory system that is known to control the expression of GelE and SprE proteases. To discriminate between genes directly regulated by Fsr, and those indirectly regulated as the result of protease expression or activity, we compared gene expression in isogenic mutants of V583 variously defective in either Fsr quorum sensing or protease expression. Quorum sensing was artificially induced by addition of the quorum signal, GBAP, exogenously in a controlled manner. The Fsr regulon was found to be restricted to five genes, gelE, sprE, ef1097, ef1351 and ef1352. Twelve additional genes were found to be dependent on the presence of GBAP-induced proteases. Induction of GelE and SprE by GBAP via Fsr resulted in accumulation of mRNA encoding lrgAB, and this induction was found to be lytRS dependent. Drosophila infection was used to discern varying levels of toxicity stemming from mutations in the fsr quorum regulatory system and the genes that it regulates, highlighting the contribution of LrgAB and bacteriocin EF1097 to infection toxicity. A contribution of SprE to infection toxicity was also detected. This work brought to light new players in E. faecalis success as a pathogen and paves the way for future studies on host tolerance mechanisms to infections caused by this important nosocomial pathogen.

  16. Global Proteomic Analysis Reveals an Exclusive Role of Thylakoid Membranes in Bioenergetics of a Model Cyanobacterium

    Energy Technology Data Exchange (ETDEWEB)

    Liberton, Michelle; Saha, Rajib; Jacobs, Jon M.; Nguyen, Amelia Y.; Gritsenko, Marina A.; Smith, Richard D.; Koppenaal, David W.; Pakrasi, Himadri B.

    2016-04-07

    Cyanobacteria are photosynthetic microbes with highlydifferentiated membrane systems. These organisms contain an outer membrane, plasma membrane, and an internal system of thylakoid membranes where the photosynthetic and respiratory machinery are found. This existence of compartmentalization and differentiation of membrane systems poses a number of challenges for cyanobacterial cells in terms of organization and distribution of proteins to the correct membrane system. Proteomics studies have long sought to identify the components of the different membrane systems in cyanobacteria, and to date about 450 different proteins have been attributed to either the plasma membrane or thylakoid membrane. Given the complexity of these membranes, many more proteins remain to be identified, and a comprehensive catalogue of plasma membrane and thylakoid membrane proteins is needed. Here we describe the identification of 635 differentially localized proteins in Synechocystis sp. PCC 6803 by quantitative iTRAQ isobaric labeling; of these, 459 proteins were localized to the plasma membrane and 176 were localized to the thylakoid membrane. Surprisingly, we found over 2.5 times the number of unique proteins identified in the plasma membrane compared with the thylakoid membrane. This suggests that the protein composition of the thylakoid membrane is more homogeneous than the plasma membrane, consistent with the role of the plasma membrane in diverse cellular processes including protein trafficking and nutrient import, compared with a more specialized role for the thylakoid membrane in cellular energetics. Thus, our data clearly define the two membrane systems with distinct functions. Overall, the protein compositions of the Synechocystis 6803 plasma membrane and thylakoid membrane are quite similar to that of the plasma membrane of Escherichia coli and thylakoid membrane of Arabidopsis chloroplasts, respectively. Synechocystis 6803 can therefore be described as a Gram

  17. A Quantitative Model of Motility Reveals Low-Dimensional Variation in Exploratory Behavior Across Multiple Nematode Species

    Science.gov (United States)

    Helms, Stephen; Avery, Leon; Stephens, Greg; Shimizu, Tom

    2014-03-01

    Animal behavior emerges from many layers of biological organization--from molecular signaling pathways and neuronal networks to mechanical outputs of muscles. In principle, the large number of interconnected variables at each of these layers could imply dynamics that are complex and hard to control or even tinker with. Yet, for organisms to survive in a competitive, ever-changing environment, behavior must readily adapt. We applied quantitative modeling to identify important aspects of behavior in chromadorean nematodes ranging from the lab strain C. elegans N2 to wild strains and distant species. We revealed subtle yet important features such as speed control and heavy-tailed directional changes. We found that the parameters describing this behavioral model varied among individuals and across species in a correlated way that is consistent with a trade-off between exploratory and exploitative behavior.

  18. A model-data comparison of Holocene timberline changes in the Swiss Alps reveals past and future drivers of mountain forest dynamics.

    Science.gov (United States)

    Schwörer, Christoph; Henne, Paul D; Tinner, Willy

    2014-05-01

    Mountain vegetation is strongly affected by temperature and is expected to shift upwards with climate change. Dynamic vegetation models are often used to assess the impact of climate on vegetation and model output can be compared with paleobotanical data as a reality check. Recent paleoecological studies have revealed regional variation in the upward shift of timberlines in the Northern and Central European Alps in response to rapid warming at the Younger Dryas/Preboreal transition ca. 11 700 years ago, probably caused by a climatic gradient across the Alps. This contrasts with previous studies that successfully simulated the early Holocene afforestation in the (warmer) Central Alps with a chironomid-inferred temperature reconstruction from the (colder) Northern Alps. We use LandClim, a dynamic landscape vegetation model to simulate mountain forests under different temperature, soil and precipitation scenarios around Iffigsee (2065 m a.s.l.) a lake in the Northwestern Swiss Alps, and compare the model output with the paleobotanical records. The model clearly overestimates the upward shift of timberline in a climate scenario that applies chironomid-inferred July-temperature anomalies to all months. However, forest establishment at 9800 cal. BP at Iffigsee is successfully simulated with lower moisture availability and monthly temperatures corrected for stronger seasonality during the early Holocene. The model-data comparison reveals a contraction in the realized niche of Abies alba due to the prominent role of anthropogenic disturbance after ca. 5000 cal. BP, which has important implications for species distribution models (SDMs) that rely on equilibrium with climate and niche stability. Under future climate projections, LandClim indicates a rapid upward shift of mountain vegetation belts by ca. 500 m and treeline positions of ca. 2500 m a.s.l. by the end of this century. Resulting biodiversity losses in the alpine vegetation belt might be mitigated with low

  19. Crystal study and econometric model

    Science.gov (United States)

    1975-01-01

    An econometric model was developed that can be used to predict demand and supply figures for crystals over a time horizon roughly concurrent with that of NASA's Space Shuttle Program - that is, 1975 through 1990. The model includes an equation to predict the impact on investment in the crystal-growing industry. Actually, two models are presented. The first is a theoretical model which follows rather strictly the standard theoretical economic concepts involved in supply and demand analysis, and a modified version of the model was developed which, though not quite as theoretically sound, was testable utilizing existing data sources.

  20. Model study on Bohai ecosystem 1. Model description and primary productivity

    Institute of Scientific and Technical Information of China (English)

    LIU Hao; YIN Baoshu

    2006-01-01

    A Nutrient-Phytoplankton-Zooplankton(NPZD) type of ecological model is developed to reflect the biochemical process, and further coupled to a primitive equation ocean model, an irradiation model as well as a river discharge model to reproduce ecosystem dynamics in the Bohai Sea. Modeled primary production shows reasonable consistency with observations quantitatively and qualitatively; in addition, f-ratio is examined in detail in the first time, which is also within the range reported in other studies and reveals some meaningful insight into the relative contributions of ammonium and nitrate to the growth of phytoplankton in the Bohai Sea.

  1. Large cross-sectional study of presbycusis reveals rapid progressive decline in auditory temporal acuity.

    Science.gov (United States)

    Ozmeral, Erol J; Eddins, Ann C; Frisina, D Robert; Eddins, David A

    2016-07-01

    The auditory system relies on extraordinarily precise timing cues for the accurate perception of speech, music, and object identification. Epidemiological research has documented the age-related progressive decline in hearing sensitivity that is known to be a major health concern for the elderly. Although smaller investigations indicate that auditory temporal processing also declines with age, such measures have not been included in larger studies. Temporal gap detection thresholds (TGDTs; an index of auditory temporal resolution) measured in 1071 listeners (aged 18-98 years) were shown to decline at a minimum rate of 1.05 ms (15%) per decade. Age was a significant predictor of TGDT when controlling for audibility (partial correlation) and when restricting analyses to persons with normal-hearing sensitivity (n = 434). The TGDTs were significantly better for males (3.5 ms; 51%) than females when averaged across the life span. These results highlight the need for indices of temporal processing in diagnostics, as treatment targets, and as factors in models of aging.

  2. Virtual screening studies reveal linarin as a potential natural inhibitor targeting CDK4 in retinoblastoma.

    Science.gov (United States)

    Sivashanmugam, Muthukumaran; Raghunath, Chandana; Vetrivel, Umashankar

    2013-10-01

    To find out whether linarin can be used as a potential natural inhibitor to target CDK4 in retinoblastoma using virtual screening studies. In this study, molecular modeling and protein structure optimization was performed for crystal structure of CDK4 (PDB id: 3G33), and was subjected to Molecular Dynamics (MD) simulation for 10 nanoseconds, as a preparatory process for docking. Furthermore, the stable conformation obtained in the MD simulation was utilized for virtual screening against the library of natural compounds in Indian Plant Anticancer Compounds Database (InPACdb) using AutoDock Vina. Finally, best docked ligands were revalidated individually through semi-flexible docking by AutoDock 4.0. The CDK4 structure was stereochemically optimized to fix clashes and bad angles, which placed 96.4% residues in the core region of Ramachandran plot. The final structure of CDK4 that emerged after MD simulation was proven to be highly stable as per different validation tools. Virtual screening and docking was carried out for CDK4 against optimized ligands from InPACdb through AutoDock Vina. This inferred Linarin (Inpacdb AC.NO. acd0073) as a potential therapeutic agent with binding energy of -8.9 kJ/mol. Furthermore, it was also found to be valid as per AutoDock 4.0 semi-flexible docking procedure, with the binding energy of -8.18 kJ/mol and Ki value of 1.01 μM. The docking results indicate linarin, a flavonoid plant compound, as a potential inhibitor of CDK4 compared to some of the currently practiced anticancer drugs for retinoblastoma. This finding can be extended to experimental validation to assess the in vivo efficacy of the identified compound.

  3. The Circumstellar Environment of Evolved Stars as Revealed by Studies of Circumstellar Water Masers

    Science.gov (United States)

    Marvel, K.

    1997-11-01

    This dissertation presents the results of a multi-epoch very long baseline interferometric (VLBI) study of water masers located in the extended atmospheres of seven evolved stars. The research was performed using the Very Long Baseline Array and Very Large Array of the National Radio Astronomy Observatory. Water masers are found to exist in the atmospheres of evolved, oxygen-rich stars where a population inversion of the rotational transition at 22 GHz can be maintained by collisional pumping. The masers are identified as individual pockets or filaments of gas, which have good velocity coherence and may be imaged using radio interferometry. Stellar winds are initiated in these sources by dust formation and acceleration of the gas through momentum coupling. The typical wind speeds in the region of the water masers are 10 to 20 \\kms. The water masers in several evolved stars (VY CMa, VX Sgr, S Per, U Her, IK Tau, RX Boo and NML Cyg) have been observed at three epochs and exhibit proper motions consistent with the assumed source distances and the measured outflow velocity in the water maser region. Estimates of the distance to the sources using statistical approximation are in agreement with the currently accepted distances to the stars. The following stars had reliable distances determined using proper motion data: S Per (2.3 +/- 0.5 kpc), VY CMa (1.4 +/- 0.2 kpc), VX Sgr (1.4 +/- 0.3 kpc). An upper limit for the distance of NML Cyg was obtained ( 3.5 kpc). The remaining stars had too few maser detections (RX BOO, IK Tau) or were not strong enough at all epochs (U Her) to self-calibrate using the VLBA. A detailed kinematic model was used to describe the flow motions of the gas in the maser region. The regions are found to be complex and not well modeled by uniform radial outflow, radial outflow with rotation, or radial outflow with acceleration. The reasons for this are explored and include the probable presence of anisotropic velocity fields induced through non

  4. Comparative Analysis of the Secretome from a Model Filarial Nematode (Litomosoides sigmodontis) Reveals Maximal Diversity in Gravid Female Parasites*

    Science.gov (United States)

    Armstrong, Stuart D.; Babayan, Simon A.; Lhermitte-Vallarino, Nathaly; Gray, Nick; Xia, Dong; Martin, Coralie; Kumar, Sujai; Taylor, David W.; Blaxter, Mark L.; Wastling, Jonathan M.; Makepeace, Benjamin L.

    2014-01-01

    Filarial nematodes (superfamily Filarioidea) are responsible for an annual global health burden of ∼6.3 million disability-adjusted life-years, which represents the greatest single component of morbidity attributable to helminths affecting humans. No vaccine exists for the major filarial diseases, lymphatic filariasis and onchocerciasis; in part because research on protective immunity against filariae has been constrained by the inability of the human-parasitic species to complete their lifecycles in laboratory mice. However, the rodent filaria Litomosoides sigmodontis has become a popular experimental model, as BALB/c mice are fully permissive for its development and reproduction. Here, we provide a comprehensive analysis of excretory-secretory products from L. sigmodontis across five lifecycle stages and identifications of host proteins associated with first-stage larvae (microfilariae) in the blood. Applying intensity-based quantification, we determined the abundance of 302 unique excretory-secretory proteins, of which 64.6% were present in quantifiable amounts only from gravid adult female nematodes. This lifecycle stage, together with immature microfilariae, released four proteins that have not previously been evaluated as vaccine candidates: a predicted 28.5 kDa filaria-specific protein, a zonadhesin and SCO-spondin-like protein, a vitellogenin, and a protein containing six metridin-like ShK toxin domains. Female nematodes also released two proteins derived from the obligate Wolbachia symbiont. Notably, excretory-secretory products from all parasite stages contained several uncharacterized members of the transthyretin-like protein family. Furthermore, biotin labeling revealed that redox proteins and enzymes involved in purinergic signaling were enriched on the adult nematode cuticle. Comparison of the L. sigmodontis adult secretome with that of the human-infective filarial nematode Brugia malayi (reported previously in three independent published studies

  5. RNA-sequencing analysis of TCDD-induced responses in zebrafish liver reveals high relatedness to in vivo mammalian models and conserved biological pathways.

    Directory of Open Access Journals (Sweden)

    Zhi-Hua Li

    Full Text Available TCDD is one of the most persistent environmental toxicants in biological systems and its effect through aryl hydrocarbon receptor (AhR has been well characterized. However, the information on TCDD-induced toxicity in other molecular pathways is rather limited. To fully understand molecular toxicity of TCDD in an in vivo animal model, adult zebrafish were exposed to TCDD at 10 nM for 96 h and the livers were sampled for RNA-sequencing based transcriptomic profiling. A total of 1,058 differently expressed genes were identified based on fold-change>2 and TPM (transcripts per million >10. Among the top 20 up-regulated genes, 10 novel responsive genes were identified and verified by RT-qPCR analysis on independent samples. Transcriptomic analysis indicated several deregulated pathways associated with cell cycle, endocrine disruptors, signal transduction and immune systems. Comparative analyses of TCDD-induced transcriptomic changes between fish and mammalian models revealed that proteomic pathway is consistently up-regulated while calcium signaling pathway and several immune-related pathways are generally down-regulated. Finally, our study also suggested that zebrafish model showed greater similarity to in vivo mammalian models than in vitro models. Our study indicated that the zebrafish is a valuable in vivo model in toxicogenomic analyses for understanding molecular toxicity of environmental toxicants relevant to human health. The expression profiles associated with TCDD could be useful for monitoring environmental dioxin and dioxin-like contamination.

  6. Mechanism of porcine liver xanthine oxidoreductase mediated N-oxide reduction of cyadox as revealed by docking and mutagenesis studies.

    Directory of Open Access Journals (Sweden)

    Chigang Chen

    Full Text Available Xanthine oxidoreductase (XOR is a cytoplasmic molybdenum-containing oxidoreductase, catalyzing both endogenous purines and exogenous compounds. It is suggested that XOR in porcine hepatocytes catalyzes the N-oxide reduction of quinoxaline 1,4-di-N-oxides (QdNOs. To elucidate the molecular mechanism underlying this metabolism, the cDNA of porcine XOR was cloned and heterologously expressed in Spodoptera frugiperda insect cells. The bovine XOR, showing sequence identity of 91% to porcine XOR, was employed as template for homology modeling. By docking cyadox, a representative compound of QdNOs, into porcine XOR model, eight amino acid residues, Gly47, Asn352, Ser360, Arg427, Asp430, Asp431, Ser1227 and Lys1230, were located at distances of less than 4Å to cyadox. Site-directed mutagenesis was performed to analyze their catalytic functions. Compared with wild type porcine XOR, G47A, S360P, D431A, S1227A, and K1230A displayed altered kinetic parameters in cyadox reduction, similarly to that in xanthine oxidation, indicating these mutations influenced electron-donating process of xanthine before subsequent electron transfer to cyadox to fulfill the N-oxide reduction. Differently, R427E and D430H, both located in the 424-434 loop, exhibited a much lower K(m and a decreased V(max respectively in cyadox reduction. Arg427 may be related to the substrate binding of porcine XOR to cyadox, and Asp430 is suggested to be involved in the transfer of electron to cyadox. This study initially reveals the possible catalytic mechanism of porcine XOR in cyadox metabolism, providing with novel insights into the structure-function relationship of XOR in the reduction of exogenous di-N-oxides.

  7. A quantitative validated model reveals two phases of transcriptional regulation for the gap gene giant in Drosophila.

    Science.gov (United States)

    Hoermann, Astrid; Cicin-Sain, Damjan; Jaeger, Johannes

    2016-03-15

    Understanding eukaryotic transcriptional regulation and its role in development and pattern formation is one of the big challenges in biology today. Most attempts at tackling this problem either focus on the molecular details of transcription factor binding, or aim at genome-wide prediction of expression patterns from sequence through bioinformatics and mathematical modelling. Here we bridge the gap between these two complementary approaches by providing an integrative model of cis-regulatory elements governing the expression of the gap gene giant (gt) in the blastoderm embryo of Drosophila melanogaster. We use a reverse-engineering method, where mathematical models are fit to quantitative spatio-temporal reporter gene expression data to infer the regulatory mechanisms underlying gt expression in its anterior and posterior domains. These models are validated through prediction of gene expression in mutant backgrounds. A detailed analysis of our data and models reveals that gt is regulated by domain-specific CREs at early stages, while a late element drives expression in both the anterior and the posterior domains. Initial gt expression depends exclusively on inputs from maternal factors. Later, gap gene cross-repression and gt auto-activation become increasingly important. We show that auto-regulation creates a positive feedback, which mediates the transition from early to late stages of regulation. We confirm the existence and role of gt auto-activation through targeted mutagenesis of Gt transcription factor binding sites. In summary, our analysis provides a comprehensive picture of spatio-temporal gene regulation by different interacting enhancer elements for an important developmental regulator.

  8. A model of gene expression based on random dynamical systems reveals modularity properties of gene regulatory networks.

    Science.gov (United States)

    Antoneli, Fernando; Ferreira, Renata C; Briones, Marcelo R S

    2016-06-01

    Here we propose a new approach to modeling gene expression based on the theory of random dynamical systems (RDS) that provides a general coupling prescription between the nodes of any given regulatory network given the dynamics of each node is modeled by a RDS. The main virtues of this approach are the following: (i) it provides a natural way to obtain arbitrarily large networks by coupling together simple basic pieces, thus revealing the modularity of regulatory networks; (ii) the assumptions about the stochastic processes used in the modeling are fairly general, in the sense that the only requirement is stationarity; (iii) there is a well developed mathematical theory, which is a blend of smooth dynamical systems theory, ergodic theory and stochastic analysis that allows one to extract relevant dynamical and statistical information without solving the system; (iv) one may obtain the classical rate equations form the corresponding stochastic version by averaging the dynamic random variables (small noise limit). It is important to emphasize that unlike the deterministic case, where coupling two equations is a trivial matter, coupling two RDS is non-trivial, specially in our case, where the coupling is performed between a state variable of one gene and the switching stochastic process of another gene and, hence, it is not a priori true that the resulting coupled system will satisfy the definition of a random dynamical system. We shall provide the necessary arguments that ensure that our coupling prescription does indeed furnish a coupled regulatory network of random dynamical systems. Finally, the fact that classical rate equations are the small noise limit of our stochastic model ensures that any validation or prediction made on the basis of the classical theory is also a validation or prediction of our model. We illustrate our framework with some simple examples of single-gene system and network motifs.

  9. Negative differential mobility for negative carriers as revealed by space charge measurements on crosslinked polyethylene insulated model cables

    Science.gov (United States)

    Teyssedre, G.; Vu, T. T. N.; Laurent, C.

    2015-12-01

    Among features observed in polyethylene materials under relatively high field, space charge packets, consisting in a pulse of net charge that remains in the form of a pulse as it crosses the insulation, are repeatedly observed but without complete theory explaining their formation and propagation. Positive charge packets are more often reported, and the models based on negative differential mobility(NDM) for the transport of holes could account for some charge packets phenomenology. Conversely, NDM for electrons transport has never been reported so far. The present contribution reports space charge measurements by pulsed electroacoustic method on miniature cables that are model of HVDC cables. The measurements were realized at room temperature or with a temperature gradient of 10 °C through the insulation under DC fields on the order 30-60 kV/mm. Space charge results reveal systematic occurrence of a negative front of charges generated at the inner electrode that moves toward the outer electrode at the beginning of the polarization step. It is observed that the transit time of the front of negative charge increases, and therefore the mobility decreases, with the applied voltage. Further, the estimated mobility, in the range 10-14-10-13 m2 V-1 s-1 for the present results, increases when the temperature increases for the same condition of applied voltage. The features substantiate the hypothesis of negative differential mobility used for modelling space charge packets.

  10. Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate.

    Directory of Open Access Journals (Sweden)

    Jatin Narula

    2010-05-01

    Full Text Available Combinatorial regulation of gene expression is ubiquitous in eukaryotes with multiple inputs converging on regulatory control elements. The dynamic properties of these elements determine the functionality of genetic networks regulating differentiation and development. Here we propose a method to quantitatively characterize the regulatory output of distant enhancers with a biophysical approach that recursively determines free energies of protein-protein and protein-DNA interactions from experimental analysis of transcriptional reporter libraries. We apply this method to model the Scl-Gata2-Fli1 triad-a network module important for cell fate specification of hematopoietic stem cells. We show that this triad module is inherently bistable with irreversible transitions in response to physiologically relevant signals such as Notch, Bmp4 and Gata1 and we use the model to predict the sensitivity of the network to mutations. We also show that the triad acts as a low-pass filter by switching between steady states only in response to signals that persist for longer than a minimum duration threshold. We have found that the auto-regulation loops connecting the slow-degrading Scl to Gata2 and Fli1 are crucial for this low-pass filtering property. Taken together our analysis not only reveals new insights into hematopoietic stem cell regulatory network functionality but also provides a novel and widely applicable strategy to incorporate experimental measurements into dynamical network models.

  11. A model of estrogen-related gene expression reveals non-linear effects in transcriptional response to tamoxifen

    Directory of Open Access Journals (Sweden)

    Lebedeva Galina

    2012-11-01

    Full Text Available Abstract Background Estrogen receptors alpha (ER are implicated in many types of female cancers, and are the common target for anti-cancer therapy using selective estrogen receptor modulators (SERMs, such as tamoxifen. However, cell-type specific and patient-to-patient variability in response to SERMs (from suppression to stimulation of cancer growth, as well as frequent emergence of drug resistance, represents a serious problem. The molecular processes behind mixed effects of SERMs remain poorly understood, and this strongly motivates application of systems approaches. In this work, we aimed to establish a mathematical model of ER-dependent gene expression to explore potential mechanisms underlying the variable actions of SERMs. Results We developed an equilibrium model of ER binding with 17β-estradiol, tamoxifen and DNA, and linked it to a simple ODE model of ER-induced gene expression. The model was parameterised on the broad range of literature available experimental data, and provided a plausible mechanistic explanation for the dual agonism/antagonism action of tamoxifen in the reference cell line used for model calibration. To extend our conclusions to other cell types we ran global sensitivity analysis and explored model behaviour in the wide range of biologically plausible parameter values, including those found in cancer cells. Our findings suggest that transcriptional response to tamoxifen is controlled in a complex non-linear way by several key parameters, including ER expression level, hormone concentration, amount of ER-responsive genes and the capacity of ER-tamoxifen complexes to stimulate transcription (e.g. by recruiting co-regulators of transcription. The model revealed non-monotonic dependence of ER-induced transcriptional response on the expression level of ER, that was confirmed experimentally in four variants of the MCF-7 breast cancer cell line. Conclusions We established a minimal mechanistic model of ER-dependent gene

  12. Analysis of the cartilage proteome from three different mouse models of genetic skeletal diseases reveals common and discrete disease signatures

    Directory of Open Access Journals (Sweden)

    Peter A. Bell

    2013-06-01

    Pseudoachondroplasia and multiple epiphyseal dysplasia are genetic skeletal diseases resulting from mutations in cartilage structural proteins. Electron microscopy and immunohistochemistry previously showed that the appearance of the cartilage extracellular matrix (ECM in targeted mouse models of these diseases is disrupted; however, the precise changes in ECM organization and the pathological consequences remain unknown. Our aim was to determine the effects of matrilin-3 and COMP mutations on the composition and extractability of ECM components to inform how these detrimental changes might influence cartilage organization and degeneration. Cartilage was sequentially extracted using increasing denaturants and the extraction profiles of specific proteins determined using SDS-PAGE/Western blotting. Furthermore, the relative composition of protein pools was determined using mass spectrometry for a non-biased semi-quantitative analysis. Western blotting revealed changes in the extraction of matrilins, COMP and collagen IX in mutant cartilage. Mass spectrometry confirmed quantitative changes in the extraction of structural and non-structural ECM proteins, including proteins with roles in cellular processes such as protein folding and trafficking. In particular, genotype-specific differences in the extraction of collagens XII and XIV and tenascins C and X were identified; interestingly, increased expression of several of these genes has recently been implicated in susceptibility and/or progression of murine osteoarthritis. We demonstrated that mutation of matrilin-3 and COMP caused changes in the extractability of other cartilage proteins and that proteomic analyses of Matn3 V194D, Comp T585M and Comp DelD469 mouse models revealed both common and discrete disease signatures that provide novel insight into skeletal disease mechanisms and cartilage degradation.

  13. Proteomics, ultrastructure, and physiology of hippocampal synapses in a fragile X syndrome mouse model reveal presynaptic phenotype.

    Science.gov (United States)

    Klemmer, Patricia; Meredith, Rhiannon M; Holmgren, Carl D; Klychnikov, Oleg I; Stahl-Zeng, Jianru; Loos, Maarten; van der Schors, Roel C; Wortel, Joke; de Wit, Heidi; Spijker, Sabine; Rotaru, Diana C; Mansvelder, Huibert D; Smit, August B; Li, Ka Wan

    2011-07-22

    Fragile X syndrome (FXS), the most common form of hereditary mental retardation, is caused by a loss-of-function mutation of the Fmr1 gene, which encodes fragile X mental retardation protein (FMRP). FMRP affects dendritic protein synthesis, thereby causing synaptic abnormalities. Here, we used a quantitative proteomics approach in an FXS mouse model to reveal changes in levels of hippocampal synapse proteins. Sixteen independent pools of Fmr1 knock-out mice and wild type mice were analyzed using two sets of 8-plex iTRAQ experiments. Of 205 proteins quantified with at least three distinct peptides in both iTRAQ series, the abundance of 23 proteins differed between Fmr1 knock-out and wild type synapses with a false discovery rate (q-value) <5%. Significant differences were confirmed by quantitative immunoblotting. A group of proteins that are known to be involved in cell differentiation and neurite outgrowth was regulated; they included Basp1 and Gap43, known PKC substrates, and Cend1. Basp1 and Gap43 are predominantly expressed in growth cones and presynaptic terminals. In line with this, ultrastructural analysis in developing hippocampal FXS synapses revealed smaller active zones with corresponding postsynaptic densities and smaller pools of clustered vesicles, indicative of immature presynaptic maturation. A second group of proteins involved in synaptic vesicle release was up-regulated in the FXS mouse model. In accordance, paired-pulse and short-term facilitation were significantly affected in these hippocampal synapses. Together, the altered regulation of presynaptically expressed proteins, immature synaptic ultrastructure, and compromised short-term plasticity points to presynaptic changes underlying glutamatergic transmission in FXS at this stage of development.

  14. Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.

    Science.gov (United States)

    Alexander, Eileen S; Martin, Lisa J; Collins, Margaret H; Kottyan, Leah C; Sucharew, Heidi; He, Hua; Mukkada, Vincent A; Succop, Paul A; Abonia, J Pablo; Foote, Heather; Eby, Michael D; Grotjan, Tommie M; Greenler, Alexandria J; Dellon, Evan S; Demain, Jeffrey G; Furuta, Glenn T; Gurian, Larry E; Harley, John B; Hopp, Russell J; Kagalwalla, Amir; Kaul, Ajay; Nadeau, Kari C; Noel, Richard J; Putnam, Philip E; von Tiehl, Karl F; Rothenberg, Marc E

    2014-11-01

    Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown. To quantify the risk associated with genes and environment on familial clustering of EoE. Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree "Nuclear-Family" relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE "Twins" probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined. Analysis of the Nuclear-Family-based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P Twins cohort, genetic heritability was 14.5% ± 4.0% (P twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins (P = .11). Greater birth weight difference between twins (P = .01), breast-feeding (P = .15), and fall birth season (P = .02) were associated with twin discordance in disease status. EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%). Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.

  15. New porcine test-model reveals remarkable differences between algorithms for spectrophotometrical haemoglobin saturation measurements with VLS

    DEFF Research Database (Denmark)

    Gade, John; Greisen, Gorm

    2016-01-01

    The study created an 'ex vivo' model to test different algorithms for measurements of mucosal haemoglobin saturation with visible light spectrophotometry (VLS). The model allowed comparison between algorithms, but it also allowed comparison with co-oximetry using a 'gold standard' method. This has......  -32.8 to  +29.9 percentage points and from  -5.0 to  +9.2 percentage points, respectively. CONCLUSION: the algorithms showed remarkable in-between differences when tested on raw-spectra from an 'ex vivo' model. All algorithms had bias, more marked at high oxygenation than low oxygenation. Three...

  16. Literature survey of high-impact journals revealed reporting weaknesses in abstracts of diagnostic accuracy studies

    NARCIS (Netherlands)

    Korevaar, Daniël A; Cohen, Jérémie F; Hooft, Lotty; Bossuyt, Patrick M M

    2015-01-01

    OBJECTIVES: Informative journal abstracts are crucial for the identification and initial appraisal of studies. We aimed to evaluate the informativeness of abstracts of diagnostic accuracy studies. STUDY DESIGN AND SETTING: PubMed was searched for reports of studies that had evaluated the diagnostic

  17. Structural and Functional Studies of the Rap1 C-Terminus Reveal Novel Separation-of-Function Mutants

    Energy Technology Data Exchange (ETDEWEB)

    Feeser, Elizabeth A.; Wolberger, Cynthia (JHU-MED)

    2010-02-19

    The yeast Rap1 protein plays an important role in transcriptional silencing and in telomere length homeostasis. Rap1 mediates silencing at the HM loci and at telomeres by recruiting the Sir3 and Sir4 proteins to chromatin via a Rap1 C-terminal domain, which also recruits the telomere length regulators, Rif1 and Rif2. We report the 1.85 {angstrom} resolution crystal structure of the Rap1 C-terminus, which adopts an all-helical fold with no structural homologues. The structure was used to engineer surface mutations in Rap1, and the effects of these mutations on silencing and telomere length regulation were assayed in vivo. Our surprising finding was that there is no overlap between mutations affecting mating-type and telomeric silencing, suggesting that Rap1 plays distinct roles in silencing at the silent mating-type loci and telomeres. We also found novel Rap1 phenotypes and new separation-of-function mutants, which provide new tools for studying Rap1 function. Yeast two-hybrid studies were used to determine how specific mutations affect recruitment of Sir3, Rif1, and Rif2. A comparison of the yeast two-hybrid and functional data reveals patterns of protein interactions that correlate with each Rap1 phenotype. We find that Sir3 interactions are important for telomeric silencing, but not mating type silencing, and that Rif1 and Rif2 interactions are important in different subsets of telomeric length mutants. Our results show that the role of Rap1 in silencing differs between the HM loci and the telomeres and offer insight into the interplay between HM silencing, telomeric silencing, and telomere length regulation. These findings suggest a model in which competition and multiple recruitment events modulate silencing and telomere length regulation.

  18. Radionuclides in fruit systems: Model-model intercomparison study

    Energy Technology Data Exchange (ETDEWEB)

    Linkov, I. [Cambridge Environmental, 58 Charles Street, Cambridge, MA 02141 (United States)]. E-mail: linkov@cambridgeenvironmental.com; Carini, F. [Universita Cattolica del Sacro Cuore, Faculty of Agricultural Sciences, Institute of Agricultural and Environmental Chemistry, Via Emilia Parmense, 84, I-29100 Piacenza (Italy); Collins, C. [T.H. Huxley School of Environment, Earth Sciences and Engineering (United Kingdom); Eged, K. [Department of Radiochemistry, University of Veszprem, P.O. Box 158 H-8201, H-8200 Veszprem (Hungary); Mitchell, N.G. [Mouchel Consulting Ltd., West Hall, Parvis Road, West Byfleet, Surrey, KT14 6EZ (United Kingdom); Mourlon, C. [Institute of Protection and Nuclear Safety (IPSN)/Division of Environmental Protection (DPRE), Laboratory of Environmental Modelling - LMODE, CE/Cadarache, 13 108 St Paul-lez-Durance Cedex (France); Ould-Dada, Z. [Food Standards Agency, Radiological Protection and Research Management Division, Aviation House, 125 Kingsway, Room 715B, London WC2B 6NH (United Kingdom); Robles, B. [CIEMAT, Dept. de Impacto Ambiental (DIAE), Edif. 3A, Avenida Complutense 22, E-28040 Madrid (Spain); Sweeck, L. [SCK.CEN, Boeretang 200, 2400 Mol (Belgium); Venter, A. [Enviros Consulting Ltd., Telegraphic House, Waterfront Quay, Salford Quays, Greater Manchester, M50 3XW (United Kingdom)

    2006-07-01

    Modeling is widely used to predict radionuclide distribution following accidental radionuclide releases. Modeling is crucial in emergency response planning and risk communication, and understanding model uncertainty is important not only in conducting analysis consistent with current regulatory guidance, but also in gaining stakeholder and decision-maker trust in the process and confidence in the results. However, while methods for dealing with parameter uncertainty are fairly well developed, an adequate representation of uncertainties associated with models remains rare. This paper addresses uncertainty about a model's structure (i.e., the relevance of simplifying assumptions and mathematical equations) that is seldom addressed in practical applications of environmental modeling. The use of several alternative models to derive a range of model outputs or risks is probably the only available technique to assess consistency in model prediction. Since each independent model requires significant resources for development and calibration, multiple models are not generally applied to the same problem. This study uses results from one such model intercomparison conducted by the Fruits Working Group, which was created under the International Atomic Energy Agency (IAEA) BIOMASS (BIOsphere Modelling and ASSessment) Program. Model-model intercomparisons presented in this study were conducted by the working group for two different scenarios (acute or continuous deposition), one radionuclide ({sup 137}Cs), and three fruit-bearing crops (strawberries, apples, and blackcurrants). The differences between models were as great as five orders of magnitude for short-term predictions following acute radionuclide deposition. For long-term predictions and for the continuous deposition scenario, the differences between models were about two orders of magnitude. The difference between strawberry, apple, and blackcurrant contamination predicted by one model is far less than the

  19. Radionuclides in fruit systems. Model-model intercomparison study

    Energy Technology Data Exchange (ETDEWEB)

    Linkov, I. [Cambridge Environmental, 58 Charles Street, Cambridge, MA 02141 (United States); Carini, F. [Universita Cattolica del Sacro Cuore, Faculty of Agricultural Sciences, Institute of Agricultural and Environmental Chemistry, Via Emilia Parmense, 84, I-29100 Piacenza (Italy); Collins, C. [T.H. Huxley School of Environment, Earth Sciences and Engineering (United Kingdom); Eged, K. [Department of Radiochemistry, University of Veszprem, P.O. Box 158 H-8201, H-8200 Veszprem (Hungary); Mitchell, N.G. [Mouchel Consulting Ltd., West Hall, Parvis Road, West Byfleet, Surrey, KT14 6EZ (United Kingdom); Mourlon, C. [Institute of Protection and Nuclear Safety IPSN, Division of Environmental Protection (DPRE), Laboratory of Environmental Modelling LMODE, CE/Cadarache, 13 108 St Paul-lez-Durance (France); Ould-Dada, Z. [Food Standards Agency, Radiological Protection and Research Management Division, Aviation House, 125 Kingsway, Room 715B, London WC2B 6NH (United Kingdom); Robles, B. [CIEMAT, Dept. de Impacto Ambiental (DIAE), Edif. 3A, Avenida Complutense 22, E-28040 Madrid (Spain); Sweeck, L. [SCK-CEN, Boeretang 200, 2400 Mol (Belgium); Venter, A. [Enviros Consulting Ltd., Telegraphic House, Waterfront Quay, Salford Quays, Greater Manchester, M50 3XW (United Kingdom)

    2006-07-01

    Modeling is widely used to predict radionuclide distribution following accidental radionuclide releases. Modeling is crucial in emergency response planning and risk communication, and understanding model uncertainty is important not only in conducting analysis consistent with current regulatory guidance, but also in gaining stakeholder and decision-maker trust in the process and confidence in the results. However, while methods for dealing with parameter uncertainty are fairly well developed, an adequate representation of uncertainties associated with models remains rare. This paper addresses uncertainty about a model's structure (i.e., the relevance of simplifying assumptions and mathematical equations) that is seldom addressed in practical applications of environmental modeling. The use of several alternative models to derive a range of model outputs or risks is probably the only available technique to assess consistency in model prediction. Since each independent model requires significant resources for development and calibration, multiple models are not generally applied to the same problem. This study uses results from one such model intercomparison conducted by the Fruits Working Group, which was created under the International Atomic Energy Agency (IAEA) BIOMASS (BIOsphere Modelling and ASSessment) Program. Model-model intercomparisons presented in this study were conducted by the working group for two different scenarios (acute or continuous deposition), one radionuclide ({sup 137}Cs), and three fruit-bearing crops (strawberries, apples, and blackcurrants). The differences between models were as great as five orders of magnitude for short-term predictions following acute radionuclide deposition. For long-term predictions and for the continuous deposition scenario, the differences between models were about two orders of magnitude. The difference between strawberry, apple, and blackcurrant contamination predicted by one model is far less than the

  20. Small angle X-ray scattering study of calreticulin reveals conformational plasticity

    DEFF Research Database (Denmark)

    Toft, Katrine Nørgaard; Larsen, Nanna; Jørgensen, Flemming Steen;

    2008-01-01

    -domains are easily identified, and the P-domain is in an extended conformation connecting to the second calreticulin molecule. The SAXS solution data enables the construction of a medium-resolution model of calreticulin. In the light of the unresolved chaperone mechanism of calreticulin and calnexin, we discuss...

  1. Abnormal connection between lateral and posterior semicircular canal revealed by a new modeling process: origin and physiological consequences.

    Science.gov (United States)

    Rousie, Dominique Louise; Deroubaix, Jean Paul; Joly, Olivier; Baudrillard, Jean Claude; Berthoz, Alain

    2009-05-01

    We developed a modeling procedure using CT scans or MRI data for exploring the bony and lymphatic canals of vestibular patients. We submitted 445 patients with instability and spatial de-orientation to this procedure. Out of the 445 patients, 95 had scoliosis, some of them, because malformations were suspected also had CT-scan modeling and functional tests. We focused on a never described, abnormal connection between the lymphatic lateral and posterior canal (LPCC) with a frequency of 67/445 (15%). In the scoliosis subgroup, the frequency was 52/95 (55%). Three scoliotic patients had CT scans. For each of them, the modeling revealed that LPCC was present on the bony canals. LPCC has pathognomic signs: no rotatory vertigo but frequent instability, transport sickness head tilt on the side of the anomaly, and spatial disorientation in new environment. We evaluated the functional impact of LPCC by testing the vestibulo-ocular reflex (VOR) in horizontal and vertical planes and found reproducible abnormal responses: in the case of left LPCC, during a counterclockwise horizontal rotation or a post clockwise horizontal rotation, added to the expected horizontal nystagmus, we found an unexpected upbeat nystagmus induced by the ampullofugal displacement of the fluid in the posterior canal. As LPCC was found in CT scans and MRI modeling for a same subject, we suggest that it could be a congenital abnormal process of ossification of the canals. The responses to the vestibular tests highlighting constant unexpected nystagmus underline the potential functional consequences of LPCC on vestibular perception and scoliosis.

  2. Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis

    Science.gov (United States)

    Alexander, Eileen S.; Martin, Lisa J.; Collins, Margaret H.; Kottyan, Leah; Sucharew, Heidi; He, Hua; Mukkada, Vincent A.; Succop, Paul A.; Abonia, J. Pablo; Foote, Heather; Eby, Michael D.; Grotjan, Tommie M.; Greenler, Alexandria J.; Dellon, Evan S.; Demain, Jeffrey G.; Furuta, Glenn T.; Gurian, Larry E.; Harley, John B.; Hopp, Russell J.; Kaul, Ajay; Nadeau, Kari C.; Noel, Richard J.; Putnam, Philip E.; von Tiehl, Karl F.; Rothenberg, Marc E.

    2014-01-01

    Background Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown. Objective To quantify risk associated with genes and environment on familial clustering of EoE. Methods Family history was obtained from a hospital-based cohort of 914 EoE probands, (n=2192 first-degree “Nuclear-Family” relatives) and the new international registry of monozygotic and dizygotic twins/triplets (n=63 EoE “Twins” probands). Frequencies, recurrence risk ratios (RRRs), heritability and twin concordance were estimated. Environmental exposures were preliminarily examined. Results Analysis of the Nuclear-Family–based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10–64, depending on the family relationship, and were higher in brothers (64.0; p=0.04), fathers (42.9; p=0.004) and males (50.7; p<0.001) compared to sisters, mothers and females, respectively. Risk of EoE for other siblings was 2.4%. In the Nuclear-Families, combined gene and common environment heritability (hgc2) was 72.0±2.7% (p<0.001). In the Twins cohort, genetic heritability was 14.5±4.0% (p<0.001), and common family environment contributed 81.0±4% (p<0.001) to phenotypic variance. Proband-wise concordance in MZ co-twins was 57.9±9.5% compared to 36.4±9.3% in DZ (p=0.11). Greater birth-weight difference between twins (p=0.01), breastfeeding (p=0.15) and Fall birth season (p=0.02) were associated with twin discordance in disease status. Conclusions EoE recurrence risk ratios are increased 10–64-fold compared with the general population. EoE in relatives is 1.8–2.4%, depending upon relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, Twins cohort analysis revealed a powerful role for common environment (81

  3. Study on Macro-traffic Model

    Institute of Scientific and Technical Information of China (English)

    FangGe; GuowuZhang; BaojunYuan; KepingLi

    2004-01-01

    Macro-traffic model is an effective tool for supporting traffic programmer to This article is based on the software products VISEM (demand model) and VISUM (supply model) from PTV Company of Germany, and studies macro-traffic model on the basis of considering that traffic system is an interactive system of between a supply system and a demand system.

  4. What Work Samples Reveal about Secondary Pre-Service Social Studies Teachers' Use of Literacy Strategies

    Science.gov (United States)

    Lenski, Susan J.; Thieman, Gayle Y.

    2013-01-01

    The purpose of this study was to answer the following research questions: (1) Do secondary social studies pre-service teachers incorporate literacy\tstrategies in their work samples during student teaching? (2) To what extent\tand\tunder what conditions do secondary social studies pre-service teachers\tuse higher levels of literacy strategies in their…

  5. Revealing a room temperature ferromagnetism in cadmium oxide nanoparticles: An experimental and first-principles study

    KAUST Repository

    Bououdina, Mohamed

    2015-03-26

    We obtain a single cadmium oxide phase from powder synthesized by a thermal decomposition method of cadmium acetate dehydrate. The yielded powder is annealed in air, vacuum, and H2 gas in order to create point defects. Magnetization-field curves reveal the appearance of diamagnetic behavior with a ferromagnetic component for all the powders. Powder annealing under vacuum and H2 atmosphere leads to a saturation magnetization 1.15 memu g-1 and 1.2 memu g-1 respectively with an increase by 45% and 16% compared to the one annealed in air. We show that annealing in vacuum produces mainly oxygen vacancies while annealing in H2 gas creates mainly Cd vacancy leading to room temperature ferromagnetic (RTFM) component together with known diamagnetic properties. Ab initio calculations performed on the CdO nanoparticles show that the magnetism is governed by polarized hybrid states of the Cd d and O p orbitals together with the vacancy. © The Royal Society of Chemistry 2015.

  6. Experiments Are Revealing a Foundation Species: A Case Study of Eastern Hemlock (Tsuga canadensis

    Directory of Open Access Journals (Sweden)

    Aaron M. Ellison

    2014-01-01

    Full Text Available Foundation species are species that create and define particular ecosystems; control in large measure the distribution and abundance of associated flora and fauna; and modulate core ecosystem processes, such as energy flux and biogeochemical cycles. However, whether a particular species plays a foundational role in a system is not simply asserted. Rather, it is a hypothesis to be tested, and such tests are best done with large-scale, long-term manipulative experiments. The utility of such experiments is illustrated through a review of the Harvard Forest Hemlock Removal Experiment (HF-HeRE, a multidecadal, multihectare experiment designed to test the foundational role of eastern hemlock, Tsuga canadensis, in eastern North American forests. Experimental removal of T. canadensis has revealed that after 10 years, this species has pronounced, long-term effects on associated flora and fauna, but shorter-term effects on energy flux and nutrient cycles. We hypothesize that on century-long scales, slower changes in soil microbial associates will further alter ecosystem processes in T. canadensis stands. HF-HeRE may indeed continue for >100 years, but at such time scales, episodic disturbances and changes in regional climate and land cover can be expected to interact in novel ways with these forests and their foundation species.

  7. Integration of genome-scale modeling and transcript profiling reveals metabolic pathways underlying light and temperature acclimation in Arabidopsis.

    Science.gov (United States)

    Töpfer, Nadine; Caldana, Camila; Grimbs, Sergio; Willmitzer, Lothar; Fernie, Alisdair R; Nikoloski, Zoran

    2013-04-01

    Understanding metabolic acclimation of plants to challenging environmental conditions is essential for dissecting the role of metabolic pathways in growth and survival. As stresses involve simultaneous physiological alterations across all levels of cellular organization, a comprehensive characterization of the role of metabolic pathways in acclimation necessitates integration of genome-scale models with high-throughput data. Here, we present an integrative optimization-based approach, which, by coupling a plant metabolic network model and transcriptomics data, can predict the metabolic pathways affected in a single, carefully controlled experiment. Moreover, we propose three optimization-based indices that characterize different aspects of metabolic pathway behavior in the context of the entire metabolic network. We demonstrate that the proposed approach and indices facilitate quantitative comparisons and characterization of the plant metabolic response under eight different light and/or temperature conditions. The predictions of the metabolic functions involved in metabolic acclimation of Arabidopsis thaliana to the changing conditions are in line with experimental evidence and result in a hypothesis about the role of homocysteine-to-Cys interconversion and Asn biosynthesis. The approach can also be used to reveal the role of particular metabolic pathways in other scenarios, while taking into consideration the entirety of characterized plant metabolism.

  8. Systems biology modeling reveals a possible mechanism of the tumor cell death upon oncogene inactivation in EGFR addicted cancers.

    Directory of Open Access Journals (Sweden)

    Jian-Ping Zhou

    Full Text Available Despite many evidences supporting the concept of "oncogene addiction" and many hypotheses rationalizing it, there is still a lack of detailed understanding to the precise molecular mechanism underlying oncogene addiction. In this account, we developed a mathematic model of epidermal growth factor receptor (EGFR associated signaling network, which involves EGFR-driving proliferation/pro-survival signaling pathways Ras/extracellular-signal-regulated kinase (ERK and phosphoinositol-3 kinase (PI3K/AKT, and pro-apoptotic signaling pathway apoptosis signal-regulating kinase 1 (ASK1/p38. In the setting of sustained EGFR activation, the simulation results show a persistent high level of proliferation/pro-survival effectors phospho-ERK and phospho-AKT, and a basal level of pro-apoptotic effector phospho-p38. The potential of p38 activation (apoptotic potential due to the elevated level of reactive oxygen species (ROS is largely suppressed by the negative crosstalk between PI3K/AKT and ASK1/p38 pathways. Upon acute EGFR inactivation, the survival signals decay rapidly, followed by a fast increase of the apoptotic signal due to the release of apoptotic potential. Overall, our systems biology modeling together with experimental validations reveals that inhibition of survival signals and concomitant release of apoptotic potential jointly contribute to the tumor cell death following the inhibition of addicted oncogene in EGFR addicted cancers.

  9. Domain Motions and Functionally-Key Residues of l-Alanine Dehydrogenase Revealed by an Elastic Network Model

    Directory of Open Access Journals (Sweden)

    Xing-Yuan Li

    2015-12-01

    Full Text Available Mycobacterium tuberculosis l-alanine dehydrogenase (l-MtAlaDH plays an important role in catalyzing l-alanine to ammonia and pyruvate, which has been considered to be a potential target for tuberculosis treatment. In the present work, the functional domain motions encoded in the structure of l-MtAlaDH were investigated by using the Gaussian network model (GNM and the anisotropy network model (ANM. The slowest modes for the open-apo and closed-holo structures of the enzyme show that the domain motions have a common hinge axis centered in residues Met133 and Met301. Accompanying the conformational transition, both the 1,4-dihydronicotinamide adenine dinucleotide (NAD-binding domain (NBD and the substrate-binding domain (SBD move in a highly coupled way. The first three slowest modes of ANM exhibit the open-closed, rotation and twist motions of l-MtAlaDH, respectively. The calculation of the fast modes reveals the residues responsible for the stability of the protein, and some of them are involved in the interaction with the ligand. Then, the functionally-important residues relevant to the binding of the ligand were identified by using a thermodynamic method. Our computational results are consistent with the experimental data, which will help us to understand the physical mechanism for the function of l-MtAlaDH.

  10. Literature survey of high-impact journals revealed reporting weaknesses in abstracts of diagnostic accuracy studies.

    Science.gov (United States)

    Korevaar, Daniël A; Cohen, Jérémie F; Hooft, Lotty; Bossuyt, Patrick M M

    2015-06-01

    Informative journal abstracts are crucial for the identification and initial appraisal of studies. We aimed to evaluate the informativeness of abstracts of diagnostic accuracy studies. PubMed was searched for reports of studies that had evaluated the diagnostic accuracy of a test against a clinical reference standard, published in 12 high-impact journals in 2012. Two reviewers independently evaluated the information contained in included abstracts using 21 items deemed important based on published guidance for adequate reporting and study quality assessment. We included 103 abstracts. Crucial information on study population, setting, patient sampling, and blinding as well as confidence intervals around accuracy estimates were reported in items per abstract was 10.1 of 21 (standard deviation 2.2). The mean number of reported items was significantly lower for multiple-gate (case-control type) studies, in reports in specialty journals, and for studies with smaller sample sizes and lower abstract word counts. No significant differences were found between studies evaluating different types of tests. Many abstracts of diagnostic accuracy study reports in high-impact journals are insufficiently informative. Developing guidelines for such abstracts could help the transparency and completeness of reporting. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Integrating Factor Analysis and a Transgenic Mouse Model to Reveal a Peripheral Blood Predictor of Breast Tumors

    Directory of Open Access Journals (Sweden)

    Nevins Joseph R

    2011-07-01

    Full Text Available Abstract Background Transgenic mouse tumor models have the advantage of facilitating controlled in vivo oncogenic perturbations in a common genetic background. This provides an idealized context for generating transcriptome-based diagnostic models while minimizing the inherent noisiness of high-throughput technologies. However, the question remains whether models developed in such a setting are suitable prototypes for useful human diagnostics. We show that latent factor modeling of the peripheral blood transcriptome in a mouse model of breast cancer provides the basis for using computational methods to link a mouse model to a prototype human diagnostic based on a common underlying biological response to the presence of a tumor. Methods We used gene expression data from mouse peripheral blood cell (PBC samples to identify significantly differentially expressed genes using supervised classification and sparse ANOVA. We employed these transcriptome data as the starting point for developing a breast tumor predictor from human peripheral blood mononuclear cells (PBMCs by using a factor modeling approach. Results The predictor distinguished breast cancer patients from healthy individuals in a cohort of patients independent from that used to build the factors and train the model with 89% sensitivity, 100% specificity and an area under the curve (AUC of 0.97 using Youden's J-statistic to objectively select the model's classification threshold. Both permutation testing of the model and evaluating the model strategy by swapping the training and validation sets highlight its stability. Conclusions We describe a human breast tumor predictor based on the gene expression of mouse PBCs. This strategy overcomes many of the limitations of earlier studies by using the model system to reduce noise and identify transcripts associated with the presence of a breast tumor over other potentially confounding factors. Our results serve as a proof-of-concept for using an

  12. Long-Term Field Study Reveals Subtle Effects of the Invasive Alga Sargassum muticum upon the Epibiota of Zostera marina.

    Directory of Open Access Journals (Sweden)

    Stacey DeAmicis

    Full Text Available Invasive species can alter coastal ecosystems both directly, e.g. through competition for substratum and nutrients, and indirectly. Indirect effects may be mediated by creation of dissimilar or inimical habitats, changes in predator and/or prey assemblages, alterations in associated biota, and perturbations of water movement and thermal regimes. Previous studies have shown that invasive algae can modify native habitat architecture, disrupt intricately linked food webs and alter epibiotic assemblages. In the UK, the seagrass Zostera marina supports a diverse epibiotic assemblage, influencing key factors such as sediment dynamics, depositional regime and trophic linkages. Increasing encroachment of the invasive alga Sargassum muticum into seagrass meadows changes the physical and chemical characteristics of the local environment and creates the potential for changes in the epibionts associated with the seagrass blades, threatening the integrity of the seagrass ecosystem. We investigated the effects of S. muticum invasion upon the epibiota of Z. marina in a drowned river valley in SW England seasonally from spring to autumn over four years in an in-situ manipulative experiment, comparing permanent quadrats with and without artificially introduced S. muticum. Epibiota were weighed, identified to the most detailed operational taxonomic unit (OTU possible, and unitary organisms were enumerated. Multivariate PERMANOVA+ analysis revealed significant differences in epibiont assemblages between Sargassum treatments. Linear mixed effects models indicated that differences in epibiota assemblage composition were not reflected as significant differences in mean biomass per sample, or number of epibiont OTUs per sample. We conclude that S. muticum invasion into Z. marina meadows may significantly alter the species composition and abundance distribution of epibiotic assemblages found on the blades of the seagrass. Thus S. muticum invasion could have more wide

  13. Casein phosphopeptides drastically increase the secretion of extracellular proteins in Aspergillus awamori. Proteomics studies reveal changes in the secretory pathway

    Directory of Open Access Journals (Sweden)

    Kosalková Katarina

    2012-01-01

    Full Text Available Abstract Background The secretion of heterologous animal proteins in filamentous fungi is usually limited by bottlenecks in the vesicle-mediated secretory pathway. Results Using the secretion of bovine chymosin in Aspergillus awamori as a model, we found a drastic increase (40 to 80-fold in cells grown with casein or casein phosphopeptides (CPPs. CPPs are rich in phosphoserine, but phosphoserine itself did not increase the secretion of chymosin. The stimulatory effect is reduced about 50% using partially dephosphorylated casein and is not exerted by casamino acids. The phosphopeptides effect was not exerted at transcriptional level, but instead, it was clearly observed on the secretion of chymosin by immunodetection analysis. Proteomics studies revealed very interesting metabolic changes in response to phosphopeptides supplementation. The oxidative metabolism was reduced, since enzymes involved in fermentative processes were overrepresented. An oxygen-binding hemoglobin-like protein was overrepresented in the proteome following phosphopeptides addition. Most interestingly, the intracellular pre-protein enzymes, including pre-prochymosin, were depleted (most of them are underrepresented in the intracellular proteome after the addition of CPPs, whereas the extracellular mature form of several of these secretable proteins and cell-wall biosynthetic enzymes was greatly overrepresented in the secretome of phosphopeptides-supplemented cells. Another important 'moonlighting' protein (glyceraldehyde-3-phosphate dehydrogenase, which has been described to have vesicle fusogenic and cytoskeleton formation modulating activities, was clearly overrepresented in phosphopeptides-supplemented cells. Conclusions In summary, CPPs cause the reprogramming of cellular metabolism, which leads to massive secretion of extracellular proteins.

  14. Long-Term Field Study Reveals Subtle Effects of the Invasive Alga Sargassum muticum upon the Epibiota of Zostera marina

    Science.gov (United States)

    2015-01-01

    Invasive species can alter coastal ecosystems both directly, e.g. through competition for substratum and nutrients, and indirectly. Indirect effects may be mediated by creation of dissimilar or inimical habitats, changes in predator and/or prey assemblages, alterations in associated biota, and perturbations of water movement and thermal regimes. Previous studies have shown that invasive algae can modify native habitat architecture, disrupt intricately linked food webs and alter epibiotic assemblages. In the UK, the seagrass Zostera marina supports a diverse epibiotic assemblage, influencing key factors such as sediment dynamics, depositional regime and trophic linkages. Increasing encroachment of the invasive alga Sargassum muticum into seagrass meadows changes the physical and chemical characteristics of the local environment and creates the potential for changes in the epibionts associated with the seagrass blades, threatening the integrity of the seagrass ecosystem. We investigated the effects of S. muticum invasion upon the epibiota of Z. marina in a drowned river valley in SW England seasonally from spring to autumn over four years in an in-situ manipulative experiment, comparing permanent quadrats with and without artificially introduced S. muticum. Epibiota were weighed, identified to the most detailed operational taxonomic unit (OTU) possible, and unitary organisms were enumerated. Multivariate PERMANOVA+ analysis revealed significant differences in epibiont assemblages between Sargassum treatments. Linear mixed effects models indicated that differences in epibiota assemblage composition were not reflected as significant differences in mean biomass per sample, or number of epibiont OTUs per sample. We conclude that S. muticum invasion into Z. marina meadows may significantly alter the species composition and abundance distribution of epibiotic assemblages found on the blades of the seagrass. Thus S. muticum invasion could have more wide-reaching effects on

  15. Negative differential mobility for negative carriers as revealed by space charge measurements on crosslinked polyethylene insulated model cables

    Energy Technology Data Exchange (ETDEWEB)

    Teyssedre, G., E-mail: gilbert.teyssedre@laplace.univ-tlse.fr; Laurent, C. [Université de Toulouse, UPS, INPT, LAPLACE (Laboratoire Plasma et Conversion d' Energie), 118 route de Narbonne, F-31062 Toulouse cedex 9 (France); CNRS, LAPLACE, F-31062 Toulouse (France); Vu, T. T. N. [Université de Toulouse, UPS, INPT, LAPLACE (Laboratoire Plasma et Conversion d' Energie), 118 route de Narbonne, F-31062 Toulouse cedex 9 (France); Electric Power University, 235 Hoang Quoc Viet, 10000 Hanoi (Viet Nam)

    2015-12-21

    Among features observed in polyethylene materials under relatively high field, space charge packets, consisting in a pulse of net charge that remains in the form of a pulse as it crosses the insulation, are repeatedly observed but without complete theory explaining their formation and propagation. Positive charge packets are more often reported, and the models based on negative differential mobility(NDM) for the transport of holes could account for some charge packets phenomenology. Conversely, NDM for electrons transport has never been reported so far. The present contribution reports space charge measurements by pulsed electroacoustic method on miniature cables that are model of HVDC cables. The measurements were realized at room temperature or with a temperature gradient of 10 °C through the insulation under DC fields on the order 30–60 kV/mm. Space charge results reveal systematic occurrence of a negative front of charges generated at the inner electrode that moves toward the outer electrode at the beginning of the polarization step. It is observed that the transit time of the front of negative charge increases, and therefore the mobility decreases, with the applied voltage. Further, the estimated mobility, in the range 10{sup −14}–10{sup −13} m{sup 2} V{sup −1} s{sup −1} for the present results, increases when the temperature increases for the same condition of applied voltage. The features substantiate the hypothesis of negative differential mobility used for modelling space charge packets.

  16. Seismic tomography model reveals mantle magma sources of recent volcanic activity at El Hierro Island (Canary Islands, Spain)

    Science.gov (United States)

    García-Yeguas, Araceli; Ibáñez, Jesús M.; Koulakov, Ivan; Jakovlev, Andrey; Romero-Ruiz, M. Carmen; Prudencio, Janire

    2014-12-01

    We present a 3-D model of P and S velocities beneath El Hierro Island, constructed using the traveltime data of more than 13 000 local earthquakes recorded by the Instituto Geográfico Nacional (IGN, Spain) in the period from 2011 July to 2012 September. The velocity models were performed using the LOTOS code for iterative passive source tomography. The results of inversion were thoroughly verified using different resolution and robustness tests. The results reveal that the majority of the onshore area of El Hierro is associated with a high-velocity anomaly observed down to 10-12-km depth. This anomaly is interpreted as the accumulation of solid igneous rocks erupted during the last 1 Myr and intrusive magmatic bodies. Below this high-velocity pattern, we observe a low-velocity anomaly, interpreted as a batch of magma coming from the mantle located beneath El Hierro. The boundary between the low- and high-velocity anomalies is marked by a prominent seismicity cluster, thought to represent anomalous stresses due to the interaction of the batch of magma with crust material. The areas of recent eruptions, Orchilla and La Restinga, are associated with low-velocity anomalies surrounding the main high-velocity block. These eruptions took place around the island where the crust is much weaker than the onshore area and where the melted material cannot penetrate. These results put constraints on the geological model that could explain the origin of the volcanism in oceanic islands, such as in the Canaries, which is not yet clearly understood.

  17. The mass balance of the Greenland ice sheet: sensitivity to climate change as revealed by energy-balance modelling

    NARCIS (Netherlands)

    Oerlemans, J.

    1991-01-01

    The sensitivity of the mass balance of the Greenland ice sheet to climate change is studied with an energy-balance model of the ice/snow surface, applied at 200 m elevation intervals for four characteristic regions of the ice sheet. Solar radiation, longwave radiation, turbulent heat fluxes and refr

  18. Landmark study reveals low national rate of frog abnormalities on Wildlife Refuges

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This U.S. Fish and Wildlife Service news releases announces the publication of an unprecedented 10-year-study of abnormal amphibians on U.S. National Wildlife...

  19. Complex network models reveal correlations among network metrics, exercise intensity and role of body changes in the fatigue process

    Science.gov (United States)

    Pereira, Vanessa Helena; Gama, Maria Carolina Traina; Sousa, Filipe Antônio Barros; Lewis, Theodore Gyle; Gobatto, Claudio Alexandre; Manchado-Gobatto, Fúlvia Barros

    2015-05-01

    The aims of the present study were analyze the fatigue process at distinct intensity efforts and to investigate its occurrence as interactions at distinct body changes during exercise, using complex network models. For this, participants were submitted to four different running intensities until exhaustion, accomplished in a non-motorized treadmill using a tethered system. The intensities were selected according to critical power model. Mechanical (force, peak power, mean power, velocity and work) and physiological related parameters (heart rate, blood lactate, time until peak blood lactate concentration (lactate time), lean mass, anaerobic and aerobic capacities) and IPAQ score were obtained during exercises and it was used to construction of four complex network models. Such models have both, theoretical and mathematical value, and enables us to perceive new insights that go beyond conventional analysis. From these, we ranked the influences of each node at the fatigue process. Our results shows that nodes, links and network metrics are sensibility according to increase of efforts intensities, been the velocity a key factor to exercise maintenance at models/intensities 1 and 2 (higher time efforts) and force and power at models 3 and 4, highlighting mechanical variables in the exhaustion occurrence and even training prescription applications.

  20. Complex network models reveal correlations among network metrics, exercise intensity and role of body changes in the fatigue process.

    Science.gov (United States)

    Pereira, Vanessa Helena; Gama, Maria Carolina Traina; Sousa, Filipe Antônio Barros; Lewis, Theodore Gyle; Gobatto, Claudio Alexandre; Manchado-Gobatto, Fúlvia Barros

    2015-05-21

    The aims of the present study were analyze the fatigue process at distinct intensity efforts and to investigate its occurrence as interactions at distinct body changes during exercise, using complex network models. For this, participants were submitted to four different running intensities until exhaustion, accomplished in a non-motorized treadmill using a tethered system. The intensities were selected according to critical power model. Mechanical (force, peak power, mean power, velocity and work) and physiological related parameters (heart rate, blood lactate, time until peak blood lactate concentration (lactate time), lean mass, anaerobic and aerobic capacities) and IPAQ score were obtained during exercises and it was used to construction of four complex network models. Such models have both, theoretical and mathematical value, and enables us to perceive new insights that go beyond conventional analysis. From these, we ranked the influences of each node at the fatigue process. Our results shows that nodes, links and network metrics are sensibility according to increase of efforts intensities, been the velocity a key factor to exercise maintenance at models/intensities 1 and 2 (higher time efforts) and force and power at models 3 and 4, highlighting mechanical variables in the exhaustion occurrence and even training prescription applications.

  1. Mitochondrial dysfunction, oxidative stress and apoptosis revealed by proteomic and transcriptomic analyses of the striata in two mouse models of Parkinson’s disease

    Energy Technology Data Exchange (ETDEWEB)

    Chin, Mark H.; Qian, Weijun; Wang, Haixing; Petyuk, Vladislav A.; Bloom, Joshua S.; Sforza, Daniel M.; Lacan, Goran; Liu, Dahai; Khan, Arshad H.; Cantor, Rita M.; Bigelow, Diana J.; Melega, William P.; Camp, David G.; Smith, Richard D.; Smith, Desmond J.

    2008-02-10

    The molecular mechanisms underlying the changes in the nigrostriatal pathway in Parkinson disease (PD) are not completely understood. Here we use mass spectrometry and microarrays to study the proteomic and transcriptomic changes in the striatum of two mouse models of PD, induced by the distinct neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH). Proteomic analyses resulted in the identification and relative quantification of 912 proteins with two or more unique peptides and 85 proteins with significant abundance changes following neurotoxin treatment. Similarly, microarray analyses revealed 181 genes with significant changes in mRNA following neurotoxin treatment. The combined protein and gene list provides a clearer picture of the potential mechanisms underlying neurodegeneration observed in PD. Functional analysis of this combined list revealed a number of significant categories, including mitochondrial dysfunction, oxidative stress response and apoptosis. Additionally, codon usage and miRNAs may play an important role in translational control in the striatum. These results constitute one of the largest datasets integrating protein and transcript changes for these neurotoxin models with many similar endpoint phenotypes but distinct mechanisms.

  2. Multi-study integration of brain cancer transcriptomes reveals organ-level molecular signatures.

    Directory of Open Access Journals (Sweden)

    Jaeyun Sung

    Full Text Available We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein--Identification of Structured Signatures and Classifiers (ISSAC--that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood.

  3. An improved source model for aircraft interior noise studies

    Science.gov (United States)

    Mahan, J. R.; Fuller, C. R.

    1985-01-01

    There is concern that advanced turboprop engines currently being developed may produce excessive aircraft cabin noise level. This concern has stimulated renewed interest in developing aircraft interior noise reduction methods that do not significnatly increase take off weight. An existing analytical model for noise transmission into aircraft cabins was utilized to investigate the behavior of an improved propeller source model for use in aircraft interior noise studies. The new source model, a virtually rotating dipole, is shown to adequately match measured fuselage sound pressure distributions, including the correct phase relationships, for published data. The virtually rotating dipole is used to study the sensitivity of synchrophasing effectiveness to the fuselage sound pressure trace velocity distribution. Results of calculations are presented which reveal the importance of correctly modeling the surface pressure phase relations in synchrophasing and other aircraft interior noise studies.

  4. A STUDY OF THE DIVERSE T DWARF POPULATION REVEALED BY WISE

    Energy Technology Data Exchange (ETDEWEB)

    Mace, Gregory N.; Wright, Edward L.; McLean, Ian S. [Department of Physics and Astronomy, UCLA, 430 Portola Plaza, Box 951547, Los Angeles, CA 90095-1547 (United States); Davy Kirkpatrick, J.; Gelino, Christopher R.; Griffith, Roger L.; Mix, Katholeen; Beichman, Charles A.; Lowrance, Patrick J. [Infrared Processing and Analysis Center, MS 100-22, California Institute of Technology, Pasadena, CA 91125 (United States); Cushing, Michael C. [Department of Physics and Astronomy, MS 111, University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606-3328 (United States); Skrutskie, Michael F. [Department of Astronomy, University of Virginia, Charlottesville, VA 22904 (United States); Marsh, Kenneth A. [School of Physics and Astronomy, Cardiff University, Cardiff CF24 3AA (United Kingdom); Eisenhardt, Peter R. [NASA Jet Propulsion Laboratory, 4800 Oak Grove Drive, Pasadena, CA 91109 (United States); Thompson, Maggie A. [Department of Astrophysical Sciences, Princeton University, Peyton Hall, 4 Ivy Lane, Princeton, NJ 08544-1001 (United States); Bailey, Vanessa; Hinz, Philip M.; Knox, Russell P. [Steward Observatory, The University of Arizona, 933 N. Cherry Ave., Tucson, AZ 85721 (United States); Bloom, Joshua S. [Department of Astronomy, University of California, Berkeley, CA 94720 (United States); Burgasser, Adam J. [Department of Physics, University of California, San Diego, CA 92093 (United States); Fortney, Jonathan J., E-mail: gmace@astro.ucla.edu [Department of Astronomy and Astrophysics, University of California, Santa Cruz, CA 95064 (United States); and others

    2013-03-01

    We report the discovery of 87 new T dwarfs uncovered with the Wide-field Infrared Survey Explorer (WISE) and 3 brown dwarfs with extremely red near-infrared colors that exhibit characteristics of both L and T dwarfs. Two of the new T dwarfs are likely binaries with L7 {+-} 1 primaries and mid-type T secondaries. In addition, our follow-up program has confirmed 10 previously identified T dwarfs and 4 photometrically selected L and T dwarf candidates in the literature. This sample, along with the previous WISE discoveries, triples the number of known brown dwarfs with spectral types later than T5. Using the WISE All-Sky Source Catalog we present updated color-color and color-type diagrams for all the WISE-discovered T and Y dwarfs. Near-infrared spectra of the new discoveries are presented along with spectral classifications. To accommodate later T dwarfs we have modified the integrated flux method of determining spectral indices to instead use the median flux. Furthermore, a newly defined J-narrow index differentiates the early-type Y dwarfs from late-type T dwarfs based on the J-band continuum slope. The K/J indices for this expanded sample show that 32% of late-type T dwarfs have suppressed K-band flux and are blue relative to the spectral standards, while only 11% are redder than the standards. Comparison of the Y/J and K/J index to models suggests diverse atmospheric conditions and supports the possible re-emergence of clouds after the L/T transition. We also discuss peculiar brown dwarfs and candidates that were found not to be substellar, including two young stellar objects and two active galactic nuclei. The substantial increase in the number of known late-type T dwarfs provides a population that will be used to test models of cold atmospheres and star formation. The coolest WISE-discovered brown dwarfs are the closest of their type and will remain the only sample of their kind for many years to come.

  5. Genome-wide association study reveals regions associated with gestation length in two pig populations

    NARCIS (Netherlands)

    Hidalgo, A.M.; Lopes, M.S.; Harlizius, B.; Bastiaansen, J.W.M.

    2016-01-01

    Reproduction traits, such as gestation length (GLE), play an important role in dam line breeding in pigs. The objective of our study was to identify single nucleotide polymorphisms (SNPs) that are associated with GLE in two pig populations. Genotypes and deregressed breeding values were available

  6. The shady past of female boxers – what case studies in the USA reveal

    DEFF Research Database (Denmark)

    Pfister, Gertrud Ursula; Gems, Gerald

    2017-01-01

    This study attempts to rectify the invisibility of female boxers and to narrow a research gap by examining the careers of four prominent female champions who managed to excel in the sport despite the social, psychological and physical restrictions imposed by the gender order of American society...

  7. A Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens as Biomarkers

    NARCIS (Netherlands)

    Vehof, Jelle; Hysi, Pirro G.; Hammond, Christopher J.

    Purpose: To test the association between serum metabolites and dry eye disease (DED) using a hypothesisfree metabolomics approach. Design: Cross-sectional association study. Participants: A total of 2819 subjects from the population-representative TwinsUK cohort in the United Kingdom, with a mean

  8. Comparative study of the extracellular proteome of Sulfolobus species reveals limited secretion

    NARCIS (Netherlands)

    Ellen, Albert F.; Albers, Sonja-Verena; Driessen, Arnold J. M.

    2010-01-01

    Although a large number of potentially secreted proteins can be predicted on the basis of genomic distribution of signal sequence-bearing proteins, protein secretion in Archaea has barely been studied. A proteomic inventory and comparison of the growth medium proteins in three hyperthermoacidophiles

  9. How Can We Explain Poverty? Case Study of Dee Reveals the Complexities

    Science.gov (United States)

    Seccombe, Karen

    2011-01-01

    Many theories have been offered to explain why people are impoverished. This article by Karen Seccombe uses the case study of "Dee," a newly single mother, to explore four of the most common: individualism, social structuralism, the culture of poverty, and fatalism. She concludes that poverty is a highly complex phenomenon, and it is likely that…

  10. Comparative study of the human ficolins reveals unique features of Ficolin-3 (Hakata antigen)

    DEFF Research Database (Denmark)

    Hummelshoj, Tina; Fog, Lea Munthe; Madsen, Hans O;

    2007-01-01

    The ficolins and mannose-binding lectin (MBL) are collagen-like defence proteins that serve as recognition molecules in lectin complement pathway. Differential features that may indicate diverse functions of these proteins are poorly understood. In this study we compared important biological...

  11. A Methodological Self-Study of Quantitizing: Negotiating Meaning and Revealing Multiplicity

    Science.gov (United States)

    Seltzer-Kelly, Deborah; Westwood, Sean J.; Pena-Guzman, David M.

    2012-01-01

    This inquiry developed during the process of "quantitizing" qualitative data the authors had gathered for a mixed methods curriculum efficacy study. Rather than providing the intended rigor to their data coding process, their use of an intercoder reliability metric prompted their investigation of the multiplicity and messiness that, as they…

  12. Trends that FCS Education Should Address: A Delphi Study Reveals Top 16

    Science.gov (United States)

    Alexander, Karen L.; Davis, Kimberlee

    2011-01-01

    This study used the Delphi method to identify trends of importance to family and consumer sciences (FCS) education. A panel of 21 FCS education experts identified 16 trends and evaluated them by importance, desirability, feasibility, and confidence in validity of the trend. Nutrition appeared as a top priority, followed by consumer economics. The…

  13. Allelic association studies of genome wide association data can reveal errors in marker position assignments

    Directory of Open Access Journals (Sweden)

    Curtis David

    2007-06-01

    Full Text Available Abstract Background Genome wide association (GWA studies provide the opportunity to develop new kinds of analysis. Analysing pairs of markers from separate regions might lead to the detection of allelic association which might indicate an interaction between nearby genes. Methods 396,591 markers typed in 541 subjects were studied. 7.8*1010 pairs of markers were screened and those showing initial evidence for allelic association were subjected to more thorough investigation along with 10 flanking markers on either side. Results No evidence was detected for interaction. However 6 markers appeared to have an incorrect map position according to NCBI Build 35. One of these was corrected in Build 36 and 2 were dropped. The remaining 3 were left with map positions inconsistent with their allelic association relationships. Discussion Although no interaction effects were detected the method was successful in identifying markers with probably incorrect map positions. Conclusion The study of allelic association can supplement other methods for assigning markers to particular map positions. Analyses of this type may usefully be applied to data from future GWA studies.

  14. Ligand- and drug-binding studies of membrane proteins revealed through circular dichroism spectroscopy.

    Science.gov (United States)

    Siligardi, Giuliano; Hussain, Rohanah; Patching, Simon G; Phillips-Jones, Mary K

    2014-01-01

    A great number of membrane proteins have proven difficult to crystallise for use in X-ray crystallographic structural determination or too complex for NMR structural studies. Circular dichroism (CD) is a fast and relatively easy spectroscopic technique to study protein conformational behaviour. In this review examples of the applications of CD and synchrotron radiation CD (SRCD) to membrane protein ligand binding interaction studies are discussed. The availability of SRCD has been an important advancement in recent progress, most particularly because it can be used to extend the spectral region in the far-UV region (important for increasing the accuracy of secondary structure estimations) and for working with membrane proteins available in only small quantities for which SRCD has facilitated molecular recognition studies. Such studies have been accomplished by probing in the near-UV region the local tertiary structure of aromatic amino acid residues upon addition of chiral or non-chiral ligands using long pathlength cells of small volume capacity. In particular, this review describes the most recent use of the technique in the following areas: to obtain quantitative data on ligand binding (exemplified by the FsrC membrane sensor kinase receptor); to distinguish between functionally similar drugs that exhibit different mechanisms of action towards membrane proteins (exemplified by secretory phospholipase A2); and to identify suitable detergent conditions to observe membrane protein-ligand interactions using stabilised proteins (exemplified by the antiseptic transporter SugE). Finally, the importance of characterising in solution the conformational behaviour and ligand binding properties of proteins in both far- and near-UV regions is discussed. This article is part of a Special Issue entitled: Structural and biophysical characterisation of membrane protein-ligand binding. © 2013.

  15. Oncogene interactions are required for glioma development and progression as revealed by a tissue specific transgenic mouse model

    Institute of Scientific and Technical Information of China (English)

    Lynette M. Moore; Kristen M. Holmes; Gregory N. Fuller; Wei Zhang

    2011-01-01

    The aggressive and invasive nature of brain tumors has hampered progress in the design and implementation of efficacious therapies. The recent success of targeted therapies in other tumor types makes this an attractive area for research yet complicating matters is the ability of brain tumors to circumvent the targeted pathways to develop drug resistance. Effective therapies will likely need to target more than one signaling pathway or target multiple nodes within a given pathway. Key to identifying these targets is the elucidation of the driver and passenger molecules within these pathways. Animal models provide a useful tool with many advantages in the study of these pathways. These models provide a means to dissect the critical components of tumorigenesis, as well as serve as agents for preclinical testing. This review focuses on the use of the RCAS/tv-a mouse model of brain tumors and describes their unique ability to provide insight into the role of oncogene cooperation in tumor development and progression.

  16. A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.

    Science.gov (United States)

    Ng, Michael; Thakkar, Dipti; Southam, Lorraine; Werker, Paul; Ophoff, Roel; Becker, Kerstin; Nothnagel, Michael; Franke, Andre; Nürnberg, Peter; Espirito-Santo, Ana Isabel; Izadi, David; Hennies, Hans Christian; Nanchahal, Jagdeep; Zeggini, Eleftheria; Furniss, Dominic

    2017-09-07

    Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10(-8). As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Intermolecular interaction studies of winter flounder antifreeze protein reveal the existence of thermally accessible binding state.

    Science.gov (United States)

    Nguyen, Dat H; Colvin, Michael E; Yeh, Yin; Feeney, Robert E; Fink, William H

    2004-10-05

    The physical nature underlying intermolecular interactions between two rod-like winter flounder antifreeze protein (AFP) molecules and their implication for the mechanism of antifreeze function are examined in this work using molecular dynamics simulations, augmented with free energy calculations employing a continuum solvation model. The energetics for different modes of interactions of two AFP molecules is examined in both vacuum and aqueous phases along with the water distribution in the region encapsulated by two antiparallel AFP backbones. The results show that in a vacuum two AFP molecules intrinsically attract each other in the antiparallel fashion, where their complementary charge side chains face each other directly. In the aqueous environment, this attraction is counteracted by both screening and entropic effects. Therefore, two nearly energetically degenerate states, an aggregated state and a dissociated state, result as a new aspect of intermolecular interaction in the paradigm for the mechanism of action of AFP. The relevance of these findings to the mechanism of function of freezing inhibition in the context of our work on Antarctic cod antifreeze glycoprotein (Nguyen et al., Biophysical Journal, 2002, Vol. 82, pp. 2892-2905) is discussed.

  18. A Qualitative Study Revealing the Relationship Between Cultural Indicators and Attitudes Toward the Ads

    Directory of Open Access Journals (Sweden)

    Emine Sahin

    2014-12-01

    Full Text Available The companies, in International markets, are required to examine the attitudes and the behaviours to recognize the consumer to be able to make their products preferable under constantly growing competitive conditions. Therefore, it is of great importance to know cultural values of the customers in the country's where global brands compete and to shape ads which is one of the marketing communication tools in this direction. In this respect, knowing the cultural similarities or differences of the countries where the ads are used (such as that country's religion, language, norms and cultural values gains importance. The consumer attitudes towards the ads change in accordance with their cultural similarities or dissimilarities and this attitude change determines the tendency of shopping. According to Geert Hofstede, social anthropologist who analyzes the cultural levels and the relationships among them the basic elements of the culture consists of symbols, heroes, rituals and values underlying them. Thorough symbols, a number of cultural values are conveyed to ads. The problem of this study which was carried out in order to determine attitude change towards the ads including cultural differences is “Is there a difference in the attitudes towards the ads including different cultural symbols? How it is distributed according to gender differences?" In this study, a qualitative research method was applied and interviewed with 20 test subject. 20 students studying in one of the universities in Turkey were selected with formal sampling, they were asked questions, and it was tried to determine the difference between the ad of Doğuş Çay-a tea brand which uses the symbols and local accent of Black sea region in Turkey in its ads- and the ad of Lipton which is an international British tea brand. At the end of the study, it was found out that sample’s the attitude was positive towards ad of Doğuş Çay, not Lipton.

  19. Continuous acoustic studies of overwintering sprat Sprattus sprattus reveal flexible behavior

    KAUST Repository

    Solberg, I

    2012-09-19

    The clupeid fish Sprattus sprattus was studied in a 150 m deep Norwegian fjord throughout an entire overwintering period during which the fjord froze over and a major water renewal occurred. A bottom-mounted (upward-facing) echosounder provided continuous high-resolution data and enabled studies of swimming speed and behavior of individual sprat in addition to population behavior. The continuous acoustic studies were supplemented with intermittent field campaigns. The sprat displayed different behavioral modes with changing environmental conditions. During the first part of the winter, the majority of the population occurred in deep waters during both day and night, yet exhibited a shallower night-time distribution. Individual sprat swam alternately up and down, a ‘rise and sink’ behavior likely a compensation for negative buoyancy because of swim bladder compression. Because feeding was negligible in deep waters, the swimming pattern was not inferred as prey search behavior. Another part of the population schooled at shallower depths during the day and carried out vertical migration to upper waters at night. However, individuals were observed as they switched between these behavioral groups. A sudden change in both swimming behavior and vertical distribution occurred as the fjord became ice covered. Near-bottom ‘rise and sink’ swimming was replaced by schooling in mid-water during the day, and the sprat aggregated in dense layers near the surface at night. We suggest that the ice made the sprat shift their antipredator strategy from hiding at depth to hiding in schools in the darker waters below the ice. This long-term acoustic study has shown that sprat have a flexible behavioral repertoire, displaying different overwintering strategies within a population, depending on environmental conditions.

  20. a Model Study of Complex Behavior in the Belousov - Reaction.

    Science.gov (United States)

    Lindberg, David Mark

    1988-12-01

    We have studied the complex oscillatory behavior in a model of the Belousov-Zhabotinskii (BZ) reaction in a continuously-fed stirred tank reactor (CSTR). The model consisted of a set of nonlinear ordinary differential equations derived from a reduced mechanism of the chemical system. These equations were integrated numerically on a computer, which yielded the concentrations of the constituent chemicals as functions of time. In addition, solutions were tracked as functions of a single parameter, the stability of the solutions was determined, and bifurcations of the solutions were located and studied. The intent of this study was to use this BZ model to explore further a region of complex oscillatory behavior found in experimental investigations, the most thorough of which revealed an alternating periodic-chaotic (P-C) sequence of states. A P-C sequence was discovered in the model which showed the same qualitative features as the experimental sequence. In order to better understand the P-C sequence, a detailed study was conducted in the vicinity of the P-C sequence, with two experimentally accessible parameters as control variables. This study mapped out the bifurcation sets, and included examination of the dynamics of the stable periodic, unstable periodic, and chaotic oscillatory motion. Observations made from the model results revealed a rough symmetry which suggests a new way of looking at the P-C sequence. Other nonlinear phenomena uncovered in the model were boundary and interior crises, several codimension-two bifurcations, and similarities in the shapes of areas of stability for periodic orbits in two-parameter space. Each earlier model study of this complex region involved only a limited one-parameter scan and had limited success in producing agreement with experiments. In contrast, for those regions of complex behavior that have been studied experimentally, the observations agree qualitatively with our model results. Several new predictions of the model

  1. Genome-wide association study reveals regions associated with gestation length in two pig populations.

    Science.gov (United States)

    Hidalgo, A M; Lopes, M S; Harlizius, B; Bastiaansen, J W M

    2016-04-01

    Reproduction traits, such as gestation length (GLE), play an important role in dam line breeding in pigs. The objective of our study was to identify single nucleotide polymorphisms (SNPs) that are associated with GLE in two pig populations. Genotypes and deregressed breeding values were available for 2081 Dutch Landrace-based (DL) and 2301 Large White-based (LW) pigs. We identified two QTL regions for GLE, one in each population. For DL, three associated SNPs were detected in one QTL region spanning 0.52 Mbp on Sus scrofa chromosome (SSC) 2. For LW, four associated SNPs were detected in one region of 0.14 Mbp on SSC5. The region on SSC2 contains the heparin-binding EGF-like growth factor (HBEGF) gene, which promotes embryo implantation and has been described to be involved in embryo survival throughout gestation. The associated SNP can be used for marker-assisted selection in the studied populations, and further studies of the HBEGF gene are warranted to investigate its role in GLE.

  2. Domain complementation studies reveal residues critical for the activity of the mannitol permease from Escherichia coli.

    Science.gov (United States)

    Vos, Erwin P P; ter Horst, Ramon; Poolman, Bert; Broos, Jaap

    2009-02-01

    This paper presents domain complementation studies in the mannitol transporter, EIImtl, from Escherichia coli. EIImtl is responsible for the transport and concomitant phosphorylation of mannitol over the cytoplasmic membrane. By using tryptophan-less EIImtl as a basis, each of the four phenylalanines located in the cytoplasmic loop between putative transmembrane helices II and III in the membrane-embedded C domain were replaced by tryptophan, yielding the mutants W97, W114, W126, and W133. Except for W97, these single-tryptophan mutants exhibited a high, wild-type-like, binding affinity for mannitol. Of the four mutants, only W114 showed a high mannitol phosphorylation activity. EIImtl is functional as a dimer and the effect of these mutations on the oligomeric activity was investigated via heterodimer formation (C/C domain complementation studies). The low phosphorylation activities of W126 and W133 could be increased 7-28 fold by forming heterodimers with either the C domain of W97 (IICmtlW97) or the inactive EIImtl mutant G196D. W126 and W133, on the other hand, did not complement each other. This study points towards a role of positions 97, 126 and 133 in the oligomeric activation of EIImtl. The involvement of specific residue positions in the oligomeric functioning of a sugar-translocating EII protein has not been presented before.

  3. Transcriptome Profiling Reveals Degree of Variability in Induced Pluripotent Stem Cell Lines: Impact for Human Disease Modeling.

    Science.gov (United States)

    Schuster, Jens; Halvardson, Jonatan; Pilar Lorenzo, Laureanne; Ameur, Adam; Sobol, Maria; Raykova, Doroteya; Annerén, Göran; Feuk, Lars; Dahl, Niklas

    2015-10-01

    Induced pluripotent stem cell (iPSC) technology has become an important tool for disease modeling. Insufficient data on the variability among iPSC lines derived from a single somatic parental cell line have in practice led to generation and analysis of several, usually three, iPSC sister lines from each parental cell line. We established iPSC lines from a human fibroblast line (HDF-K1) and used transcriptome sequencing to investigate the variation among three sister lines (iPSC-K1A, B, and C). For comparison, we analyzed the transcriptome of an iPSC line (iPSC-K5B) derived from a different fibroblast line (HDF-K5), a human embryonic stem cell (ESC) line (ESC-HS181), as well as the two parental fibroblast lines. All iPSC lines fulfilled stringent criteria for pluripotency. In an unbiased cluster analysis, all stem cell lines (four iPSCs and one ESC) clustered together as opposed to the parental fibroblasts. The transcriptome profiles of the three iPSC sister lines were indistinguishable from each other, and functional pathway analysis did not reveal any significant hits. In contrast, the expression profiles of the ESC line and the iPSC-K5B line were distinct from that of the sister lines iPSC-K1A, B, and C. Differentiation to embryoid bodies and subsequent analysis of germ layer markers in the five stem cell clones confirmed that the distribution of their expression profiles was retained. Taken together, our observations stress the importance of using iPSCs of different parental origin rather than several sister iPSC lines to distinguish disease-associated mechanisms from genetic background effects in disease modeling.

  4. Large scale full-length cDNA sequencing reveals a unique genomic landscape in a lepidopteran model insect, Bombyx mori.

    Science.gov (United States)

    Suetsugu, Yoshitaka; Futahashi, Ryo; Kanamori, Hiroyuki; Kadono-Okuda, Keiko; Sasanuma, Shun-ichi; Narukawa, Junko; Ajimura, Masahiro; Jouraku, Akiya; Namiki, Nobukazu; Shimomura, Michihiko; Sezutsu, Hideki; Osanai-Futahashi, Mizuko; Suzuki, Masataka G; Daimon, Takaaki; Shinoda, Tetsuro; Taniai, Kiyoko; Asaoka, Kiyoshi; Niwa, Ryusuke; Kawaoka, Shinpei; Katsuma, Susumu; Tamura, Toshiki; Noda, Hiroaki; Kasahara, Masahiro; Sugano, Sumio; Suzuki, Yutaka; Fujiwara, Haruhiko; Kataoka, Hiroshi; Arunkumar, Kallare P; Tomar, Archana; Nagaraju, Javaregowda; Goldsmith, Marian R; Feng, Qili; Xia, Qingyou; Yamamoto, Kimiko; Shimada, Toru; Mita, Kazuei

    2013-09-01

    The establishment of a complete genomic sequence of silkworm, the model species of Lepidoptera, laid a foundation for its functional genomics. A more complete annotation of the genome will benefit functional and comparative studies and accelerate extensive industrial applications for this insect. To realize these goals, we embarked upon a large-scale full-length cDNA collection from 21 full-length cDNA libraries derived from 14 tissues of the domesticated silkworm and performed full sequencing by primer walking for 11,104 full-length cDNAs. The large average intron size was 1904 bp, resulting from a high accumulation of transposons. Using gene models predicted by GLEAN and published mRNAs, we identified 16,823 gene loci on the silkworm genome assembly. Orthology analysis of 153 species, including 11 insects, revealed that among three Lepidoptera including Monarch and Heliconius butterflies, the 403 largest silkworm-specific genes were composed mainly of protective immunity, hormone-related, and characteristic structural proteins. Analysis of testis-/ovary-specific genes revealed distinctive features of sexual dimorphism, including depletion of ovary-specific genes on the Z chromosome in contrast to an enrichment of testis-specific genes. More than 40% of genes expressed in specific tissues mapped in tissue-specific chromosomal clusters. The newly obtained FL-cDNA sequences enabled us to annotate the genome of this lepidopteran model insect more accurately, enhancing genomic and functional studies of Lepidoptera and comparative analyses with other insect orders, and yielding new insights into the evolution and organization of lepidopteran-specific genes.

  5. Feedback control strategies for spatial navigation revealed by dynamic modelling of learning in the Morris water maze.

    Science.gov (United States)

    Fey, Dirk; Commins, Sean; Bullinger, Eric

    2011-04-01

    The Morris water maze is an experimental procedure in which animals learn to escape swimming in a pool using environmental cues. Despite its success in neuroscience and psychology for studying spatial learning and memory, the exact mnemonic and navigational demands of the task are not well understood. Here, we provide a mathematical model of rat swimming dynamics on a behavioural level. The model consists of a random walk, a heading change and a feedback control component in which learning is reflected in parameter changes of the feedback mechanism. The simplicity of the model renders it accessible and useful for analysis of experiments in which swimming paths are recorded. Here, we used the model to analyse an experiment in which rats were trained to find the platform with either three or one extramaze cue. Results indicate that the 3-cues group employs stronger feedback relying only on the actual visual input, whereas the 1-cue group employs weaker feedback relying to some extent on memory. Because the model parameters are linked to neurological processes, identifying different parameter values suggests the activation of different neuronal pathways.

  6. Expression profiling of a genetic animal model of depression reveals novel molecular pathways underlying depressive-like behaviours.

    Directory of Open Access Journals (Sweden)

    Ekaterini Blaveri

    Full Text Available BACKGROUND: The Flinders model is a validated genetic rat model of depression that exhibits a number of behavioural, neurochemical and pharmacological features consistent with those observed in human depression. PRINCIPAL FINDINGS: In this study we have used genome-wide microarray expression profiling of the hippocampus and prefrontal/frontal cortex of Flinders Depression Sensitive (FSL and control Flinders Depression Resistant (FRL lines to understand molecular basis for the differences between the two lines. We profiled two independent cohorts of Flinders animals derived from the same colony six months apart, each cohort statistically powered to allow independent as well as combined analysis. Using this approach, we were able to validate using real-time-PCR a core set of gene expression differences that showed statistical significance in each of the temporally distinct cohorts, representing consistently maintained features of the model. Small but statistically significant increases were confirmed for cholinergic (chrm2, chrna7 and serotonergic receptors (Htr1a, Htr2a in FSL rats consistent with known neurochemical changes in the model. Much larger gene changes were validated in a number of novel genes as exemplified by TMEM176A, which showed 35-fold enrichment in the cortex and 30-fold enrichment in hippocampus of FRL animals relative to FSL. CONCLUSIONS: These data provide significant insights into the molecular differences underlying the Flinders model, and have potential relevance to broader depression research.

  7. Modeling human Coenzyme A synthase mutation in yeast reveals altered mitochondrial function, lipid content and iron metabolism

    Directory of Open Access Journals (Sweden)

    Camilla Ceccatelli Berti

    2015-04-01

    Full Text Available Mutations in nuclear genes associated with defective coenzyme A biosynthesis have been identified as responsible for some forms of neurodegeneration with brain iron accumulation (NBIA, namely PKAN and CoPAN. PKAN are defined by mutations in PANK2, encoding the pantothenate kinase 2 enzyme, that account for about 50% of cases of NBIA, whereas mutations in CoA synthase COASY have been recently reported as the second inborn error of CoA synthesis leading to CoPAN. As reported previously, yeast cells expressing the pathogenic mutation exhibited a temperature-sensitive growth defect in the absence of pantothenate and a reduced CoA content. Additional characterization revealed decreased oxygen consumption, reduced activities of mitochondrial respiratory complexes, higher iron content, increased sensitivity to oxidative stress and reduced amount of lipid droplets, thus partially recapitulating the phenotypes found in patients and establishing yeast as a potential model to clarify the pathogenesis underlying PKAN and CoPAN diseases.

  8. Nucleolus-tethering system (NoTS) reveals that assembly of photobodies follows a self-organization model.

    Science.gov (United States)

    Liu, Yin; Liu, Qi; Yan, Qingqing; Shi, Leilei; Fang, Yuda

    2014-04-01

    Protein-protein interactions play essential roles in regulating many biological processes. At the cellular level, many proteins form nuclear foci known as nuclear bodies in which many components interact with each other. Photobodies are nuclear bodies containing proteins for light-signaling pathways in plants. What initiates the formation of photobodies is poorly understood. Here we develop a nucleolar marker protein nucleolin2 (Nuc2)-based method called the nucleolus-tethering system (NoTS) by artificially tethering a protein of interest to the nucleolus to analyze the initiation of photobodies. A candidate initiator is evaluated by visualizing whether a protein fused with Nuc2 forms body-like structures at the periphery of the nucleolus, and other components are recruited to the de novo-formed bodies. The interaction between two proteins can also be revealed through relocation and recruitment of interacting proteins to the nucleolus. Using the NoTS, we test the interactions among components in photobodies. In addition, we demonstrate that components of photobodies such as CONSTITUTIVELY PHOTOMORPHOGENIC 1, photoreceptors, and transcription factors tethered to the nucleolus have the capacity to form body-like structures at the periphery of the nucleolus, which contain other components of photobodies, suggesting a self-organization model for the biogenesis of photobodies.

  9. Comprehensive analysis of ultrasonic vocalizations in a mouse model of fragile X syndrome reveals limited, call type specific deficits.

    Directory of Open Access Journals (Sweden)

    Snigdha Roy

    Full Text Available Fragile X syndrome (FXS is a well-recognized form of inherited mental retardation, caused by a mutation in the fragile X mental retardation 1 (Fmr1 gene. The gene is located on the long arm of the X chromosome and encodes fragile X mental retardation protein (FMRP. Absence of FMRP in fragile X patients as well as in Fmr1 knockout (KO mice results, among other changes, in abnormal dendritic spine formation and altered synaptic plasticity in the neocortex and hippocampus. Clinical features of FXS include cognitive impairment, anxiety, abnormal social interaction, mental retardation, motor coordination and speech articulation deficits. Mouse pups generate ultrasonic vocalizations (USVs when isolated from their mothers. Whether those social ultrasonic vocalizations are deficient in mouse models of FXS is unknown. Here we compared isolation-induced USVs generated by pups of Fmr1-KO mice with those of their wild type (WT littermates. Though the total number of calls was not significantly different between genotypes, a detailed analysis of 10 different categories of calls revealed that loss of Fmr1 expression in mice causes limited and call-type specific deficits in ultrasonic vocalization: the carrier frequency of flat calls was higher, the percentage of downward calls was lower and that the frequency range of complex calls was wider in Fmr1-KO mice compared to their WT littermates.

  10. Comparative analyses reveal potential uses of Brachypodium distachyon as a model for cold stress responses in temperate grasses

    Directory of Open Access Journals (Sweden)

    Li Chuan

    2012-05-01

    Full Text Available Abstract Background Little is known about the potential of Brachypodium distachyon as a model for low temperature stress responses in Pooideae. The ice recrystallization inhibition protein (IRIP genes, fructosyltransferase (FST genes, and many C-repeat binding factor (CBF genes are Pooideae specific and important in low temperature responses. Here we used comparative analyses to study conservation and evolution of these gene families in B. distachyon to better understand its potential as a model species for agriculturally important temperate grasses. Results Brachypodium distachyon contains cold responsive IRIP genes which have evolved through Brachypodium specific gene family expansions. A large cold responsive CBF3 subfamily was identified in B. distachyon, while CBF4 homologs are absent from the genome. No B. distachyon FST gene homologs encode typical core Pooideae FST-motifs and low temperature induced fructan accumulation was dramatically different in B. distachyon compared to core Pooideae species. Conclusions We conclude that B. distachyon can serve as an interesting model for specific molecular mechanisms involved in low temperature responses in core Pooideae species. However, the evolutionary history of key genes involved in low temperature responses has been different in Brachypodium and core Pooideae species. These differences limit the use of B. distachyon as a model for holistic studies relevant for agricultural core Pooideae species.

  11. Statistical models for stability studies

    OpenAIRE

    Uwimpuhwe, Germaine

    2015-01-01

    Stability studies are conducted at all phases of the drug development cycle, with the main objective of having a stable product on market. In this project we aimed at evaluating if the shelf life could be extended from 24 (current shelf life) to 36 months, quantifying pharmaceutical stability such as shelf life, release limit, degradation rate ( annually and at the end of both shelf lives) and consumer/producer risk. The assay data are longitudinal from 50 different batches, whi...

  12. A comprehensive immunoinformatics and target site study revealed the corner-stone toward Chikungunya virus treatment.

    Science.gov (United States)

    Hasan, Md Anayet; Khan, Md Arif; Datta, Amit; Mazumder, Md Habibul Hasan; Hossain, Mohammad Uzzal

    2015-05-01

    Recent concerning facts of Chikungunya virus (CHIKV); a Togaviridae family alphavirus has proved this as a worldwide emerging threat which causes Chikungunya fever and devitalizing arthritis. Despite severe outbreaks and lack of antiviral drug, a mere progress has been made regarding to an epitope-based vaccine designed for CHIKV. In this study, we aimed to design an epitope-based vaccine that can trigger a significant immune response as well as to prognosticate inhibitor that can bind with potential drug target sites by using various immunoinformatics and docking simulation tools. Initially, whole proteome of CHIKV was retrieved from database and perused to identify the most immunogenic protein. Structural properties of the selected protein were analyzed. The capacity to induce both humoral and cell-mediated immunity by T cell and B cell were checked for the selected protein. The peptide region spanning 9 amino acids from 397 to 405 and the sequence YYYELYPTM were found as the most potential B cell and T cell epitopes respectively. This peptide could interact with as many as 19 HLAs and showed high population coverage ranging from 69.50% to 84.94%. By using in silico docking techniques the epitope was further assessed for binding against HLA molecules to verify the binding cleft interaction. In addition with this, the allergenicity of the epitopes was also evaluated. In the post therapeutic strategy, three dimensional structure was predicted along with validation and verification that resulted in molecular docking study to identify the potential drug binding sites and suitable therapeutic inhibitor against targeted protein. Finally, pharmacophore study was also performed in quest of seeing potent drug activity. However, this computational epitope-based peptide vaccine designing and target site prediction against CHIKV opens up a new horizon which may be the prospective way in Chikungunya virus research; the results require validation by in vitro and in vivo

  13. Earthquake studies reveal the magmatic plumbing system of the Katmai volcanoes

    Science.gov (United States)

    Thurber, Clifford; Murphy, Rachel; Prejean, Stephanie G.; Haney, Matthew M.; Bennington, Ninfa; Powell, Lee; Paskievitch, John F.

    2012-01-01

    The 1912 eruption of Novarupta was the largest of the 1900s (Fierstein and Hildreth 2001, Hildreth et al. 2003). A century later, fundamental questions remain regarding the source of the magma for that eruption. A previous seismic study of the Katmai area (Jolly et al. 2007) identified a single large area of anomalous structure in the subsurface centered beneath Katmai Pass (Figure 2), but the magma source for the 1912 eruption is thought to have been beneath Mt. Katmai (Hildreth et al. 2003). This mystery was a prime motivation for the research project described here.

  14. Rumor Propagation Model: An Equilibrium Study

    Directory of Open Access Journals (Sweden)

    José Roberto C. Piqueira

    2010-01-01

    information is analogous phenomena. Here, in an analogy with the SIR (Susceptible-Infected-Removed epidemiological model, the ISS (Ignorant-Spreader-Stifler rumor spreading model is studied. By using concepts from the Dynamical Systems Theory, stability of equilibrium points is established, according to propagation parameters and initial conditions. Some numerical experiments are conducted in order to validate the model.

  15. Fine Particle Pollution, Alanine Transaminase, and Liver Cancer: A Taiwanese Prospective Cohort Study (REVEAL-HBV).

    Science.gov (United States)

    Pan, Wen-Chi; Wu, Chih-Da; Chen, Mu-Jean; Huang, Yen-Tsung; Chen, Chien-Jen; Su, Huey-Jen; Yang, Hwai-I

    2016-03-01

    Exposure to fine particulate matter (PM2.5) may promote hepatic tumorgenesis through low-grade inflammation. Therefore, we assessed the association of long-term exposure levels of PM2.5 and subsequent risk of hepatocellular carcinoma (HCC) and investigated the mediation effect of inflammation as represented by alanine aminotransferase (ALT) on this association. Between 1991 and 1992, we recruited 23 820 participants in Taiwan with no history of HCC. Case patients of HCC were ascertained through computerized data linkage with the National Cancer Registry and death certification systems. Participants' exposures to PM2.5 were based on a four-year average retrieved from stationary monitoring sites. Cox proportional hazards models were used to assess the association between PM2.5 exposure and HCC incidence. Mediation effects of ALT on PM2.5-associated HCC incidence were estimated. A total of 464 HCC cases were newly diagnosed with a median follow-up of 16.9 years. Statistically significantly increasing trends between PM2.5 exposures and ALT were observed on the Main Island and Penghu Islets. The adjusted hazard ratio (HR) for HCC on the Penghu Islets was 1.22 (95% confidence interval [CI] = 1.02 to 1.47) per PM2.5 interquartile range (IQR) increment (0.73 µg/m(3)) exposure. We also found a positive association between PM2.5 exposure (per IQR increment, 13.1 µg/m(3)) and HCC incidence on the Main Island. Furthermore, ALT had a statistically significant mediation effect on PM2.5-associated HCC incidence (HR = 1.17, 95% CI = 1.02 to1.52 on the Main Island; HR = 1.04, 95% CI = 1.03 to 1.07 on the Penghu Islets) per PM2.5 IQR increment. Long-term PM2.5 exposure increased the risk for liver cancer, and chronic inflammation of the liver may underlie the pathogenesis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. An fMRI Study of Audiovisual Speech Perception Reveals Multisensory Interactions in Auditory Cortex.

    Science.gov (United States)

    Okada, Kayoko; Venezia, Jonathan H; Matchin, William; Saberi, Kourosh; Hickok, Gregory

    2013-01-01

    Research on the neural basis of speech-reading implicates a network of auditory language regions involving inferior frontal cortex, premotor cortex and sites along superior temporal cortex. In audiovisual speech studies, neural activity is consistently reported in posterior superior temporal Sulcus (pSTS) and this site has been implicated in multimodal integration. Traditionally, multisensory interactions are considered high-level processing that engages heteromodal association cortices (such as STS). Recent work, however, challenges this notion and suggests that multisensory interactions may occur in low-level unimodal sensory cortices. While previous audiovisual speech studies demonstrate that high-level multisensory interactions occur in pSTS, what remains unclear is how early in the processing hierarchy these multisensory interactions may occur. The goal of the present fMRI experiment is to investigate how visual speech can influence activity in auditory cortex above and beyond its response to auditory speech. In an audiovisual speech experiment, subjects were presented with auditory speech with and without congruent visual input. Holding the auditory stimulus constant across the experiment, we investigated how the addition of visual speech influences activity in auditory cortex. We demonstrate that congruent visual speech increases the activity in auditory cortex.

  17. XMM-Newton reveals ~100 new LMXBs in M31 from variability studies

    CERN Document Server

    Barnard, R; Tonkin, C; Kolb, U; Osborne, J P

    2005-01-01

    We have conducted a survey of X-ray sources in XMM-Newton observations of M31, examining their power density spectra (PDS) and spectral energy distributions (SEDs). Our automated source detection yielded 535 good X-ray sources; to date, we have studied 225 of them. In particular, we examined the PDS because low mass X-ray binaries (LMXBs) exhibit two distinctive types of PDS. At low accretion rates, the PDS is characterised by a broken power law, with the spectral index changing from ~0 to ~1 at some frequency in the range \\~0.01--1 Hz; we refer to such PDS as Type A. At higher accretion rates, the PDS is described by a simple power law; we call these PDS Type B. Of the 225 sources studied to date, 75 exhibit Type A variability, and are almost certainly LMXBs, while 6 show Type B but not Type A, and are likely LMXBs. Of these 81 candidate LMXBs, 71 are newly identified in this survey; furthermore, they are mostly found near the centre of M31. Furthermore, most of the X-ray population in the disc are associate...

  18. Long-stay psychiatric patients: a prospective study revealing persistent antipsychotic-induced movement disorder.

    Directory of Open Access Journals (Sweden)

    P Roberto Bakker

    Full Text Available OBJECTIVE: The purpose of this study was to assess the frequency of persistent drug-induced movement disorders namely, tardive dyskinesia (TD, parkinsonism, akathisia and tardive dystonia in a representative sample of long-stay patients with chronic severe mental illness. METHOD: Naturalistic study of 209, mainly white, antipsychotic-treated patients, mostly diagnosed with psychotic disorder. Of this group, the same rater examined 194 patients at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. RESULTS: The frequencies of persistent movement disorders in the sample were 28.4% for TD, 56.2% for parkinsonism, 4.6% for akathisia and 5.7% for tardive dystonia. Two-thirds of the participants displayed at least one type of persistent movement disorder. CONCLUSIONS: Persistent movement disorder continues to be the norm for long-stay patients with chronic mental illness and long-term antipsychotic treatment. Measures are required to remedy this situation.

  19. Smartphones reveal angler behavior: A case study of a popular mobile fishing application in Alberta, Canada

    Science.gov (United States)

    Papenfuss, Jason T.; Phelps, Nicholas; Fulton, David C.; Venturelli, Paul A.

    2015-01-01

    Successfully managing fisheries and controlling the spread of invasive species depends on the ability to describe and predict angler behavior. However, finite resources restrict conventional survey approaches and tend to produce retrospective data that are limited in time or space and rely on intentions or attitudes rather than actual behavior. In this study, we used three years of angler data from a popular mobile fishing application in Alberta, Canada, to determine province-wide, seasonal patterns of (1) lake popularity that were consistent with conventional data and (2) anthropogenic lake connectivity that has not been widely described in North America. Our proof-of-concept analyses showed that mobile apps can be an inexpensive source of high-resolution, real-time data for managing fisheries and invasive species. We also identified key challenges that underscore the need for further research and development in this new frontier that combines big data with increased stakeholder interaction and cooperation.

  20. Reveal or Conceal? An Explorative Study of Signaling Strategies to Build Legitimacy in Cleantech Ventures

    DEFF Research Database (Denmark)

    Bjørnåli, Ekaterina; Giones, Ferran; Billström, Anders

    The emergence of cleantech industry offers a unique context to explore and develop entrepreneurship theories. Cleantech ventures are important agents of environmental innovation, they exploit technological knowledge contribute to an increased use of energy from renewable sources or to a more......, compared to high-tech ventures operating in more established (legitimized) industries. Zimmermann and Zeitz (2002) suggested that achieving a legitimacy threshold is related to the emergence of a new venture. However, from the stage-based theory perspective, gaining legitimacy is associated with overcoming...... critical junctures (Vohora et al. 2004). Instead of a unique threshold, cleantech ventures might have to build and sustain legitimacy across different stages, overcoming legitimacy thresholds (Fisher et al. 2016). Our study examines how cleantech ventures pursue the process of signaling towards external...

  1. Comparative study of the extracellular proteome of Sulfolobus species reveals limited secretion.

    Science.gov (United States)

    Ellen, Albert F; Albers, Sonja-Verena; Driessen, Arnold J M

    2010-01-01

    Although a large number of potentially secreted proteins can be predicted on the basis of genomic distribution of signal sequence-bearing proteins, protein secretion in Archaea has barely been studied. A proteomic inventory and comparison of the growth medium proteins in three hyperthermoacidophiles, i.e., Sulfolobus solfataricus, S. acidocaldarius and S. tokodaii, indicates that only few proteins are freely secreted into the growth medium and that the majority originates from cell envelope bound forms. In S. acidocaldarius both cell-associated and secreted alpha-amylase activities are detected. Inactivation of the amyA gene resulted in a complete loss of activity, suggesting that the same protein is responsible for the a-amylase activity at both locations. It is concluded that protein secretion in Sulfolobus is a limited process, and it is suggested that the S-layer may act as a barrier for the free diffusion of folded proteins into the medium.

  2. A biodistribution study of two differently shaped plant virus nanoparticles reveals new peculiar traits.

    Science.gov (United States)

    Lico, Chiara; Giardullo, Paola; Mancuso, Mariateresa; Benvenuto, Eugenio; Santi, Luca; Baschieri, Selene

    2016-12-01

    Self-assembling plant virus nanoparticles (pVNPs) have started to be explored as nanometre-sized objects for biomedical applications, such as vaccine or drug delivery and imaging. Plant VNPs may be ideal tools in terms of biocompatibility and biodegradability endowed with a wide diversity of symmetries and dimensions, easy chemical/biological engineering, and rapid production in plants. Recently, we defined that icosahedral Tomato bushy stunt virus (TBSV) and filamentous Potato virus X (PVX) are neither toxic nor teratogenic. We report here the results of an interdisciplinary study aimed to define for the first time the biodistribution of unlabelled, unpegylated, underivatized TBSV and PVX by proved detecting antibodies. These data add new insights on the in vivo behaviour of these nano-objects and demonstrate that the pVNPs under scrutiny are each intrinsically endowed with peculiar properties foreshadowing different applications in molecular medicine.

  3. A joint x-ray and neutron study on amicyanin reveals the role of protein dynamics in electron transfer.

    Science.gov (United States)

    Sukumar, N; Mathews, F S; Langan, P; Davidson, V L

    2010-04-13

    The joint x-ray/neutron diffraction model of the Type I copper protein, amicyanin from Paracoccus denitrificans was determined at 1.8 A resolution. The protein was crystallized using reagents prepared in D(2)O. About 86% of the amide hydrogen atoms are either partially or fully exchanged, which correlates well with the atomic depth of the amide nitrogen atom and the secondary structure type, but with notable exceptions. Each of the four residues that provide copper ligands is partially deuterated. The model reveals the dynamic nature of the protein, especially around the copper-binding site. A detailed analysis of the presence of deuterated water molecules near the exchange sites indicates that amide hydrogen exchange is primarily due to the flexibility of the protein. Analysis of the electron transfer path through the protein shows that residues in that region are highly dynamic, as judged by hydrogen/deuterium exchange. This could increase the rate of electron transfer by transiently shortening through-space jumps in pathways or by increasing the atomic packing density. Analysis of C-HX bonding reveals previously undefined roles of these relatively weak H bonds, which, when present in sufficient number can collectively influence the structure, redox, and electron transfer properties of amicyanin.

  4. Identification of Promising Mutants Associated with Egg Production Traits Revealed by Genome-Wide Association Study.

    Directory of Open Access Journals (Sweden)

    Jingwei Yuan

    Full Text Available Egg number (EN, egg laying rate (LR and age at first egg (AFE are important production traits related to egg production in poultry industry. To better understand the knowledge of genetic architecture of dynamic EN during the whole laying cycle and provide the precise positions of associated variants for EN, LR and AFE, laying records from 21 to 72 weeks of age were collected individually for 1,534 F2 hens produced by reciprocal crosses between White Leghorn and Dongxiang Blue-shelled chicken, and their genotypes were assayed by chicken 600 K Affymetrix high density genotyping arrays. Subsequently, pedigree and SNP-based genetic parameters were estimated and a genome-wide association study (GWAS was conducted on EN, LR and AFE. The heritability estimates were similar between pedigree and SNP-based estimates varying from 0.17 to 0.36. In the GWA analysis, we identified nine genome-wide significant loci associated with EN of the laying periods from 21 to 26 weeks, 27 to 36 weeks and 37 to 72 weeks. Analysis of GTF2A1 and CLSPN suggested that they influenced the function of ovary and uterus, and may be considered as relevant candidates. The identified SNP rs314448799 for accumulative EN from 21 to 40 weeks on chromosome 5 created phenotypic differences of 6.86 eggs between two homozygous genotypes, which could be potentially applied to the molecular breeding for EN selection. Moreover, our finding showed that LR was a moderate polygenic trait. The suggestive significant region on chromosome 16 for AFE suggested the relationship between sex maturity and immune in the current population. The present study comprehensively evaluates the role of genetic variants in the development of egg laying. The findings will be helpful to investigation of causative genes function and future marker-assisted selection and genomic selection in chickens.

  5. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

    Directory of Open Access Journals (Sweden)

    J Brent Richards

    2009-12-01

    Full Text Available The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D and coronary heart disease (CHD. We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531 and sought validation of the lead single nucleotide polymorphisms (SNPs in 5 additional cohorts (n = 6,202. Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8. We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19 for lead SNP, rs266717, n = 14,733. A novel variant in the ARL15 (ADP-ribosylation factor-like 15 gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8, n = 14,733. This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6, n = 22,421 more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3, n = 10,128, and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

  6. Systems Perturbation Analysis of a Large-Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics

    Science.gov (United States)

    Puniya, Bhanwar Lal; Allen, Laura; Hochfelder, Colleen; Majumder, Mahbubul; Helikar, Tomáš

    2016-01-01

    Dysregulation in signal transduction pathways can lead to a variety of complex disorders, including cancer. Computational approaches such as network analysis are important tools to understand system dynamics as well as to identify critical components that could be further explored as therapeutic targets. Here, we performed perturbation analysis of a large-scale signal transduction model in extracellular environments that stimulate cell death, growth, motility, and quiescence. Each of the model’s components was perturbed under both loss-of-function and gain-of-function mutations. Using 1,300 simulations under both types of perturbations across various extracellular conditions, we identified the most and least influential components based on the magnitude of their influence on the rest of the system. Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins. The most influential components under all environmental conditions were enriched with several biological processes. The inositol pathway was found as most influential under inactivating perturbations, whereas the kinase and small lung cancer pathways were identified as the most influential under activating perturbations. The most influential components were enriched with essential genes and druggable proteins. Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network. Additionally, the systemic perturbation analysis of the model revealed a network motif of most influential components which affect each other. Furthermore, our analysis predicted novel combinations of cancer drug targets with various effects on other most influential components. We found that the combinatorial perturbation consisting of PI3K inactivation and overactivation of IP3R1 can lead to increased activity levels of apoptosis

  7. Computational Model Reveals Limited Correlation between Germinal Center B-Cell Subclone Abundancy and Affinity: Implications for Repertoire Sequencing

    Science.gov (United States)

    Reshetova, Polina; van Schaik, Barbera D. C.; Klarenbeek, Paul L.; Doorenspleet, Marieke E.; Esveldt, Rebecca E. E.; Tak, Paul-Peter; Guikema, Jeroen E. J.; de Vries, Niek; van Kampen, Antoine H. C.

    2017-01-01

    Immunoglobulin repertoire sequencing has successfully been applied to identify expanded antigen-activated B-cell clones that play a role in the pathogenesis of immune disorders. One challenge is the selection of the Ag-specific B cells from the measured repertoire for downstream analyses. A general feature of an immune response is the expansion of specific clones resulting in a set of subclones with common ancestry varying in abundance and in the number of acquired somatic mutations. The expanded subclones are expected to have BCR affinities for the Ag higher than the affinities of the naive B cells in the background population. For these reasons, several groups successfully proceeded or suggested selecting highly abundant subclones from the repertoire to obtain the Ag-specific B cells. Given the nature of affinity maturation one would expect that abundant subclones are of high affinity but since repertoire sequencing only provides information about abundancies, this can only be verified with additional experiments, which are very labor intensive. Moreover, this would also require knowledge of the Ag, which is often not available for clinical samples. Consequently, in general we do not know if the selected highly abundant subclone(s) are also the high(est) affinity subclones. Such knowledge would likely improve the selection of relevant subclones for further characterization and Ag screening. Therefore, to gain insight in the relation between subclone abundancy and affinity, we developed a computational model that simulates affinity maturation in a single GC while tracking individual subclones in terms of abundancy and affinity. We show that the model correctly captures the overall GC dynamics, and that the amount of expansion is qualitatively comparable to expansion observed from B cells isolated from human lymph nodes. Analysis of the fraction of high- and low-affinity subclones among the unexpanded and expanded subclones reveals a limited correlation between

  8. Study of LPG Release & Dispersion Model

    Institute of Scientific and Technical Information of China (English)

    Mu Shanjun; Peng Xiangwei

    2003-01-01

    The current applicable release & dispersion models are reviewed. A typical model is developed on the basis of LPG storage conditions in China and the authors' research. The study is focused on the relationship between LPG composition and release rate, and on the influence of buildings or structures located in the surrounding area on the dispersion of gas plume. The established model is compared with existing models by the use of published field test data.

  9. Hereditary angioedema nationwide study in Slovenia reveals four novel mutations in SERPING1 gene.

    Directory of Open Access Journals (Sweden)

    Matija Rijavec

    Full Text Available Hereditary angioedema (HAE is a rare autosomal dominant disease characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intra-abdominal edema. HAE is caused by mutations affecting the C1 inhibitor gene, SERPING1, resulting in low levels of C1 inhibitor (Type I HAE or normal levels of ineffective C1 inhibitor (Type II HAE. A nationwide survey identified nine unrelated families with HAE in Slovenia, among whom 17 individuals from eight families were recruited for genetic analyses. A diagnosis of HAE was established in the presence of clinical and laboratory criteria (low C1 inhibitor antigenic levels and/or function, followed up by a positive family history. Genetic studies were carried out using PCR and sequencing to detect SERPING1 mutations in promoter, noncoding exon 1, the 7 coding exons, and exon-intron boundaries. Multiplex ligation-dependent probe amplification was performed in order to search for large deletions/duplications in SERPING1 gene. A mutation responsible for HAE was identified in patients from seven families with the disease. In HAE type I families, one previously reported substitution (Gln67Stop, c.265C>T and four novel mutations were identified. The new mutations included two missense substitutions, Ser128Phe (c.449C>T, and Glu429Lys (c.1351G>A, together with two frameshift mutations, indel (c.49delGinsTT and deletion (c.593_594delCT. Both families with HAE type II harbored the two well-known substitutions affecting the arginyl residue at the reactive center in exon 8, Arg444Cys (c.1396C>T and Arg444His (c.1397G>A, respectively. In one patient only the homozygous variant g.566T>C (c.-21T>C was identified. Our study identified four novel mutations in the Slovenian HAE population, highlighting the heterogeneity of mutations in the SERPING1 gene causing C1 inhibitor deficiency and HAE. In a single patient with HAE a homozygous variant g.566T>C (c.-21T>C might be

  10. QCD and Standard Model Studies

    Energy Technology Data Exchange (ETDEWEB)

    Gagliardi, Carl A [Texas A & M Univ., College Station, TX (United States)

    2017-02-28

    Our group has focused on using jets in STAR to investigate the longitudinal and transverse spin structure of the proton. We performed measurements of the longitudinal double-spin asymmetry for inclusive jet production that provide the strongest evidence to date that the gluons in the proton with x>0.05 are polarized. We also made the first observation of the Collins effect in pp collisions, thereby providing an important test of the universality of the Collins fragmentation function and opening a new tool to probe quark transversity in the proton. Our studies of forward rapidity electromagnetic jet-like events raise serious question whether the large transverse spin asymmetries that have been seen for forward inclusive hadron production arise from conventional 2 → 2 parton scattering. This is the final technical report for DOE Grant DE-FG02-93ER40765. It covers activities during the period January 1, 2015 through November 30, 2016.

  11. Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders

    NARCIS (Netherlands)

    H. Wesseling (Hendrik); P.C. Guest (Paul); C.-M. Lee (Chi-Ming); E.H.F. Wong (Erik); H. Rahmoune (Hassan); S. Bahn (Sabine)

    2014-01-01

    textabstractBackground: Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1neo-/-) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symp

  12. Drawings of Blood Cells Reveal People's Perception of Their Blood Disorder: A Pilot Study.

    Directory of Open Access Journals (Sweden)

    Steven Ramondt

    Full Text Available Sickle cell disease (SCD and thalassemia are rare but chronic blood disorders. Recent literature showed impaired quality of life (QOL in people with these blood disorders. Assessing one of the determinants of QOL (i.e. illness perceptions therefore, is an important next research area.We aimed to explore illness perceptions of people with a blood disorder with drawings in addition to the Brief Illness Perception Questionnaire (Brief IPQ. Drawings are a novel method to assess illness perceptions and the free-range answers drawings offer can add additional insight into how people perceive their illness.We conducted a cross-sectional study including 17 participants with a blood disorder. Participants' illness perceptions were assessed by the Brief IPQ and drawings. Brief IPQ scores were compared with reference groups from the literature (i.e. people with asthma or lupus erythematosus.Participants with SCD or thalassemia perceived their blood disorder as being more chronic and reported more severe symptoms than people with either asthma or lupus erythematosus. In the drawings of these participants with a blood disorder, a greater number of blood cells drawn was negatively correlated with perceived personal control (P<0.05, indicating that a greater quantity in the drawing is associated with more negative or distressing beliefs.Participants with a blood disorder perceive their disease as fairly threatening compared with people with other chronic illnesses. Drawings can add additional insight into how people perceive their illness by offering free-range answers.

  13. [Salmonella typhi vaccination response study reveals defective antibody production selective IgA deficiency patient].

    Science.gov (United States)

    Pleguezuelo, Daniel E; Gianelli, Carla

    2015-01-01

    Selective IgA deficiency (SIgAD) is the most prevalent immunodeficiency worldwide, progressing to common variable immunodeficiency only in few reported cases. We report the case of a Spanish female aged 22 and diagnosed of selective IgA deficiency, a long history of bronchitis, several episodes of pneumonia, bilateral bronchiectasis, normal IgG, IgM, IgG subclasses, and detectable pre-vaccination IgG antibodies against tetanus toxoid and Streptococcus pneumoniae. She was evaluated in our clinic in order to rule out common variable immunodeficiency. We observed good antibody response to tetanus toxoid, absence of circulating switched memory B cells, decreased response to pneumococcal polysaccharide antigens and a lack of response to Salmonella typhi vaccine. Most SIgAD patients presents with upper respiratory tract infections or mild diarrhea. Those with lower tract infections, pneumonia or untreatable diarrhea should follow B-cell subpopulations' study and antibody response to vaccines. Absence of response to Salmonella typhi vaccine allowed us to expose the defective antibody production.

  14. Dating rice remains through phytolith carbon-14 study reveals domestication at the beginning of the Holocene.

    Science.gov (United States)

    Zuo, Xinxin; Lu, Houyuan; Jiang, Leping; Zhang, Jianping; Yang, Xiaoyan; Huan, Xiujia; He, Keyang; Wang, Can; Wu, Naiqin

    2017-06-20

    Phytolith remains of rice (Oryza sativa L.) recovered from the Shangshan site in the Lower Yangtze of China have previously been recognized as the earliest examples of rice cultivation. However, because of the poor preservation of macroplant fossils, many radiocarbon dates were derived from undifferentiated organic materials in pottery sherds. These materials remain a source of debate because of potential contamination by old carbon. Direct dating of the rice remains might serve to clarify their age. Here, we first validate the reliability of phytolith dating in the study region through a comparison with dates obtained from other material from the same layer or context. Our phytolith data indicate that rice remains retrieved from early stages of the Shangshan and Hehuashan sites have ages of approximately 9,400 and 9,000 calibrated years before the present, respectively. The morphology of rice bulliform phytoliths indicates they are closer to modern domesticated species than to wild species, suggesting that rice domestication may have begun at Shangshan during the beginning of the Holocene.

  15. Spine anatomy reveals the diversity of catfish through time: a case study of Synodontis (Siluriformes)

    Science.gov (United States)

    Pinton, Aurélie; Fara, Emmanuel; Otero, Olga

    2006-01-01

    Synodontis (Mochokidae, Siluriformes) is a freshwater catfish endemic to Africa. The 118 extant species are present in almost all hydrographic basins. Some species are restricted to a single stream, whereas others have a vast distribution. Synodontis is known in the fossil record since the Miocene, and its history depends on the connections among African basins through time. The identification of species in the fossil record is essential to reconstruct this historical pattern. Catfish pectoral and dorsal spines are robust, they preserve well and they form most of the fossil remains for the genus Synodontis. Unfortunately, the criteria for the identification of extant Synodontis species are not applicable to fossil specimens. Here, we define 11 original morphological characters that permit to discriminate four extant species from the Chad-Chari hydrographic system. Six of these characters are defined on pectoral spines and five on dorsal spines. We then show that these characters can be used successfully for identifying fossil specimens. In particular, we present a case study in which we identify Synodontis cf. schall and Brachysynodontis cf. batensoda in the hominid-bearing sector Toros-Menalla (Late Miocene, northern Chad). We show that spine anatomy can be a powerful tool to recognise catfish species through time and thus to identify historical diversity pattern.

  16. Genetic and socioeconomic study of mate choice in Latinos reveals novel assortment patterns.

    Science.gov (United States)

    Zou, James Y; Park, Danny S; Burchard, Esteban G; Torgerson, Dara G; Pino-Yanes, Maria; Song, Yun S; Sankararaman, Sriram; Halperin, Eran; Zaitlen, Noah

    2015-11-01

    Nonrandom mating in human populations has important implications for genetics and medicine as well as for economics and sociology. In this study, we performed an integrative analysis of a large cohort of Mexican and Puerto Rican couples using detailed socioeconomic attributes and genotypes. We found that in ethnically homogeneous Latino communities, partners are significantly more similar in their genomic ancestries than expected by chance. Consistent with this, we also found that partners are more closely related--equivalent to between third and fourth cousins in Mexicans and Puerto Ricans--than matched random male-female pairs. Our analysis showed that this genomic ancestry similarity cannot be explained by the standard socioeconomic measurables alone. Strikingly, the assortment of genomic ancestry in couples was consistently stronger than even the assortment of education. We found enriched correlation of partners' genotypes at genes known to be involved in facial development. We replicated our results across multiple geographic locations. We discuss the implications of assortment and assortment-specific loci on disease dynamics and disease mapping methods in Latinos.

  17. Adsorption of arsenic and phosphate onto the surface of calcite as revealed by batch experiments and surface complexation modelling

    DEFF Research Database (Denmark)

    Sø, Helle Ugilt

    The adsorption of phosphate, arsenate (As(V)) and arsenite (As(III)) onto synthetic calcite was studied in a series of batch experiments. The adsorption of the three ions was studied separately followed by studies of the competition between arsenate and phosphate. The experimental data was utilized...... is complete after 1 and 2-3 hours, respectively). Also desorption is fast and complete for both ions within 0.5 h. The reversibility of the sorption process indicates that neither arsenate nor phosphate is readily incorporated into the calcite crystal lattice under our experimental conditions. The phosphate....... This clearly shows the importance of competition studies in validating multicomponent models. Extrapolation of the experimental results to calcite bearing aquifers suggests a large variability in the mobility of arsenic. Under reduced conditions, arsenite, which does not adsorb onto calcite, will dominate and...

  18. Genomic markers reveal introgressive hybridization in the Indo-West Pacific mangroves: a case study.

    Directory of Open Access Journals (Sweden)

    Mei Sun

    Full Text Available Biodiversity of mangrove ecosystems is difficult to assess, at least partly due to lack of genetic verification of morphology-based documentation of species. Natural hybridization, on the one hand, plays an important role in evolution as a source of novel gene combinations and a mechanism of speciation. However, on the other hand, recurrent introgression allows gene flow between species and could reverse the process of genetic differentiation among populations required for speciation. To understand the dynamic evolutionary consequences of hybridization, this study examines genomic structure of hybrids and parental species at the population level. In the Indo-West Pacific, Bruguiera is one of the dominant mangrove genera and species ranges overlap extensively with one another. Morphological intermediates between sympatric Bruguiera gymnorrhiza and Bruguiera sexangula have been reported as a variety of B. sexangula or a new hybrid species, B. × rhynchopetala. However, the direction of hybridization and extent of introgression are unclear. A large number of species-specific inter-simple sequence repeat (ISSR markers were found in B. gymnorrhiza and B. sexangula, and the additive ISSR profiling of B. × rhynchopetala ascertained its hybrid status and identified its parental origin. The varying degree of scatterness among hybrid individuals in Principal Coordinate Analysis and results from NewHybrids analysis indicate that B. × rhynchopetala comprises different generations of introgressants in addition to F(1s. High genetic relatedness between B. × rhynchopetala and B. gymnorrhiza based on nuclear and chloroplast sequences suggests preferential hybrid backcrosses to B. gymnorrhiza. We conclude that B. × rhynchopetala has not evolved into an incipient hybrid species, and its persistence can be explained by recurrent hybridization and introgression. Genomic data provide insights into the hybridization dynamics of mangrove plants. Such information

  19. Comparative mitogenomic analysis reveals cryptic species: A case study in Mactridae (Mollusca: Bivalvia).

    Science.gov (United States)

    Shen, Xin; Meng, Xue Ping; Chu, Ka Hou; Zhao, Na Na; Tian, Mei; Liang, Meng; Hao, Jue

    2014-12-01

    The Chinese surf clam Mactra chinensis Philippi, 1846 is a commercially important marine bivalve belonging to the family Mactridae (Mollusca: Bivalvia). In this study, the M. chinensis mitochondrial genomic features are analyzed. The genome has 34 genes on the same strand, lacking atp8 and both trnS (trnS1 and trnS2) as compared with the typical gene content of metazoan mitochondrial genomes. The A+T content of M. chinensis mitochondrial genome is 63.72%, which is slightly lower than that of M. veneriformis (67.59%) and Coelomactra antiquata (64.33% and 64.14% for the samples from Ri Zhao, Shandong Province, and Zhang Zhou, Fujian Province, China, respectively) in the same family. There are 22 NCRs in the M. chinensis mitochondrial genome, accounting for 12.91% of the genome length. The longest NCR (1,075bp in length) is located between trnT and trnQ. A TRS (127bp×8.15) accounts for 96.3% (1,035/1,075) of this NCR. The occurrence of TRS in NCR is shared by the two Mactra mitochondrial genomes, but is not found in the two Coelomactra mitochondrial genomes. A phylogenetic tree constructed based on 12 PCGs of 25 bivalve mitochondrial genomes shows that all seven genera (Mactra, Coelomactra, Paphia, Meretrix, Solen, Mytilus, and Crassostrea) constitute monophyletic groups with very high support values. Pairwise genetic distance analyses indicate that the genetic distance of C. antiquata from the two localities is 0.084, which is greater than values between congeneric species, such as those in Mactra, Mytilus, Meretrix, and Crassostrea. The results show that the C. antiquata from the two localities represent cryptic species. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Association Studies and Legume Synteny Reveal Haplotypes Determining Seed Size in Vigna unguiculata.

    Science.gov (United States)

    Lucas, Mitchell R; Huynh, Bao-Lam; da Silva Vinholes, Patricia; Cisse, Ndiaga; Drabo, Issa; Ehlers, Jeffrey D; Roberts, Philip A; Close, Timothy J

    2013-01-01

    Highly specific seed market classes for cowpea and other grain legumes exist because grain is most commonly cooked and consumed whole. Size, shape, color, and texture are critical features of these market classes and breeders target development of cultivars for market acceptance. Resistance to biotic and abiotic stresses that are absent from elite breeding material are often introgressed through crosses to landraces or wild relatives. When crosses are made between parents with different grain quality characteristics, recovery of progeny with acceptable or enhanced grain quality is problematic. Thus genetic markers for grain quality traits can help in pyramiding genes needed for specific market classes. Allelic variation dictating the inheritance of seed size can be tagged and used to assist the selection of large seeded lines. In this work we applied 1,536-plex SNP genotyping and knowledge of legume synteny to characterize regions of the cowpea genome associated with seed size. These marker-trait associations will enable breeders to use marker-based selection approaches to increase the frequency of progeny with large seed. For 804 individuals derived from eight bi-parental populations, QTL analysis was used to identify markers linked to 10 trait determinants. In addition, the population structure of 171 samples from the USDA core collection was identified and incorporated into a genome-wide association study which supported more than half of the trait-associated regions important in the bi-parental populations. Seven of the total 10 QTLs were supported based on synteny to seed size associated regions identified in the related legume soybean. In addition to delivering markers linked to major trait determinants in the context of modern breeding, we provide an analysis of the diversity of the USDA core collection of cowpea to identify genepools, migrants, admixture, and duplicates.

  1. Imaging studies in congenital anophthalmia reveal preservation of brain architecture in 'visual' cortex.

    Science.gov (United States)

    Bridge, Holly; Cowey, Alan; Ragge, Nicola; Watkins, Kate

    2009-12-01

    The functional specialization of the human brain means that many regions are dedicated to processing a single sensory modality. When a modality is absent, as in congenital total blindness, 'visual' regions can be reliably activated by non-visual stimuli. The connections underlying this functional adaptation, however, remain elusive. In this study, using structural and diffusion-weighted magnetic resonance imaging, we investigated the structural differences in the brains of six bilaterally anophthalmic subjects compared with sighted subjects. Surprisingly, the gross structural differences in the brains were small, even in the occipital lobe where only a small region of the primary visual cortex showed a bilateral reduction in grey matter volume in the anophthalmic subjects compared with controls. Regions of increased cortical thickness were apparent on the banks of the Calcarine sulcus, but not in the fundus. Subcortically, the white matter volume around the optic tract and internal capsule in anophthalmic subjects showed a large decrease, yet the optic radiation volume did not differ significantly. However, the white matter integrity, as measured with fractional anisotropy showed an extensive reduction throughout the brain in the anophthalmic subjects, with the greatest difference in the optic radiations. In apparent contradiction to the latter finding, the connectivity between the lateral geniculate nucleus and primary visual cortex measured with diffusion tractography did not differ between the two populations. However, these findings can be reconciled by a demonstration that at least some of the reduction in fractional anisotropy in the optic radiation is due to an increase in the strength of fibres crossing the radiations. In summary, the major changes in the 'visual' brain in anophthalmic subjects may be subcortical, although the evidence of decreased fractional anisotropy and increased crossing fibres could indicate considerable re-organization.

  2. Mechanisms of radiation strengthening in Fe–Cr alloys as revealed by atomistic studies

    Energy Technology Data Exchange (ETDEWEB)

    Terentyev, D.; Bonny, G. [Structural Materials Modelling and Microstructure Unit, SMA/NMS, Studiecentrum voor Kernenergie, Centre d’Etudes de l’Energie Nucléaire (SCK-CEN), Boeretang 200, 2400 Mol (Belgium); Domain, C.; Monnet, G. [EDF-R and D, Département MMC, Les Renardières, 77818 Moret sur Loing Cedex (France); Malerba, L., E-mail: lmalerba@sckcen.be [Structural Materials Modelling and Microstructure Unit, SMA/NMS, Studiecentrum voor Kernenergie, Centre d’Etudes de l’Energie Nucléaire (SCK-CEN), Boeretang 200, 2400 Mol (Belgium)

    2013-11-15

    A review of experimental results shows that the dependence on Cr content of radiation-induced strengthening in Fe–Cr alloys and ferritic/martensitic steels is peculiar, exhibiting an increase as soon as Cr is added, followed by a local maximum and then a local minimum. This dependence is to date unexplained. In this paper we try to rationalise it, by reviewing recent (published and unpublished) molecular dynamics simulations work, devoted to the investigation of several possible mechanisms of radiation strengthening in Fe–Cr. In particular, the following questions are addressed quantitatively: (i) Does Cr influence the glide of dislocations? If so, how? (ii) Does Cr influence the interaction between dislocations and radiation-produced defects? If so, why? The latter question involves also a study of the interaction of moving dislocations with experimentally observed Cr-enriched loops. We find that the fact of shifting from a loop-absorption (pure Fe) to a loop-non-absorption (Fe–Cr) regime, because of the Cr–enrichment of loops, contributes to explaining why Fe–Cr alloys harden more under irradiation than Fe. If, in addition, the existence of a large density of invisible and Cr-enriched loops is postulated, the origin of the effect becomes even more clear. Moreover, the different strength of 〈1 1 1〉 and 〈1 0 0〉 loops as obstacles to dislocations movement, depending on whether or not loop absorption can occur, might explain why radiation strengthening decreases between 2% and 9%Cr. The formation of α′ precipitates, on the other hand, explains why radiation strengthening increases again above 9%Cr. Altogether, these effects might explain the origin of the minimum of radiation-induced embrittlement at 9%Cr, as correlated to strengthening.

  3. Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology.

    Directory of Open Access Journals (Sweden)

    John R Shaffer

    2016-08-01

    Full Text Available Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array imputed to the 1000 Genomes reference panel (Phase 3. We observed genome-wide significant associations (p < 5 x 10-8 for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

  4. Association studies and legume synteny reveal haplotypes determining seed size in Vigna unguiculata

    Directory of Open Access Journals (Sweden)

    Mitchell R Lucas

    2013-04-01

    Full Text Available Highly specific seed market classes for cowpea and other grain legumes exists because grain is most commonly cooked and consumed whole. Size, shape, color, and texture are critical features of these market classes and breeders target development of cultivars for market acceptance. Resistance to biotic and abiotic stresses that are absent from elite breeding material are often introgressed through crosses to landraces or wild relatives. When crosses are made between parents with different grain quality characteristics, recovery of progeny with acceptable or enhanced grain quality is problematic. Thus genetic markers for grain quality traits can help in pyramiding genes needed for specific market classes. Allelic variation dictating the inheritance of seed size can be tagged and used to assist the selection of large-seeded lines. In this work we applied SNP genotyping and knowledge of legume synteny to characterize regions of the cowpea genome associated with seed size. These marker-trait associations will enable breeders to use marker based selection approaches to increase the frequency of progeny with large seed. For ~800 samples derived from eight bi-parental populations, QTL analysis was used to identify markers linked to ten trait determinants. In addition, the population structure of 171 samples from the USDA core collection was identified and incorporated into a genome-wide association study which supported more than half of the trait-associated regions important in the bi-parental populations. Seven of the total ten QTL were supported based on synteny to seed size associated regions identified in the related legume soybean. In addition to delivering markers linked to major trait determinants in the context of modern breeding, we provide an analysis of the diversity of the USDA core collection of cowpea to identify genepools, migrants, admixture, and duplicates.

  5. Revealing anti-cariogenic efficacy of smokeless tobacco: A pilot study

    Directory of Open Access Journals (Sweden)

    Ankita Tandon

    2013-01-01

    Full Text Available Background: The tobacco plant, Nicotiana tabacum, has been responsible for more deaths than any other herb. However, the literature has also been endowed with its use as "holy herb" since the pre-Columbian era. Used for treating pain, poisonous bites, ulcers, nasal polyps, and basal cell carcinoma; it also acts as an important ingredient of commercially available toothpastes; and even used as tobacco vaccines against Streptococcus species as highlighted in the literature. Aims and Objectives: (1 To elicit the anti-microbial property of tobacco against Streptococcus mutans, if any, in raw smokeless tobacco. (2 To study the relationship of duration and growth inhibition efficacy of smokeless tobacco. Materials and Methods: Extracts were prepared by centrifugation of mixed raw smokeless tobacco with Ringer′s lactate solution and with saliva. The extracts were placed in wells prepared on Mitis salivarius culture plate and incubated at 37΀C for 24 h after 0 h, 1 h, and 2 h of extract preparation. The inhibition zones were measured on the underside of plate using the vernier calipers. Results: Smokeless tobacco has a statistically significant zone of inhibition, which proves its anti-microbial activity against S. mutans. However, the mean zones of inhibition were greater for Ringer′s lactate and tobacco group as compared to test samples (saliva and tobacco with subsequent reduction of inhibition zones with an increase in duration. Conclusion: The anti-microbial property of extensive tobacco resources can be utilized from their extracts in order to balance the deterioration it had caused to mankind.

  6. Metabolomic Profiles of Body Mass Index in the Framingham Heart Study Reveal Distinct Cardiometabolic Phenotypes.

    Directory of Open Access Journals (Sweden)

    Jennifer E Ho

    Full Text Available Although obesity and cardiometabolic traits commonly overlap, underlying pathways remain incompletely defined. The association of metabolite profiles across multiple cardiometabolic traits may lend insights into the interaction of obesity and metabolic health. We sought to investigate metabolic signatures of obesity and related cardiometabolic traits in the community using broad-based metabolomic profiling.We evaluated the association of 217 assayed metabolites and cross-sectional as well as longitudinal changes in cardiometabolic traits among 2,383 Framingham Offspring cohort participants. Body mass index (BMI was associated with 69 of 217 metabolites (P<0.00023 for all, including aromatic (tyrosine, phenylalanine and branched chain amino acids (valine, isoleucine, leucine. Additional metabolic pathways associated with BMI included the citric acid cycle (isocitrate, alpha-ketoglutarate, aconitate, the tryptophan pathway (kynurenine, kynurenic acid, and the urea cycle. There was considerable overlap in metabolite profiles between BMI, abdominal adiposity, insulin resistance [IR] and dyslipidemia, modest overlap of metabolite profiles between BMI and hyperglycemia, and little overlap with fasting glucose or elevated blood pressure. Metabolite profiles were associated with longitudinal changes in fasting glucose, but the involved metabolites (ornithine, 5-HIAA, aminoadipic acid, isoleucine, cotinine were distinct from those associated with baseline glucose or other traits. Obesity status appeared to "modify" the association of 9 metabolites with IR. For example, bile acid metabolites were strongly associated with IR among obese but not lean individuals, whereas isoleucine had a stronger association with IR in lean individuals.In this large-scale metabolite profiling study, body mass index was associated with a broad range of metabolic alterations. Metabolite profiling highlighted considerable overlap with abdominal adiposity, insulin resistance

  7. A general model of distant hybridization reveals the conditions for extinction in Atlantic salmon and brown trout.

    Directory of Open Access Journals (Sweden)

    Claudio S Quilodrán

    Full Text Available Interspecific hybridization is common in nature but can be increased in frequency or even originated by human actions, such as species introduction or habitat modification, which may threaten species persistence. When hybridization occurs between distantly related species, referred to as "distant hybridization," the resulting hybrids are generally infertile or fertile but do not undergo chromosomal recombination during gametogenesis. Here, we present a model describing this frequent but poorly studied interspecific hybridization to assess its consequences on parental species and to anticipate the conditions under which they can reach extinction. Our general model fully incorporates three important processes: density-dependent competition, dominance/recessivity inheritance of traits and assortative mating. We demonstrate its use and flexibility by assessing population extinction risk between Atlantic salmon and brown trout in Norway, whose interbreeding has recently increased due to farmed fish releases into the wild. We identified the set of conditions under which hybridization may threaten salmonid species. Thanks to the flexibility of our model, we evaluated the effect of an additional risk factor, a parasitic disease, and showed that the cumulative effects dramatically increase the extinction risk. The consequences of distant hybridization are not genetically, but demographically mediated. Our general model is useful to better comprehend the evolution of such hybrid systems and we demonstrated its importance in the field of conservation biology to set up management recommendations when this increasingly frequent type of hybridization is in action.

  8. Validation of a Prediction Model for Vaginal Birth after Cesarean Delivery Reveals Unexpected Success in a Diverse American Population

    Science.gov (United States)

    Maykin, Melanie Mai; Mularz, Amanda J.; Lee, Lydia K.; Valderramos, Stephanie Gaw

    2017-01-01

    Objective To investigate the validity of a prediction model for success of vaginal birth after cesarean delivery (VBAC) in an ethnically diverse population. Methods We performed a retrospective cohort study of women admitted at a single academic institution for a trial of labor after cesarean from May 2007 to January 2015. Individual predicted success rates were calculated using the Maternal–Fetal Medicine Units Network prediction model. Participants were stratified into three probability-of-success groups: low (65%). The actual versus predicted success rates were compared. Results In total, 568 women met inclusion criteria. Successful VBAC occurred in 402 (71%), compared with a predicted success rate of 66% (p = 0.016). Actual VBAC success rates were higher than predicted by the model in the low (57 vs. 29%; p < 0.001) and moderate (61 vs. 52%; p = 0.003) groups. In the high probability group, the observed and predicted VBAC rates were the same (79%). Conclusion When the predicted success rate was above 65%, the model was highly accurate. In contrast, for women with predicted success rates <35%, actual VBAC rates were nearly twofold higher in our population, suggesting that they should not be discouraged by a low prediction score.

  9. New gene models and alternative splicing in the maize pathogen Colletotrichum graminicola revealed by RNA-Seq analysis.

    Science.gov (United States)

    Schliebner, Ivo; Becher, Rayko; Hempel, Marcus; Deising, Holger B; Horbach, Ralf

    2014-10-02

    An annotated genomic sequence of the corn anthracnose fungus Colletotrichum graminicola has been published previously, but correct identification of gene models by means of automated gene annotation remains a challenge. RNA-Seq offers the potential for substantially improved gene annotations and for the identification of posttranscriptional RNA modifications, such as alternative splicing and RNA editing. Based on the nucleotide sequence information of transcripts, we identified 819 novel transcriptionally active regions (nTARs) and revised 906 incorrectly predicted gene models, including revisions of exon-intron structure, gene orientation and sequencing errors. Among the nTARs, 146 share significant similarity with proteins that have been identified in other species suggesting that they are hitherto unidentified genes in C. graminicola. Moreover, 5'- and 3'-UTR sequences of 4378 genes have been retrieved and alternatively spliced variants of 69 genes have been identified. Comparative analysis of RNA-Seq data and the genome sequence did not provide evidence for RNA editing in C. graminicola. We successfully employed deep sequencing RNA-Seq data in combination with an elaborate bioinformatics strategy in order to identify novel genes, incorrect gene models and mechanisms of transcript processing in the corn anthracnose fungus C. graminicola. Sequence data of the revised genome annotation including several hundreds of novel transcripts, improved gene models and candidate genes for alternative splicing have been made accessible in a comprehensive database. Our results significantly contribute to both routine laboratory experiments and large-scale genomics or transcriptomic studies in C. graminicola.

  10. Functional magnetic resonance imaging reveals abnormal brain connectivity in EGR3 gene transfected rat model of schizophrenia.

    Science.gov (United States)

    Song, Tianbin; Nie, Binbin; Ma, Ensen; Che, Jing; Sun, Shilong; Wang, Yuli; Shan, Baoci; Liu, Yawu; Luo, Senlin; Ma, Guolin; Li, Kefeng

    2015-05-01

    Schizophrenia is characterized by the disorder of "social brain". However, the alternation of connectivity density in brain areas of schizophrenia patients remains largely unknown. In this study, we successfully created a rat model of schizophrenia by the transfection of EGR3 gene into rat brain. We then investigated the connectivity density of schizophrenia susceptible regions in rat brain using functional magnetic resonance imaging (fMRI) in combination with multivariate Granger causality (GC) model. We found that the average signal strength in prefrontal lobe and hippocampus of schizophrenia model group was significantly higher than the control group. Bidirectional Granger causality connection was observed between hippocampus and thalamic in schizophrenia model group. Both connectivity density and Granger causality connection were changed in prefrontal lobe, hippocampus and thalamus after risperidone treatment. Our results indicated that fMRI in combination with GC connection analysis may be used as an important method in diagnosis of schizophrenia and evaluation the effect of antipsychotic treatment. These findings support the connectivity disorder hypothesis of schizophrenia and increase our understanding of the neural mechanisms of schizophrenia.

  11. Validation of a Prediction Model for Vaginal Birth after Cesarean Delivery Reveals Unexpected Success in a Diverse American Population.

    Science.gov (United States)

    Maykin, Melanie Mai; Mularz, Amanda J; Lee, Lydia K; Valderramos, Stephanie Gaw

    2017-01-01

    Objective To investigate the validity of a prediction model for success of vaginal birth after cesarean delivery (VBAC) in an ethnically diverse population. Methods We performed a retrospective cohort study of women admitted at a single academic institution for a trial of labor after cesarean from May 2007 to January 2015. Individual predicted success rates were calculated using the Maternal-Fetal Medicine Units Network prediction model. Participants were stratified into three probability-of-success groups: low (65%). The actual versus predicted success rates were compared. Results In total, 568 women met inclusion criteria. Successful VBAC occurred in 402 (71%), compared with a predicted success rate of 66% (p = 0.016). Actual VBAC success rates were higher than predicted by the model in the low (57 vs. 29%; p success rate was above 65%, the model was highly accurate. In contrast, for women with predicted success rates <35%, actual VBAC rates were nearly twofold higher in our population, suggesting that they should not be discouraged by a low prediction score.

  12. Neospora caninum tachyzoite immunome study reveals differences among three biologically different isolates.

    Science.gov (United States)

    Regidor-Cerrillo, Javier; García-Lunar, Paula; Pastor-Fernández, Iván; Álvarez-García, Gema; Collantes-Fernández, Esther; Gómez-Bautista, Mercedes; Ortega-Mora, Luis M

    2015-09-15

    Pathogenesis of bovine neosporosis is determined by different host- and parasite-dependent factors, including isolate virulence. A previous study identified that several Neospora caninum tachyzoite proteins were more abundant in virulent isolates, Nc-Liv and Nc-Spain7, compared with the low-virulent isolate Nc-Spain1H. Herein, we explored differences in the immunomes of these three isolates. Protein extracts from the Nc-Liv, Nc-Spain1H and Nc-Spain7 isolates were analysed in a 3×3 design by 2-DE immunoblot using sera from experimentally infected mice with these same three isolates. All isolates displayed a highly similar antigenic pattern when they were assessed using the same serum. Most of the reactive spots were located in the acidic region (pH 3-7) and grouped in 3 antigenic areas (250-70, 45-37 and 35-15 KDa). Differences found in the immunome depended on the sera used, regardless of the extract employed. In this sense, sera from Nc-Liv and Nc-Spain7 infected mice recognized the highest number of antigens, followed by Nc-Spain1H infected mice sera. In fact, 4 proteins identified by MS were not consistently detected in each isolate extract by sera from low-virulent Nc-Spain1H-infected mice: serine-threonine phosphatase 2C and superoxide dismutase (related to metabolism), gliding associated protein GAP45 (related to tachyzoites invasion), and NcGRA1 (located on dense granules). Similarly, 4 non-identified spots and another 2 spots chains located in 45-37 kDa area were not detected by this pooled sera. Variations between virulent Nc-Spain7 and Nc-Liv were limited to the absence of recognition by sera from Nc-Spain7-infected mice of GAP45 and the spot chains located in the 45-37 kDa area. These results suggest that variations in the immunome profiles rely on the immune response induced by each isolate and that these differentially recognized antigens could be investigated as putative virulence markers of neosporosis.

  13. A human ESC model for MLL-AF4 leukemic fusion gene reveals an impaired early hematopoietic-endothelial specification

    Institute of Scientific and Technical Information of China (English)

    Clara Bueno; Agustin F Femández; Mario F Fraga; Inmaculada Moreno-Gimeno; Deborah Burks; Maria del Carmen Plaza-Calonge; Juan C Rodríguez-Manzaneque; Pablo Menendez; Rosa Montes; Gustavo J Melen; Verónica Ramos-Mejia; Pedro J Real; Verónica Ayllón; Laura Sanchez; Gertrudis Ligero; Iván Gutierrez-Aranda

    2012-01-01

    The MLL-AF4 fusion gene is a hallmark genomic aberration in high-risk acute lymphoblastic leukemia in inants.Although it is well established that MLL-AF4 arises prenatally during human development,its effects on hematopoieric development in utero remain unexplored.We have created a human-specific cellular system to study early hemato-endothelial development in MLL-AF4-expressing human embryonic stem cells (hESCs).Functional studies,clonal analysis and gene expression profiling reveal that expression of MLL-AF4 in hESCs has a phenotypic,functional and gene expression impact.MLL-AF4 acts as a global transcriptional activator and a positive regulator of homeobox gene expression in hESCs.Functionally,MLL-AF4 enhances the specification of hemogenic precursors from hESCs but strongly impairs further hematopoietic commitment in favor of an endothelial cell fate.MLL-AF4 hESCs are transcriptionally primed to differentiate towards hemogenic precursors prone to endothelial maturation,as reflected by the marked upregulation of master genes associated to vascular-endothelial functions and early hematopoiesis.Furthermore,we report that MLL-AF4 expression is not sufficient to transform hESC-derived hematopoietic cells.This work illustrates how hESCs may provide unique insights into human development and further our understanding of how leukemic fusion genes,known to arise prenatally,regulate human embryonic hematopoietic specification.

  14. Molecular and phenotypic characterization of a mouse model of oculopharyngeal muscular dystrophy reveals severe muscular atrophy restricted to fast glycolytic fibres.

    Science.gov (United States)

    Trollet, Capucine; Anvar, Seyed Yahya; Venema, Andrea; Hargreaves, Iain P; Foster, Keith; Vignaud, Alban; Ferry, Arnaud; Negroni, Elisa; Hourde, Christophe; Baraibar, Martin A; 't Hoen, Peter A C; Davies, Janet E; Rubinsztein, David C; Heales, Simon J; Mouly, Vincent; van der Maarel, Silvère M; Butler-Browne, Gillian; Raz, Vered; Dickson, George

    2010-06-01

    Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)(8-13) expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets.

  15. Revealing Rembrandt

    Directory of Open Access Journals (Sweden)

    Andrew J Parker

    2014-04-01

    Full Text Available The power and significance of artwork in shaping human cognition is self-evident. The starting point for our empirical investigations is the view that the task of neuroscience is to integrate itself with other forms of knowledge, rather than to seek to supplant them. In our recent work, we examined a particular aspect of the appreciation of artwork using present-day functional magnetic resonance imaging (fMRI. Our results emphasised the continuity between viewing artwork and other human cognitive activities. We also showed that appreciation of a particular aspect of artwork, namely authenticity, depends upon the co-ordinated activity between the brain regions involved in multiple decision making and those responsible for processing visual information. The findings about brain function probably have no specific consequences for understanding how people respond to the art of Rembrandt in comparison with their response to other artworks. However, the use of images of Rembrandt’s portraits, his most intimate and personal works, clearly had a significant impact upon our viewers, even though they have been spatially confined to the interior of an MRI scanner at the time of viewing. Neuroscientific studies of humans viewing artwork have the capacity to reveal the diversity of human cognitive responses that may be induced by external advice or context as people view artwork in a variety of frameworks and settings.

  16. Psoriasis and Diabetes: A Multicenter Study in 222078 Type 2 Diabetes Patients Reveals High Levels of Depression

    Directory of Open Access Journals (Sweden)

    Anke Schwandt

    2015-01-01

    Full Text Available Objective. This study aimed to investigate the association between psoriasis and disease outcome in type 2 diabetes (T2D. Methods. 222078 T2D patients (≥10 years old from the prospective, multicenter diabetes patient registry were analyzed. Specific search items were used to identify psoriasis patients. Multiple regression models were fitted and adjusted for demographic confounder. Results. 232 T2D patients had comorbid psoriasis. After adjusting psoriasis patients revealed a higher BMI (31.8 [31.0; 32.6] versus 30.6 [30.5; 30.6] kg/m2, p=0.004 and HbA1c (64.8 [62.1; 67.6] versus 59.0 [58.9; 59.1] mmol/mol, p<0.0001. Insulin was used more frequently (62.3 [55.7; 68.5] versus 50.9 [50.7; 51.1] %, p=0.001, only OAD/GLP-1 was similar, and nonpharmacological treatment was less common (13.3 [9.5; 18.3] versus 21.9 [21.7; 22.1] %, p=0.002. Severe hypoglycemia (0.31 [0.238; 0.399] versus 0.06 [0.057; 0.060] events per patient-year, p<0.0001, hypertension (86.1 [81.1; 90.0] versus 68.0 [67.8; 68.2] %, p<0.0001, and thyroid disease (14.0 [10.1; 19.2] versus 4.6 [4.5; 4.7] %, p<0.0001 were more prevalent. Depression occurred more often (10.5 [7.1; 15.2] versus 2.8 [2.7; 2.8] %, p<0.0001. Conclusions. Clinical diabetes characteristics in psoriasis T2D patients were clearly worse compared to patients without psoriasis. Comorbid conditions and depression were more prevalent, and more intensive diabetes therapy was required.

  17. Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation.

    Science.gov (United States)

    Reyes-Reyes, E Merit; Šalipur, Francesca R; Shams, Mitra; Forsthoefel, Matthew K; Bates, Paula J

    2015-08-01

    AS1411 is a G-rich quadruplex-forming oligodeoxynucleotide that binds specifically to nucleolin, a protein found on the surface and in the cytoplasm of most malignant cells but absent from the surface/cytoplasm of most normal cells. AS1411 has shown promising clinical activity and is being widely used as a tumor-targeting agent, but its mechanism of action is not fully understood. Previously, we showed that AS1411 is taken up in cancer cells by macropinocytosis (fluid phase endocytosis) and subsequently stimulates further macropinocytosis by a nucleolin-dependent mechanism. In the current study, we have investigated the significance and molecular mechanisms of AS1411-induced macropinocytosis. Our results indicate that the antiproliferative activity of AS1411 in various cell lines correlated with its capacity to stimulate macropinocytosis. In DU145 prostate cancer cells, AS1411 induced activation of EGFR, Akt, p38, and Rac1. Activation of Akt and p38 were not critical for AS1411 activity because Akt activation was not observed in all AS1411-responsive cell lines and knockdown of p38 had no effect on AS1411's ability to inhibit proliferation. On the other hand, activation of EGFR and Rac1 appeared to play a role in AS1411 activity in all cancer cell lines examined (DU145, MDA-MB-468, A549, LNCaP) and their inhibition significantly reduced AS1411-mediated macropinocytosis and AS1411 antiproliferative activity. Interestingly, downregulation of nucleolin expression by siRNA also produced a substantial increase in activated Rac1, revealing a previously unknown role for nucleolin as a negative regulator of Rac1 activation. Our results are consistent with a model whereby AS1411 binding to nucleolin leads to sustained activation of Rac1 and causes methuosis, a novel type of nonapoptotic cell death characterized by hyperstimulation of macropinocytosis. We speculate that methuosis is a tumor/metastasis suppressor mechanism that opposes the malignant functions of Rac1 and that

  18. Mouse Models for Studying Diabetic Nephropathy.

    Science.gov (United States)

    Chow, Bryna S M; Allen, Terri J

    2015-06-01

    Diabetic nephropathy (DN) is a term used to describe kidney damage cause by diabetes. With DN as one of the leading causes of end-stage renal disease worldwide, there is a strong need for appropriate animal models to study DN pathogenesis and develop therapeutic strategies. To date, most experiments are carried out in mouse models as opposed to other species for several reasons including lower cost, ease of handling, and easy manipulation of the mouse genome to generate transgenic and knockout animals. This unit provides detailed insights and technical knowledge in setting up one of the most widely used models of DN, the streptozotocin (STZ)-induced model. This model has been extensively exploited to study the mechanism of diabetic renal injury. The advantages and limitations of the STZ model and the availability of other genetic models of DN are also discussed.

  19. Hypermutation signature reveals a slippage and realignment model of translesion synthesis by Rev3 polymerase in cisplatin-treated yeast.

    Science.gov (United States)

    Segovia, Romulo; Shen, Yaoqing; Lujan, Scott A; Jones, Steven J M; Stirling, Peter C

    2017-02-21

    Gene-gene or gene-drug interactions are typically quantified using fitness as a readout because the data are continuous and easily measured in high throughput. However, to what extent fitness captures the range of other phenotypes that show synergistic effects is usually unknown. Using Saccharomyces cerevisiae and focusing on a matrix of DNA repair mutants and genotoxic drugs, we quantify 76 gene-drug interactions based on both mutation rate and fitness and find that these parameters are not connected. Independent of fitness defects, we identified six cases of synthetic hypermutation, where the combined effect of the drug and mutant on mutation rate was greater than predicted. One example occurred when yeast lacking RAD1 were exposed to cisplatin, and we characterized this interaction using whole-genome sequencing. Our sequencing results indicate mutagenesis by cisplatin in rad1Δ cells appeared to depend almost entirely on interstrand cross-links at GpCpN motifs. Interestingly, our data suggest that the following base on the template strand dictates the addition of the mutated base. This result differs from cisplatin mutation signatures in XPF-deficient Caenorhabditis elegans and supports a model in which translesion synthesis polymerases perform a slippage and realignment extension across from the damaged base. Accordingly, DNA polymerase ζ activity was essential for mutagenesis in cisplatin-treated rad1Δ cells. Together these data reveal the potential to gain new mechanistic insights from nonfitness measures of gene-drug interactions and extend the use of mutation accumulation and whole-genome sequencing analysis to define DNA repair mechanisms.

  20. Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder.

    Directory of Open Access Journals (Sweden)

    Md Suhail Alam

    Full Text Available Niemann-Pick Type C (NPC disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/- mice relative to Npc1(+/- at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/- as well as Balb/c Npc1(nmf164 mice (bearing a point mutation closer to human disease mutants and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/- mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/- spleen and liver (where large foci were detected proximal to damaged tissue. Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs

  1. Joint Profiling of miRNAs and mRNAs Reveals miRNA Mediated Gene Regulation in the Göttingen Minipig Obesity Model.

    Science.gov (United States)

    Mentzel, Caroline M Junker; Alkan, Ferhat; Keinicke, Helle; Jacobsen, Mette J; Gorodkin, Jan; Fredholm, Merete; Cirera, Susanna

    2016-01-01

    Obesity and its comorbidities are an increasing challenge for both affected individuals and health care systems, worldwide. In obese individuals, perturbation of expression of both protein-coding genes and microRNAs (miRNA) are seen in obesity-relevant tissues (i.e. adipose tissue, liver and skeletal muscle). miRNAs are small non-coding RNA molecules which have important regulatory roles in a wide range of biological processes, including obesity. Rodents are widely used animal models for human diseases including obesity. However, not all research is applicable for human health or diseases. In contrast, pigs are emerging as an excellent animal model for obesity studies, due to their similarities in their metabolism, their digestive tract and their genetics, when compared to humans. The Göttingen minipig is a small sized easy-to-handle pig breed which has been extensively used for modeling human obesity, due to its capacity to develop severe obesity when fed ad libitum. The aim of this study was to identify differentially expressed of protein-coding genes and miRNAs in a Göttingen minipig obesity model. Liver, skeletal muscle and abdominal adipose tissue were sampled from 7 lean and 7 obese minipigs. Differential gene expression was investigated using high-throughput quantitative real-time PCR (qPCR) on 90 mRNAs and 72 miRNAs. The results revealed de-regulation of several obesity and inflammation-relevant protein-coding genes and miRNAs in all tissues examined. Many genes that are known to be de-regulated in obese humans were confirmed in the obese minipigs and several of these genes have target sites for miRNAs expressed in the opposing direction of the gene, confirming miRNA-mediated regulation in obesity. These results confirm the translational value of the pig for human obesity studies.

  2. Population genetic studies revealed local adaptation in a high gene-flow marine fish, the small yellow croaker (Larimichthys polyactis.

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    Le Wang

    Full Text Available The genetic differentiation of many marine fish species is low. Yet local adaptation may be common in marine fish species as the vast and changing marine environment provides more chances for natural selection. Here, we used anonymous as well as known protein gene linked microsatellites and mitochondrial DNA to detect the population structure of the small yellow croaker (Larimichthys polyactis in the Northwest Pacific marginal seas. Among these loci, we detected at least two microsatellites, anonymous H16 and HSP27 to be clearly under diversifying selection in outlier tests. Sequence cloning and analysis revealed that H16 was located in the intron of BAHCC1 gene. Landscape genetic analysis showed that H16 mutations were significantly associated with temperature, which further supported the diversifying selection at this locus. These marker types presented different patterns of population structure: (i mitochondrial DNA phylogeny showed no evidence of genetic divergence and demonstrated only one glacial linage; (ii population differentiation using putatively neutral microsatellites presented a pattern of high gene flow in the L. polyactis. In addition, several genetic barriers were identified; (iii the population differentiation pattern revealed by loci under diversifying selection was rather different from that revealed by putatively neutral loci. The results above suggest local adaptation in the small yellow croaker. In summary, population genetic studies based on different marker types disentangle the effects of demographic history, migration, genetic drift and local adaptation on population structure and also provide valuable new insights for the design of management strategies in L. polyactis.

  3. Shell Model Predictions for Very Neutron-Rich Nuclei in 132SN Region Interesting Features of Effective- Charge Revealed

    CERN Document Server

    Sarkar, S; Sarkar, Sukhendusekhar

    2005-01-01

    Shell model studies have been done for very neutron - rich nuclei in the range Z=50-55 and N=82-87. Good agreement of the theoretical level spectra with the experimental one for N=82, 83 I and Te nuclei is shown. Then the results for three very neutron-rich nuclei 137Sn and 136-137Sb have been presented. The present calculation favour a 2- ground state for 136Sb instead of 1- identified through beta decay.Interesting observation about the E2 effective charges for this region has been discussed.

  4. Microbiome-metabolome analysis reveals unhealthy alterations in the composition and metabolism of ruminal microbiota with increasing dietary grain in a goat model.

    Science.gov (United States)

    Mao, Sheng-Yong; Huo, Wen-Jie; Zhu, Wei-Yun

    2016-02-01

    Currently, knowledge about the impact of high-grain (HG) feeding on rumen microbiota and metabolome is limited. In this study, a combination of the 454 pyrosequencing strategy and the mass spectrometry-based metabolomics technique was applied to investigate the effects of increased dietary grain (0%, 25% and 50% maize grain) on changes in whole ruminal microbiota and their metabolites using goat as a ruminant model. We observed a significant influence of HG feeding in shaping the ruminal bacterial community structure, diversity and composition, with an overall dominance of bacteria of the phylum Firmicutes along with a low abundance of Bacteriodetes in the HG group. High-grain feeding increased the number of ciliate and methanogens, and decreased the density of anaerobic fungi and the richness of the archaeal community. The metabolomics analysis revealed that HG feeding increased the levels of several toxic, inflammatory and unnatural compounds, including endotoxin, tryptamine, tyramine, histamine and phenylacetate. Correlation analysis on the combined datasets revealed some potential relationships between ruminal metabolites and certain microbial species. Information about these relationships may prove useful in either direct (therapeutic) or indirect (dietary) interventions for ruminal disorders due to microbial compositional shifts, such as ruminal acidosis. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

  5. Reactive puff model SCICHEM: Model enhancements and performance studies

    Science.gov (United States)

    Chowdhury, B.; Karamchandani, P. K.; Sykes, R. I.; Henn, D. S.; Knipping, E.

    2015-09-01

    The SCICHEM model incorporates complete gas phase, aqueous and aerosol phase chemistry within a state-of-the-science Gaussian puff model SCIPUFF (Second-order Closure Integrated Puff). The model is a valuable tool that can be used to calculate the impacts of a single source or a small number of sources on downwind ozone and PM2.5. The model has flexible data requirements: it can be run with routine surface and upper air observations or with prognostic meteorological model outputs and source emissions are specified in a simple text format. This paper describes significant advances to the dispersion and chemistry components of the model in the latest release, SCICHEM 3.0. Some of the major advancements include modeling of skewed turbulence for convective boundary layer and updated chemistry schemes (CB05 gas phase chemical mechanism; AERO5 aerosol and aqueous modules). The results from SCICHEM 3.0 are compared with observations from a tracer study as well as aircraft measurements of reactive species in power plant plumes from two field studies. The results with the tracer experiment (Copenhagen study) show that the incorporation of skewed turbulence improves the calculation of tracer dispersion and transport. The comparisons with the Cumberland and Dolet Hills power plume measurements show good correlation between the observed and predicted concentrations of reactive gaseous species at most downwind distances from the source.

  6. Revealed Preference and Effectiveness of Public Investment in Ecological River Restoration Projects: An Application of the Count Data Model

    Directory of Open Access Journals (Sweden)

    Yoon Lee

    2016-04-01

    Full Text Available Ecological river restoration projects aim to revitalize healthy and self-sustaining river systems that can provide irreplaceable benefits to human society. Cheonggyecheon and Anyangcheon are two sites of recent river restoration projects in Korea. To assess the economic value of two rivers, count data was collected to conduct the individual travel cost method (ITCM in this study. Five statistical models such as the Poisson, the negative binomial, the zero-truncated Poisson, the negative binomial, and negative binomial model adjusted for both truncation and endogenous stratification were used in the analysis due to the nature of count data. Empirical results showed that regressors were statistically significant and corresponded to conventional consumer theory. Since collected count data indicated over-dispersion and endogenous stratification, the adjusted Negative Binomial was selected as an optimal model to analyze the recreational value of Cheonggyecheon and Anyangcheon. Estimates of the annual economic value of two river restoration projects were approximately US $170.1 million and US $50.5 million, respectively.

  7. Demographic models reveal the shape of density dependence for a specialist insect herbivore on variable host plants.

    Science.gov (United States)

    Miller, Tom E X

    2007-07-01

    1. It is widely accepted that density-dependent processes play an important role in most natural populations. However, persistent challenges in our understanding of density-dependent population dynamics include evaluating the shape of the relationship between density and demographic rates (linear, concave, convex), and identifying extrinsic factors that can mediate this relationship. 2. I studied the population dynamics of the cactus bug Narnia pallidicornis on host plants (Opuntia imbricata) that varied naturally in relative reproductive effort (RRE, the proportion of meristems allocated to reproduction), an important plant quality trait. I manipulated per-plant cactus bug densities, quantified subsequent dynamics, and fit stage-structured models to the experimental data to ask if and how density influences demographic parameters. 3. In the field experiment, I found that populations with variable starting densities quickly converged upon similar growth trajectories. In the model-fitting analyses, the data strongly supported a model that defined the juvenile cactus bug retention parameter (joint probability of surviving and not dispersing) as a nonlinear decreasing function of density. The estimated shape of this relationship shifted from concave to convex with increasing host-plant RRE. 4. The results demonstrate that host-plant traits are critical sources of variation in the strength and shape of density dependence in insects, and highlight the utility of integrated experimental-theoretical approaches for identifying processes underlying patterns of change in natural populations.

  8. Modeling the effector - regulatory T cell cross-regulation reveals the intrinsic character of relapses in Multiple Sclerosis

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    Torrealdea Javier

    2011-07-01

    Full Text Available Abstract Background The relapsing-remitting dynamics is a hallmark of autoimmune diseases such as Multiple Sclerosis (MS. Although current understanding of both cellular and molecular mechanisms involved in the pathogenesis of autoimmune diseases is significant, how their activity generates this prototypical dynamics is not understood yet. In order to gain insight about the mechanisms that drive these relapsing-remitting dynamics, we developed a computational model using such biological knowledge. We hypothesized that the relapsing dynamics in autoimmunity can arise through the failure in the mechanisms controlling cross-regulation between regulatory and effector T cells with the interplay of stochastic events (e.g. failure in central tolerance, activation by pathogens that are able to trigger the immune system. Results The model represents five concepts: central tolerance (T-cell generation by the thymus, T-cell activation, T-cell memory, cross-regulation (negative feedback between regulatory and effector T-cells and tissue damage. We enriched the model with reversible and irreversible tissue damage, which aims to provide a comprehensible link between autoimmune activity and clinical relapses and active lesions in the magnetic resonances studies in patients with Multiple Sclerosis. Our analysis shows that the weakness in this negative feedback between effector and regulatory T-cells, allows the immune system to generate the characteristic relapsing-remitting dynamics of autoimmune diseases, without the need of additional environmental triggers. The simulations show that the timing at which relapses appear is highly unpredictable. We also introduced targeted perturbations into the model that mimicked immunotherapies that modulate effector and regulatory populations. The effects of such therapies happened to be highly dependent on the timing and/or dose, and on the underlying dynamic of the immune system. Conclusion The relapsing dynamic in MS

  9. A model study for tardigrade identification