Science.gov

Sample records for pathways interaction effects

  1. Pathway Interaction Database (PID) —

    Cancer.gov

    The National Cancer Institute (NCI) in collaboration with Nature Publishing Group has established the Pathway Interaction Database (PID) in order to provide a highly structured, curated collection of information about known biomolecular interactions and key cellular processes assembled into signaling pathways.

  2. Pathway Analysis Incorporating Protein-Protein Interaction Networks Identified Candidate Pathways for the Seven Common Diseases.

    PubMed

    Lin, Peng-Lin; Yu, Ya-Wen; Chung, Ren-Hua

    2016-01-01

    Pathway analysis has become popular as a secondary analysis strategy for genome-wide association studies (GWAS). Most of the current pathway analysis methods aggregate signals from the main effects of single nucleotide polymorphisms (SNPs) in genes within a pathway without considering the effects of gene-gene interactions. However, gene-gene interactions can also have critical effects on complex diseases. Protein-protein interaction (PPI) networks have been used to define gene pairs for the gene-gene interaction tests. Incorporating the PPI information to define gene pairs for interaction tests within pathways can increase the power for pathway-based association tests. We propose a pathway association test, which aggregates the interaction signals in PPI networks within a pathway, for GWAS with case-control samples. Gene size is properly considered in the test so that genes do not contribute more to the test statistic simply due to their size. Simulation studies were performed to verify that the method is a valid test and can have more power than other pathway association tests in the presence of gene-gene interactions within a pathway under different scenarios. We applied the test to the Wellcome Trust Case Control Consortium GWAS datasets for seven common diseases. The most significant pathway is the chaperones modulate interferon signaling pathway for Crohn's disease (p-value = 0.0003). The pathway modulates interferon gamma, which induces the JAK/STAT pathway that is involved in Crohn's disease. Several other pathways that have functional implications for the seven diseases were also identified. The proposed test based on gene-gene interaction signals in PPI networks can be used as a complementary tool to the current existing pathway analysis methods focusing on main effects of genes. An efficient software implementing the method is freely available at http://puppi.sourceforge.net. PMID:27622767

  3. Effective connectivity of ascending and descending frontalthalamic pathways during sustained attention: Complex brain network interactions in adolescence.

    PubMed

    Jagtap, Pranav; Diwadkar, Vaibhav A

    2016-07-01

    Frontal-thalamic interactions are crucial for bottom-up gating and top-down control, yet have not been well studied from brain network perspectives. We applied network modeling of fMRI signals [dynamic causal modeling (DCM)] to investigate frontal-thalamic interactions during an attention task with parametrically varying levels of demand. fMRI was collected while subjects participated in a sustained continuous performance task with low and high attention demands. 162 competing model architectures were employed in DCM to evaluate hypotheses on bilateral frontal-thalamic connections and their modulation by attention demand, selected at a second level using Bayesian model selection. The model architecture evinced significant contextual modulation by attention of ascending (thalamus → dPFC) and descending (dPFC → thalamus) pathways. However, modulation of these pathways was asymmetric: while positive modulation of the ascending pathway was comparable across attention demand, modulation of the descending pathway was significantly greater when attention demands were increased. Increased modulation of the (dPFC → thalamus) pathway in response to increased attention demand constitutes novel evidence of attention-related gain in the connectivity of the descending attention pathway. By comparison demand-independent modulation of the ascending (thalamus → dPFC) pathway suggests unbiased thalamic inputs to the cortex in the context of the paradigm. Hum Brain Mapp 37:2557-2570, 2016. © 2016 Wiley Periodicals, Inc. PMID:27145923

  4. Minimal metabolic pathway structure is consistent with associated biomolecular interactions

    PubMed Central

    Bordbar, Aarash; Nagarajan, Harish; Lewis, Nathan E; Latif, Haythem; Ebrahim, Ali; Federowicz, Stephen; Schellenberger, Jan; Palsson, Bernhard O

    2014-01-01

    Pathways are a universal paradigm for functionally describing cellular processes. Even though advances in high-throughput data generation have transformed biology, the core of our biological understanding, and hence data interpretation, is still predicated on human-defined pathways. Here, we introduce an unbiased, pathway structure for genome-scale metabolic networks defined based on principles of parsimony that do not mimic canonical human-defined textbook pathways. Instead, these minimal pathways better describe multiple independent pathway-associated biomolecular interaction datasets suggesting a functional organization for metabolism based on parsimonious use of cellular components. We use the inherent predictive capability of these pathways to experimentally discover novel transcriptional regulatory interactions in Escherichia coli metabolism for three transcription factors, effectively doubling the known regulatory roles for Nac and MntR. This study suggests an underlying and fundamental principle in the evolutionary selection of pathway structures; namely, that pathways may be minimal, independent, and segregated. PMID:24987116

  5. Minimal metabolic pathway structure is consistent with associated biomolecular interactions.

    PubMed

    Bordbar, Aarash; Nagarajan, Harish; Lewis, Nathan E; Latif, Haythem; Ebrahim, Ali; Federowicz, Stephen; Schellenberger, Jan; Palsson, Bernhard O

    2014-01-01

    Pathways are a universal paradigm for functionally describing cellular processes. Even though advances in high-throughput data generation have transformed biology, the core of our biological understanding, and hence data interpretation, is still predicated on human-defined pathways. Here, we introduce an unbiased, pathway structure for genome-scale metabolic networks defined based on principles of parsimony that do not mimic canonical human-defined textbook pathways. Instead, these minimal pathways better describe multiple independent pathway-associated biomolecular interaction datasets suggesting a functional organization for metabolism based on parsimonious use of cellular components. We use the inherent predictive capability of these pathways to experimentally discover novel transcriptional regulatory interactions in Escherichia coli metabolism for three transcription factors, effectively doubling the known regulatory roles for Nac and MntR. This study suggests an underlying and fundamental principle in the evolutionary selection of pathway structures; namely, that pathways may be minimal, independent, and segregated. PMID:24987116

  6. The effect of CD137-CD137 ligand interaction on phospholipase C signaling pathway in human endothelial cells.

    PubMed

    Yan, Jinchuan; Wang, Cuiping; Wang, Zhongqun; Yuan, Wei

    2013-11-25

    We previously reported the emerging role of CD137-CD137L interaction in inflammation and atherosclerosis. The mechanism of CD137-CD137L interaction may be related to a variety of signaling pathways. The most important signaling pathway involves the activation of phospholipase C(PLC) which induces the diacylglycerol-protein kinase C(DAG-PKC) and the inositol trisphosphate-intracellular free calcium (IP3-[Ca(2+)]i) pathway. In the current study, we investigated whether CD137-CD137L interaction can stimulate the PLC signaling pathway in human umbilical vein endothelial cells (HUVEC). The diacylglycerol (DAG) and inositol trisphosphate (IP3) levels in HUVEC were measured by radioenzymatic assay. The activity of protein kinase (PKC) was detected by its ability to transfer phosphate from [γ-(32)P]ATP to lysine-rich histone. The [Ca(2+)]i concentrations were measured by flow cytometric analysis. The DAG level and PKC activity were increased in a concentration-dependent, biphasic manner in HUVEC induced by anti-CD137. PKC activity was mainly in the cytosol at rest, and then translocated to the membrane when stimulated by anti-CD137. Similarly, rapid IP3 formation induced by anti-CD137 coincided with the peak of the DAG level. Moreover, anti-CD137 induced peak [Ca(2+)]i responses including the rapid transient phase and the sustained phase. However, anti-CD137L suppressed the activation of the DAG-PKC and IP3-[Ca(2+)]i signaling pathway, which was stimulated by anti-CD137 in HUVEC. In conclusion, the data suggested that CD137-CD137L interaction induces robust activation of the PLC signaling pathway in HUVEC. PMID:24070733

  7. Effects of Rivaroxaban on Platelet Activation and Platelet–Coagulation Pathway Interaction

    PubMed Central

    Heitmeier, Stefan; Laux, Volker

    2015-01-01

    Introduction: Activation of coagulation and platelets is closely linked, and arterial thrombosis involves coagulation activation as well as platelet activation and aggregation. In these studies, we investigated the possible synergistic effects of rivaroxaban in combination with antiplatelet agents on thrombin generation and platelet aggregation in vitro and on arterial thrombosis and hemostasis in rat models. Materials and Methods: Thrombin generation was measured by the Calibrated Automated Thrombogram method (0.5 pmol/L tissue factor) using human platelet-rich plasma (PRP) spiked with rivaroxaban (15, 30, or 60 ng/mL), ticagrelor (1.0 µg/mL), and acetylsalicylic acid (ASA; 100 µg/mL). Tissue factor-induced platelet aggregation was measured in PRP spiked with rivaroxaban (15 or 30 ng/mL), ticagrelor (1 or 3 µg/mL), or a combination of these. An arteriovenous (AV) shunt model in rats was used to determine the effects of rivaroxaban (0.01, 0.03, or 0.1 mg/kg), clopidogrel (1 mg/kg), ASA (3 mg/kg), and combinations on arterial thrombosis. Results: Rivaroxaban inhibited thrombin generation in a concentration-dependent manner and the effect was enhanced with ticagrelor and ticagrelor plus ASA. Rivaroxaban and ticagrelor also concentration-dependently inhibited tissue factor-induced platelet aggregation, and their combination increased the inhibition synergistically. In the AV shunt model, rivaroxaban dose-dependently reduced thrombus formation. Combining subefficacious or weakly efficacious doses of rivaroxaban with ASA or ASA plus clopidogrel increased the antithrombotic effect. Conclusion: These data indicate that the combination of rivaroxaban with single or dual antiplatelet agents works synergistically to reduce platelet activation, which may in turn lead to the delayed/reduced formation of coagulation complexes and vice versa, thereby enhancing antithrombotic potency. PMID:25848131

  8. Effects of Tumor Suppressor Lysyl Oxidase Propeptide on Prostate Cancer Xenograft Growth and Its Direct Interactions with DNA Repair Pathways

    PubMed Central

    Bais, Manish V.; Ozdener, Gokhan Baris; Sonenshein, Gail E.; Trackman, Philip C.

    2014-01-01

    Lysyl oxidase (LOX) is a multifunctional protein required for normal collagen and elastin biosynthesis and maturation. In addition, LOX has complex roles in cancer in which the lysyl oxidase propeptide (LOX-PP) domain of secreted pro-LOX has tumor suppressor activity, while the active enzyme promotes metastasis. In prostate cancer cell lines, recombinant LOX-PP (rLOX-PP) inhibits the growth of PC3 cells in vitro by mechanisms which were not characterized, while in DU145 cells rLOX-PP targeted FGF signaling. Because rLOX-PP can enhance effects of a genotoxic chemotherapeutic on breast cancer cell apoptosis, we reasoned that rLOX-PP could target DNA repair pathways typically elevated in cancer. Here we demonstrate for the first time that rLOX-PP inhibits prostate xenograft growth in vivo and that activating phosphorylations of the key DNA repair molecules ATM and CHK2 are inhibited by rLOX-PP expression in vivo. In addition, in vitro studies showed that rLOX-PP inhibits radiation induced activating phosphorylations of ATM and CHK2, and that exogenously added rLOX-PP protein can localize to the nucleus in both DU145 and PC3 cells. rLOX-PP pull-down studies resulted in detection of a protein complex with the nuclear DNA repair regulator MRE11 in both cell lines, and rLOX-PP localized to radiation-induced nuclear DNA repair foci. Finally, rLOX-PP was shown to sensitize both DU145 and PC3 cells to radiation-induced cell death determined in colony formation assays. These data provide evidence that rLOX-PP has a nuclear mechanism of action in which it directly interacts with DNA repair proteins to sensitize prostate cancer cells to the effects of ionizing radiation. PMID:24882580

  9. Discovering pathways by orienting edges in protein interaction networks

    PubMed Central

    Gitter, Anthony; Klein-Seetharaman, Judith; Gupta, Anupam; Bar-Joseph, Ziv

    2011-01-01

    Modern experimental technology enables the identification of the sensory proteins that interact with the cells’ environment or various pathogens. Expression and knockdown studies can determine the downstream effects of these interactions. However, when attempting to reconstruct the signaling networks and pathways between these sources and targets, one faces a substantial challenge. Although pathways are directed, high-throughput protein interaction data are undirected. In order to utilize the available data, we need methods that can orient protein interaction edges and discover high-confidence pathways that explain the observed experimental outcomes. We formalize the orientation problem in weighted protein interaction graphs as an optimization problem and present three approximation algorithms based on either weighted Boolean satisfiability solvers or probabilistic assignments. We use these algorithms to identify pathways in yeast. Our approach recovers twice as many known signaling cascades as a recent unoriented signaling pathway prediction technique and over 13 times as many as an existing network orientation algorithm. The discovered paths match several known signaling pathways and suggest new mechanisms that are not currently present in signaling databases. For some pathways, including the pheromone signaling pathway and the high-osmolarity glycerol pathway, our method suggests interesting and novel components that extend current annotations. PMID:21109539

  10. Discerning mechanistically rewired biological pathways by cumulative interaction heterogeneity statistics

    PubMed Central

    Cotton, Travis B.; Nguyen, Hien H.; Said, Joseph I.; Ouyang, Zhengyu; Zhang, Jinfa; Song, Mingzhou

    2015-01-01

    Changes in response of a biological pathway could be a consequence of either pathway rewiring, changed input, or a combination of both. Most pathway analysis methods are not designed for mechanistic rewiring such as regulatory element variations. This limits our understanding of biological pathway evolution. Here we present a Q-method to discern whether changed pathway response is caused by mechanistic rewiring of pathways due to evolution. The main innovation is a cumulative pathway interaction heterogeneity statistic accounting for rewiring-specific effects on the rate of change of each molecular variable across conditions. The Q-method remarkably outperformed differential-correlation based approaches on data from diverse biological processes. Strikingly, it also worked well in differentiating rewired chaotic systems, whose dynamics are notoriously difficult to predict. Applying the Q-method on transcriptome data of four yeasts, we show that pathway interaction heterogeneity for known metabolic and signaling pathways is indeed a predictor of interspecies genetic rewiring due to unbalanced TATA box-containing genes among the yeasts. The demonstrated effectiveness of the Q-method paves the way to understanding network evolution at the resolution of functional biological pathways. PMID:25921728

  11. Discerning mechanistically rewired biological pathways by cumulative interaction heterogeneity statistics.

    PubMed

    Cotton, Travis B; Nguyen, Hien H; Said, Joseph I; Ouyang, Zhengyu; Zhang, Jinfa; Song, Mingzhou

    2015-01-01

    Changes in response of a biological pathway could be a consequence of either pathway rewiring, changed input, or a combination of both. Most pathway analysis methods are not designed for mechanistic rewiring such as regulatory element variations. This limits our understanding of biological pathway evolution. Here we present a Q-method to discern whether changed pathway response is caused by mechanistic rewiring of pathways due to evolution. The main innovation is a cumulative pathway interaction heterogeneity statistic accounting for rewiring-specific effects on the rate of change of each molecular variable across conditions. The Q-method remarkably outperformed differential-correlation based approaches on data from diverse biological processes. Strikingly, it also worked well in differentiating rewired chaotic systems, whose dynamics are notoriously difficult to predict. Applying the Q-method on transcriptome data of four yeasts, we show that pathway interaction heterogeneity for known metabolic and signaling pathways is indeed a predictor of interspecies genetic rewiring due to unbalanced TATA box-containing genes among the yeasts. The demonstrated effectiveness of the Q-method paves the way to understanding network evolution at the resolution of functional biological pathways. PMID:25921728

  12. Integrated pathway and epistasis analysis reveals interactive effect of genetic variants at TERF1 and AFAP1L2 loci on melanoma risk.

    PubMed

    Brossard, Myriam; Fang, Shenying; Vaysse, Amaury; Wei, Qingyi; Chen, Wei V; Mohamdi, Hamida; Maubec, Eve; Lavielle, Nolwenn; Galan, Pilar; Lathrop, Mark; Avril, Marie-Françoise; Lee, Jeffrey E; Amos, Christopher I; Demenais, Florence

    2015-10-15

    Genome-wide association studies (GWASs) have characterized 13 loci associated with melanoma, which only account for a small part of melanoma risk. To identify new genes with too small an effect to be detected individually but which collectively influence melanoma risk and/or show interactive effects, we used a two-step analysis strategy including pathway analysis of genome-wide SNP data, in a first step, and epistasis analysis within significant pathways, in a second step. Pathway analysis, using the gene-set enrichment analysis (GSEA) approach and the gene ontology (GO) database, was applied to the outcomes of MELARISK (3,976 subjects) and MDACC (2,827 subjects) GWASs. Cross-gene SNP-SNP interaction analysis within melanoma-associated GOs was performed using the INTERSNP software. Five GO categories were significantly enriched in genes associated with melanoma (false discovery rate ≤ 5% in both studies): response to light stimulus, regulation of mitotic cell cycle, induction of programmed cell death, cytokine activity and oxidative phosphorylation. Epistasis analysis, within each of the five significant GOs, showed significant evidence for interaction for one SNP pair at TERF1 and AFAP1L2 loci (pmeta-int  = 2.0 × 10(-7) , which met both the pathway and overall multiple-testing corrected thresholds that are equal to 9.8 × 10(-7) and 2.0 × 10(-7) , respectively) and suggestive evidence for another pair involving correlated SNPs at the same loci (pmeta-int  = 3.6 × 10(-6) ). This interaction has important biological relevance given the key role of TERF1 in telomere biology and the reported physical interaction between TERF1 and AFAP1L2 proteins. This finding brings a novel piece of evidence for the emerging role of telomere dysfunction into melanoma development. PMID:25892537

  13. Alcohol Effects on Stress Pathways

    PubMed Central

    Blaine, Sara K.; Milivojevic, Verica; Fox, Helen

    2016-01-01

    A significant amount of neurobiological research regarding the development of alcohol use disorders (AUDs) has focused on alcohol-related activation and long-term alterations in the mesocortical dopaminergic reward pathways. However, alcohol does not only interact with brain reward systems. Many of its acute and chronic effects may be related to allostatic adaptations in hypothalamic and extrahypothalamic stress regulation pathways. For example, acute binge intoxication is associated with hypothalamically driven increases in blood cortisol, norepinephrine, and sex steroid metabolite levels. This may contribute to the development of mesocortical sensitization to alcohol. Furthermore, chronic alcohol exposure is associated with systemic dysregulation of the hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and sex steroid systems. This dysregulation appears to manifest as neuroendocrine tolerance. In this review, we first summarize the literature suggesting that alcohol-induced alterations in these hypothalamic systems influence craving and contribute to the development of AUDs. We note that for women, the effects of alcohol on these neuroendocrine stress regulation systems may be influenced by the rhythmic variations of hormones and steroids across the menstrual cycle. Second, we discuss how changes in these systems may indicate progression of AUDs and increased risk of relapse in both sexes. Specifically, neuroendocrine tolerance may contribute to mesocortical sensitization, which in turn may lead to decreased prefrontal inhibitory control of the dopaminergic reward and hypothalamic stress systems. Thus, pharmacological strategies that counteract alcohol-associated changes in hypothalamic and extrahypothalamic stress regulation pathways may slow the development and progression of AUDs. PMID:27254089

  14. Hsa-miR-590-5p Interaction with SMAD3 Transcript Supports Its Regulatory Effect on The TGFβ Signaling Pathway

    PubMed Central

    Jafarzadeh, Meisam; Soltani, Bahram M.

    2016-01-01

    Objective SMAD proteins are the core players of the transforming growth factor-beta (TGFβ) signaling pathway, a pathway which is involved in cell proliferation, differentiation and migration. On the other hand, hsa-miRNA-590-5p (miR-590-5p) is known to have a negative regulatory effect on TGFβ signaling pathway receptors. Since, RNAhybrid analy- sis suggested SMAD3 as a bona fide target gene for miR-590, we intended to investigate the effect of miR-590-5p on SMAD3 transcription. Materials and Methods In this experimental study, miR-590-5p was overexpressed in different cell lines and its increased expression was detected through quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Western blot analysis was then used to investigate the effect of miR-590-5p overexpression on SMAD3 protein level. Next, the direct interaction of miR-590-5p with the 3´-UTR sequence of SMAD3 transcript was investigated using the dual luciferase assay. Finally, flow cytometery was used to inves- tigate the effect of miR-590-5p overexpression on cell cycle progression in HeLa and SW480 cell lines. Results miR-590-5p was overexpressed in the SW480 cell line and its overexpression resulted in significant reduction of the SMAD3 protein level. Consistently, direct interaction of miR-590-5p with 3´-UTR sequence of SMAD3 was detected. Finally, miR-590-5p over- expression did not show a significant effect on cell cycle progression of Hela and SW480 cell lines. Conclusion Consistent with previous reports about the negative regulatory effect of miR-590 on TGFβ receptors, our data suggest that miR-590-5p also attenuates the TGFβ signaling pathway through down-regulation of SMAD3. PMID:27054113

  15. Michigan molecular interactions r2: from interacting proteins to pathways.

    PubMed

    Tarcea, V Glenn; Weymouth, Terry; Ade, Alex; Bookvich, Aaron; Gao, Jing; Mahavisno, Vasudeva; Wright, Zach; Chapman, Adriane; Jayapandian, Magesh; Ozgür, Arzucan; Tian, Yuanyuan; Cavalcoli, Jim; Mirel, Barbara; Patel, Jignesh; Radev, Dragomir; Athey, Brian; States, David; Jagadish, H V

    2009-01-01

    Molecular interaction data exists in a number of repositories, each with its own data format, molecule identifier and information coverage. Michigan molecular interactions (MiMI) assists scientists searching through this profusion of molecular interaction data. The original release of MiMI gathered data from well-known protein interaction databases, and deep merged this information while keeping track of provenance. Based on the feedback received from users, MiMI has been completely redesigned. This article describes the resulting MiMI Release 2 (MiMIr2). New functionality includes extension from proteins to genes and to pathways; identification of highlighted sentences in source publications; seamless two-way linkage with Cytoscape; query facilities based on MeSH/GO terms and other concepts; approximate graph matching to find relevant pathways; support for querying in bulk; and a user focus-group driven interface design. MiMI is part of the NIH's; National Center for Integrative Biomedical Informatics (NCIBI) and is publicly available at: http://mimi.ncibi.org. PMID:18978014

  16. An integrated pathway interaction network for the combination of four effective compounds from ShengMai preparations in the treatment of cardio-cerebral ischemic diseases

    PubMed Central

    Li, Fang; Lv, Yan-ni; Tan, Yi-sha; Shen, Kai; Zhai, Ke-feng; Chen, Hong-lin; Kou, Jun-ping; Yu, Bo-yang

    2015-01-01

    Aim: SMXZF (a combination of ginsenoside Rb1, ginsenoside Rg1, schizandrin and DT-13) derived from Chinese traditional medicine formula ShengMai preparations) is capable of alleviating cerebral ischemia-reperfusion injury in mice. In this study we used network pharmacology approach to explore the mechanisms of SMXZF in the treatment of cardio-cerebral ischemic diseases. Methods: Based upon the chemical predictors, such as chemical structure, pharmacological information and systems biology functional data analysis, a target-pathway interaction network was constructed to identify potential pathways and targets of SMXZF in the treatment of cardio-cerebral ischemia. Furthermore, the most related pathways were verified in TNF-α-treated human vascular endothelial EA.hy926 cells and H2O2-treated rat PC12 cells. Results: Three signaling pathways including the NF-κB pathway, oxidative stress pathway and cytokine network pathway were demonstrated to be the main signaling pathways. The results from the gene ontology analysis were in accordance with these signaling pathways. The target proteins were found to be associated with other diseases such as vision, renal and metabolic diseases, although they exerted therapeutic actions on cardio-cerebral ischemic diseases. Furthermore, SMXZF not only dose-dependently inhibited the phosphorylation of NF-κB, p50, p65 and IKKα/β in TNF-α-treated EA.hy926 cells, but also regulated the Nrf2/HO-1 pathway in H2O2-treated PC12 cells. Conclusion: NF-κB signaling pathway, oxidative stress pathway and cytokine network pathway are mainly responsible for the therapeutic actions of SMXZF against cardio-cerebral ischemic diseases. PMID:26456587

  17. Module-based functional pathway enrichment analysis of a protein-protein interaction network to study the effects of intestinal microbiota depletion in mice

    PubMed Central

    JIA, ZHEN-YI; XIA, YANG; TONG, DANIAN; YAO, JING; CHEN, HONG-QI; YANG, JUN

    2014-01-01

    Complex communities of microorganisms play important roles in human health, and alterations in the intestinal microbiota may induce intestinal inflammation and numerous diseases. The purpose of this study was to identify the key genes and processes affected by depletion of the intestinal microbiota in a murine model. The Affymetrix microarray dataset GSE22648 was downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified using the limma package in R. A protein-protein interaction (PPI) network was constructed for the DEGs using the Cytoscape software, and the network was divided into several modules using the MCODE plugin. Furthermore, the modules were functionally annotated using the PiNGO plugin, and DEG-related pathways were retrieved and analyzed using the GenMAPP software. A total of 53 DEGs were identified, of which 26 were upregulated and 27 were downregulated. The PPI network of these DEGs comprised 3 modules. The most significant module-related DEGs were the cytochrome P450 (CYP) 4B1 isozyme gene (CYP4B1) in module 1, CYP4F14 in module 2 and the tachykinin precursor 1 gene (TAC1) in module 3. The majority of enriched pathways of module 1 and 2 were oxidation reduction pathways (metabolism of xenobiotics by CYPs) and lipid metabolism-related pathways, including linoleic acid and arachidonic acid metabolism. The neuropeptide signaling pathway was the most significantly enriched functional pathway of module 3. In conclusion, our findings strongly suggest that intestinal microbiota depletion affects cellular metabolism and oxidation reduction pathways. In addition, this is the first time, to the best of our knowledge, that the neuropeptide signaling pathway is reported to be affected by intestinal microbiota depletion in mice. The present study provides a list of candidate genes and processes related to the interaction of microbiota with the intestinal tract. PMID:24718810

  18. Module-based functional pathway enrichment analysis of a protein-protein interaction network to study the effects of intestinal microbiota depletion in mice.

    PubMed

    Jia, Zhen-Yi; Xia, Yang; Tong, Danian; Yao, Jing; Chen, Hong-Qi; Yang, Jun

    2014-06-01

    Complex communities of microorganisms play important roles in human health, and alterations in the intestinal microbiota may induce intestinal inflammation and numerous diseases. The purpose of this study was to identify the key genes and processes affected by depletion of the intestinal microbiota in a murine model. The Affymetrix microarray dataset GSE22648 was downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified using the limma package in R. A protein-protein interaction (PPI) network was constructed for the DEGs using the Cytoscape software, and the network was divided into several modules using the MCODE plugin. Furthermore, the modules were functionally annotated using the PiNGO plugin, and DEG-related pathways were retrieved and analyzed using the GenMAPP software. A total of 53 DEGs were identified, of which 26 were upregulated and 27 were downregulated. The PPI network of these DEGs comprised 3 modules. The most significant module-related DEGs were the cytochrome P450 (CYP) 4B1 isozyme gene (CYP4B1) in module 1, CYP4F14 in module 2 and the tachykinin precursor 1 gene (TAC1) in module 3. The majority of enriched pathways of module 1 and 2 were oxidation reduction pathways (metabolism of xenobiotics by CYPs) and lipid metabolism-related pathways, including linoleic acid and arachidonic acid metabolism. The neuropeptide signaling pathway was the most significantly enriched functional pathway of module 3. In conclusion, our findings strongly suggest that intestinal microbiota depletion affects cellular metabolism and oxidation reduction pathways. In addition, this is the first time, to the best of our knowledge, that the neuropeptide signaling pathway is reported to be affected by intestinal microbiota depletion in mice. The present study provides a list of candidate genes and processes related to the interaction of microbiota with the intestinal tract. PMID:24718810

  19. Interaction of TGFβ and BMP Signaling Pathways during Chondrogenesis

    PubMed Central

    Keller, Bettina; Yang, Tao; Chen, Yuqing; Munivez, Elda; Bertin, Terry; Zabel, Bernhard; Lee, Brendan

    2011-01-01

    TGFβ and BMP signaling pathways exhibit antagonistic activities during the development of many tissues. Although the crosstalk between BMP and TGFβ signaling pathways is well established in bone development, the relationship between these two pathways is less well defined during cartilage development and postnatal homeostasis. We generated hypomorphic mouse models of cartilage-specific loss of BMP and TGFβ signaling to assess the interaction of these pathways in postnatal growth plate homeostasis. We further used the chondrogenic ATDC5 cell line to test effects of BMP and TGFβ signaling on each other's downstream targets. We found that conditional deletion of Smad1 in chondrocytes resulted in a shortening of the growth plate. The addition of Smad5 haploinsufficiency led to a more severe phenotype with shorter prehypertrophic and hypertrophic zones and decreased chondrocyte proliferation. The opposite growth plate phenotype was observed in a transgenic mouse model of decreased chondrocytic TGFβ signaling that was generated by expressing a dominant negative form of the TGFβ receptor I (ΔTβRI) in cartilage. Histological analysis demonstrated elongated growth plates with enhanced Ihh expression, as well as an increased proliferation rate with altered production of extracellular matrix components. In contrast, in chondrogenic ATDC5 cells, TGFβ was able to enhance BMP signaling, while BMP2 significantly reduces levels of TGF signaling. In summary, our data demonstrate that during endochondral ossification, BMP and TGFβ signaling can have antagonistic effects on chondrocyte proliferation and differentiation in vivo. We also found evidence of direct interaction between the two signaling pathways in a cell model of chondrogenesis in vitro. PMID:21297990

  20. Signaling pathways mediating alcohol effects.

    PubMed

    Ron, Dorit; Messing, Robert O

    2013-01-01

    Ethanol's effects on intracellular signaling pathways contribute to acute effects of ethanol as well as to neuroadaptive responses to repeated ethanol exposure. In this chapter we review recent discoveries that demonstrate how ethanol alters signaling pathways involving several receptor tyrosine kinases and intracellular tyrosine and serine-threonine kinases, with consequences for regulation of cell surface receptor function, gene expression, protein translation, neuronal excitability and animal behavior. We also describe recent work that demonstrates a key role for ethanol in regulating the function of scaffolding proteins that organize signaling complexes into functional units. Finally, we review recent exciting studies demonstrating ethanol modulation of DNA and histone modification and the expression of microRNAs, indicating epigenetic mechanisms by which ethanol regulates neuronal gene expression and addictive behaviors. PMID:21877259

  1. Actionable pathways: interactive discovery of therapeutic targets using signaling pathway models

    PubMed Central

    Salavert, Francisco; Hidago, Marta R.; Amadoz, Alicia; Çubuk, Cankut; Medina, Ignacio; Crespo, Daniel; Carbonell-Caballero, Jose; Dopazo, Joaquín

    2016-01-01

    The discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org. PMID:27137885

  2. Actionable pathways: interactive discovery of therapeutic targets using signaling pathway models.

    PubMed

    Salavert, Francisco; Hidago, Marta R; Amadoz, Alicia; Çubuk, Cankut; Medina, Ignacio; Crespo, Daniel; Carbonell-Caballero, Jose; Dopazo, Joaquín

    2016-07-01

    The discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org. PMID:27137885

  3. [A novel biological pathway expansion method based on the knowledge of protein-protein interactions].

    PubMed

    Zhao, Xiaolei; Zuo, Xiaoyu; Qin, Jiheng; Liang, Yan; Zhang, Naizun; Luan, Yizhao; Rao, Shaoqi

    2014-04-01

    Biological pathways have been widely used in gene function studies; however, the current knowledge for biological pathways is per se incomplete and has to be further expanded. Bioinformatics prediction provides us a cheap but effective way for pathway expansion. Here, we proposed a novel method for biological pathway prediction, by intergrating prior knowledge of protein?protein interactions and Gene Ontology (GO) database. First, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways to which the interacting neighbors of a targe gene (at the level of protein?protein interaction) belong were chosen as the candidate pathways. Then, the pathways to which the target gene belong were determined by testing whether the genes in the candidate pathways were enriched in the GO terms to which the target gene were annotated. The protein?protein interaction data obtained from the Human Protein Reference Database (HPRD) and Biological General Repository for Interaction Datasets (BioGRID) were respectively used to predict the pathway attribution(s) of the target gene. The results demanstrated that both the average accuracy (the ratio of the correctly predicted pathways to the totally pathways to which all the target genes were annotated) and the relative accuracy (of the genes with at least one annotated pathway being successful predicted, the percentage of the genes with all the annotated pathways being correctly predicted) for pathway predictions were increased with the number of the interacting neighbours. When the number of interacting neighbours reached 22, the average accuracy was 96.2% (HPRD) and 96.3% (BioGRID), respectively, and the relative accuracy was 93.3% (HPRD) and 84.1% (BioGRID), respectively. Further validation analysis of 89 genes whose pathway knowledge was updated in a new database release indicated that 50 genes were correctly predicted for at least one updated pathway, and 43 genes were accurately predicted for all the updated pathways, giving an

  4. AN INTEGRATED NETWORK APPROACH TO IDENTIFYING BIOLOGICAL PATHWAYS AND ENVIRONMENTAL EXPOSURE INTERACTIONS IN COMPLEX DISEASES

    PubMed Central

    DARABOS, CHRISTIAN; QIU, JINGYA; MOORE, JASON H.

    2015-01-01

    Complex diseases are the result of intricate interactions between genetic, epigenetic and environmental factors. In previous studies, we used epidemiological and genetic data linking environmental exposure or genetic variants to phenotypic disease to construct Human Phenotype Networks and separately analyze the effects of both environment and genetic factors on disease interactions. To better capture the intricacies of the interactions between environmental exposure and the biological pathways in complex disorders, we integrate both aspects into a single “tripartite” network. Despite extensive research, the mechanisms by which chemical agents disrupt biological pathways are still poorly understood. In this study, we use our integrated network model to identify specific biological pathway candidates possibly disrupted by environmental agents. We conjecture that a higher number of co-occurrences between an environmental substance and biological pathway pair can be associated with a higher likelihood that the substance is involved in disrupting that pathway. We validate our model by demonstrating its ability to detect known arsenic and signal transduction pathway interactions and speculate on candidate cell-cell junction organization pathways disrupted by cadmium. The validation was supported by distinct publications of cell biology and genetic studies that associated environmental exposure to pathway disruption. The integrated network approach is a novel method for detecting the biological effects of environmental exposures. A better understanding of the molecular processes associated with specific environmental exposures will help in developing targeted molecular therapies for patients who have been exposed to the toxicity of environmental chemicals. PMID:26776169

  5. Protein Disulfide Isomerase-2 of Arabidopsis Mediates Protein Folding and Localizes to Both the Secretory Pathway and Nucleus, Where It Interacts with Maternal Effect Embryo Arrest Factor

    PubMed Central

    Cho, Eun Ju; Yuen, Christen Y.L.; Kang, Byung-Ho; Ondzighi, Christine A.; Staehelin, L. Andrew; Christopher, David A.

    2011-01-01

    Protein disulfide isomerase (PDI) is a thiodisulfide oxidoreductase that catalyzes the formation, reduction and rearrangement of disulfide bonds in proteins of eukaryotes. The classical PDI has a signal peptide, two CXXCcontaining thioredoxin catalytic sites (a,a′), two noncatalytic thioredoxin fold domains (b,b′), an acidic domain (c) and a C-terminal endoplasmic reticulum (ER) retention signal. Although PDI resides in the ER where it mediates the folding of nascent polypeptides of the secretory pathway, we recently showed that PDI5 of Arabidopsis thaliana chaperones and inhibits cysteine proteases during trafficking to vacuoles prior to programmed cell death of the endothelium in developing seeds. Here we describe Arabidopsis PDI2, which shares a primary structure similar to that of classical PDI. Recombinant PDI2 is imported into ER-derived microsomes and complements the E. coli protein- folding mutant, dsbA. PDI2 interacted with proteins in both the ER and nucleus, including ER-resident protein folding chaperone, BiP1, and nuclear embryo transcription factor, MEE8. The PDI2-MEE8 interaction was confirmed to occur in vitro and in vivo. Transient expression of PDI2- GFP fusions in mesophyll protoplasts resulted in labeling of the ER, nucleus and vacuole. PDI2 is expressed in multiple tissues, with relatively high expression in seeds and root tips. Immunoelectron microscopy with GFP- and PDI2-specific antisera on transgenic seeds (PDI2-GFP) and wild type roots demonstrated that PDI2 was found in the secretory pathway (ER, Golgi, vacuole, cell wall) and the nuclei. Our results indicate that PDI2 mediates protein folding in the ER and has new functional roles in the nucleus. PMID:21909944

  6. Computational Reconstruction of NFκB Pathway Interaction Mechanisms during Prostate Cancer

    PubMed Central

    Börnigen, Daniela; Tyekucheva, Svitlana; Wang, Xiaodong; Rider, Jennifer R.; Lee, Gwo-Shu; Mucci, Lorelei A.; Sweeney, Christopher; Huttenhower, Curtis

    2016-01-01

    Molecular research in cancer is one of the largest areas of bioinformatic investigation, but it remains a challenge to understand biomolecular mechanisms in cancer-related pathways from high-throughput genomic data. This includes the Nuclear-factor-kappa-B (NFκB) pathway, which is central to the inflammatory response and cell proliferation in prostate cancer development and progression. Despite close scrutiny and a deep understanding of many of its members’ biomolecular activities, the current list of pathway members and a systems-level understanding of their interactions remains incomplete. Here, we provide the first steps toward computational reconstruction of interaction mechanisms of the NFκB pathway in prostate cancer. We identified novel roles for ATF3, CXCL2, DUSP5, JUNB, NEDD9, SELE, TRIB1, and ZFP36 in this pathway, in addition to new mechanistic interactions between these genes and 10 known NFκB pathway members. A newly predicted interaction between NEDD9 and ZFP36 in particular was validated by co-immunoprecipitation, as was NEDD9's potential biological role in prostate cancer cell growth regulation. We combined 651 gene expression datasets with 1.4M gene product interactions to predict the inclusion of 40 additional genes in the pathway. Molecular mechanisms of interaction among pathway members were inferred using recent advances in Bayesian data integration to simultaneously provide information specific to biological contexts and individual biomolecular activities, resulting in a total of 112 interactions in the fully reconstructed NFκB pathway: 13 (11%) previously known, 29 (26%) supported by existing literature, and 70 (63%) novel. This method is generalizable to other tissue types, cancers, and organisms, and this new information about the NFκB pathway will allow us to further understand prostate cancer and to develop more effective prevention and treatment strategies. PMID:27078000

  7. Elucidating the Complex Interactions between Stress and Epileptogenic Pathways

    PubMed Central

    Friedman, Aaron R.; Cacheaux, Luisa P.; Ivens, Sebastian; Kaufer, Daniela

    2011-01-01

    Clinical and experimental data suggest that stress contributes to the pathology of epilepsy. We review mechanisms by which stress, primarily via stress hormones, may exacerbate epilepsy, focusing on the intersection between stress-induced pathways and the progression of pathological events that occur before, during, and after the onset of epileptogenesis. In addition to this temporal nuance, we discuss other complexities in stress-epilepsy interactions, including the role of blood-brain barrier dysfunction, neuron-glia interactions, and inflammatory/cytokine pathways that may be protective or damaging depending on context. We advocate the use of global analytical tools, such as microarray, in support of a shift away from a narrow focus on seizures and towards profiling the complex, early process of epileptogenesis, in which multiple pathways may interact to dictate the ultimate onset of chronic, recurring seizures. PMID:21547249

  8. Integrated Interactive Chart as a Tool for Teaching Metabolic Pathways

    ERIC Educational Resources Information Center

    Kalogiannis, Stavros; Pagkalos, Ioannis; Koufoudakis, Panagiotis; Dashi, Ino; Pontikeri, Kyriaki; Christodoulou, Constantina

    2014-01-01

    An interactive chart of energy metabolism with didactic function, complementary to the already existing metabolic maps, located at the URL www.metpath.teithe.gr is being presented. The chart illustrates the major catabolic and biosynthetic pathways of glucose, fatty acids, and aminoacids, individually as well as in an integrated view. For every…

  9. Cyclone-cyclone Interactions through the Ocean Pathway

    SciTech Connect

    Balaguru, Karthik; Taraphdar, Sourav; Leung, Lai-Yung R.; Foltz, Gregory R.; Knaff, John A.

    2014-10-16

    The intense SST (Sea Surface Temperature) cooling caused by hurricane-induced mixing is restored at timescales on the order of weeks(1) and thus may persist long enough to influence a later hurricane passing over it. Though many studies have evaluated the effects of SST cool-ing induced by a hurricane on its own intensification(2, 3), none has looked at its effect on later storms. Using an analysis of observations and numerical model simulations, we demonstrate that hurricanes may influence the intensity of later hurricanes that pass over their linger-ing wakes. On average, when hurricanes encounter cold wakes, they experience SSTs that are ~0.4oC lower than when they do not encounter wakes and consequently decay(intensify) at a rate that is nearly three times faster(slower). In the region of warm SSTs (* 26.5oC) where the most intense and damaging hurricanes tend to occur, the percentage of hurricanes that encounter lingering cold wakes increases with hurricane frequency and was found to be as high as 40%. Furthermore, we estimate that the cumulative power dissipated(4) by the most energetic hurricanes has been reduced by as much as ~7% in a season through this effect. As the debate on changes in Atlantic hurricane activity associated with global warming(5) continues, the negative feedback between hurricane frequency and intensity resulting from hurricane-hurricane interactions through the ocean pathway deserves attention.

  10. Gene interaction enrichment and network analysis to identify dysregulated pathways and their interactions in complex diseases

    PubMed Central

    2012-01-01

    Background The molecular behavior of biological systems can be described in terms of three fundamental components: (i) the physical entities, (ii) the interactions among these entities, and (iii) the dynamics of these entities and interactions. The mechanisms that drive complex disease can be productively viewed in the context of the perturbations of these components. One challenge in this regard is to identify the pathways altered in specific diseases. To address this challenge, Gene Set Enrichment Analysis (GSEA) and others have been developed, which focus on alterations of individual properties of the entities (such as gene expression). However, the dynamics of the interactions with respect to disease have been less well studied (i.e., properties of components ii and iii). Results Here, we present a novel method called Gene Interaction Enrichment and Network Analysis (GIENA) to identify dysregulated gene interactions, i.e., pairs of genes whose relationships differ between disease and control. Four functions are defined to model the biologically relevant gene interactions of cooperation (sum of mRNA expression), competition (difference between mRNA expression), redundancy (maximum of expression), or dependency (minimum of expression) among the expression levels. The proposed framework identifies dysregulated interactions and pathways enriched in dysregulated interactions; points out interactions that are perturbed across pathways; and moreover, based on the biological annotation of each type of dysregulated interaction gives clues about the regulatory logic governing the systems level perturbation. We demonstrated the potential of GIENA using published datasets related to cancer. Conclusions We showed that GIENA identifies dysregulated pathways that are missed by traditional enrichment methods based on the individual gene properties and that use of traditional methods combined with GIENA provides coverage of the largest number of relevant pathways. In addition

  11. Interactions of Bacterial Proteins with Host Eukaryotic Ubiquitin Pathways

    PubMed Central

    Perrett, Charlotte Averil; Lin, David Yin-Wei; Zhou, Daoguo

    2011-01-01

    Ubiquitination is a post-translational modification in which one or more 76 amino acid polypeptide ubiquitin molecules are covalently linked to the lysine residues of target proteins. Ubiquitination is the main pathway for protein degradation that governs a variety of eukaryotic cellular processes, including the cell-cycle, vesicle trafficking, antigen presentation, and signal transduction. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of many diseases including inflammatory and neurodegenerative disorders. Recent studies have revealed that viruses and bacterial pathogens exploit the host ubiquitination pathways to gain entry and to aid their survival/replication inside host cells. This review will summarize recent developments in understanding the biochemical and structural mechanisms utilized by bacterial pathogens to interact with the host ubiquitination pathways. PMID:21772834

  12. An Interactive, Integrated, Instructional Pathway to the LEAD Science Gateway

    NASA Astrophysics Data System (ADS)

    Yalda, S.; Clark, R.; Davis, L.; Wiziecki, E. N.

    2008-12-01

    of learning materials, as well as new tools and features, to enhance the appearance and use of the LEAD portal gateway and its underlying cyberinfrastructure in an educational setting. The development of educational materials has centered on promoting the accessibility and use of meteorological data and analysis tools through the LEAD portal by providing instructional materials, additional custom designed tools that build off of Unidata's Integrated Data Viewer (IDV) (e.g. IDV Basic and NCDestroyer), and an interactive component that takes the user through specific tasks utilizing multiple tools. In fact, select improvements to parameter lists and domain subsetting have inspired IDV developers to incorporate changes in IDV revisions that are now available to the entire community. This collection of materials, demonstrations, interactive guides, student exercises, and customized tools, which are now available to the educator and student through the LEAD portal gateway, can serve as an instructional pathway for a set of guided, phenomenon-based exercises (e.g. fronts, lake-effect snows, etc.). This paper will provide an overview of the LEAD education and outreach efforts with a focus on the design of Web-based educational materials and instructional approaches for user interaction with the LEAD portal gateway and the underlying cyberinfrastructure, and will encourage educators, especially those involved in undergraduate meteorology education, to begin incorporating these capabilities into their course materials.

  13. Effects of PDT on the endocytic pathway

    NASA Astrophysics Data System (ADS)

    Kessel, David

    2010-02-01

    Two lines of evidence point to an early effect of photodamage on membrane trafficking. [1] Internalization of a fluorescent probe for hydrophobic membrane loci was impaired by prior photodamage. [2] Interference with the endocytic pathway by the PI-3 kinase antagonist wortmannin led to accumulation of cytoplasmic vacuoles suggesting a block in the recycling of plasma membrane components. Prior photodamage blocked this pathway so that no vacuoles were formed upon exposure of cells to wortmannin. In a murine hepatoma line, the endocytic pathway was preferentially sensitive to lysosomal photodamage. The role of photodamage to the endocytic pathway as a factor in PDT efficacy remains to be assessed.

  14. The UCSC Interaction Browser: multidimensional data views in pathway context

    PubMed Central

    Wong, Christopher K.; Vaske, Charles J.; Ng, Sam; Sanborn, J. Zachary; Benz, Stephen C.; Haussler, David; Stuart, Joshua M.

    2013-01-01

    High-throughput data sets such as genome-wide protein–protein interactions, protein–DNA interactions and gene expression data have been published for several model systems, especially for human cancer samples. The University of California, Santa Cruz (UCSC) Interaction Browser (http://sysbio.soe.ucsc.edu/nets) is an online tool for biologists to view high-throughput data sets simultaneously for the analysis of functional relationships between biological entities. Users can access several public interaction networks and functional genomics data sets through the portal as well as upload their own networks and data sets for analysis. Users can navigate through correlative relationships for focused sets of genes belonging to biological pathways using a standard web browser. Using a new visual modality called the CircleMap, multiple ‘omics’ data sets can be viewed simultaneously within the context of curated, predicted, directed and undirected regulatory interactions. The Interaction Browser provides an integrative viewing of biological networks based on the consensus of many observations about genes and their products, which may provide new insights about normal and disease processes not obvious from any isolated data set. PMID:23748957

  15. Phylogenetic distances are encoded in networks of interacting pathways

    PubMed Central

    Mazurie, Aurélien; Bonchev, Danail; Schwikowski, Benno; Buck, Gregory A.

    2008-01-01

    Motivation: Although metabolic reactions are unquestionably shaped by evolutionary processes, the degree to which the overall structure and complexity of their interconnections are linked to the phylogeny of species has not been evaluated in depth. Here, we apply an original metabolome representation, termed Network of Interacting Pathways or NIP, with a combination of graph theoretical and machine learning strategies, to address this question. NIPs compress the information of the metabolic network exhibited by a species into much smaller networks of overlapping metabolic pathways, where nodes are pathways and links are the metabolites they exchange. Results: Our analysis shows that a small set of descriptors of the structure and complexity of the NIPs combined into regression models reproduce very accurately reference phylogenetic distances derived from 16S rRNA sequences (10-fold cross-validation correlation coefficient higher than 0.9). Our method also showed better scores than previous work on metabolism-based phylogenetic reconstructions, as assessed by branch distances score, topological similarity and second cousins score. Thus, our metabolome representation as network of overlapping metabolic pathways captures sufficient information about the underlying evolutionary events leading to the formation of metabolic networks and species phylogeny. It is important to note that precise knowledge of all of the reactions in these pathways is not required for these reconstructions. These observations underscore the potential for the use of abstract, modular representations of metabolic reactions as tools in studying the evolution of species. Contact: aurelien.mazurie@pasteur.fr Supplementary information: Supplementary data are available at Bioinformatics online. PMID:18820265

  16. Machine Learning of Protein Interactions in Fungal Secretory Pathways.

    PubMed

    Kludas, Jana; Arvas, Mikko; Castillo, Sandra; Pakula, Tiina; Oja, Merja; Brouard, Céline; Jäntti, Jussi; Penttilä, Merja; Rousu, Juho

    2016-01-01

    In this paper we apply machine learning methods for predicting protein interactions in fungal secretion pathways. We assume an inter-species transfer setting, where training data is obtained from a single species and the objective is to predict protein interactions in other, related species. In our methodology, we combine several state of the art machine learning approaches, namely, multiple kernel learning (MKL), pairwise kernels and kernelized structured output prediction in the supervised graph inference framework. For MKL, we apply recently proposed centered kernel alignment and p-norm path following approaches to integrate several feature sets describing the proteins, demonstrating improved performance. For graph inference, we apply input-output kernel regression (IOKR) in supervised and semi-supervised modes as well as output kernel trees (OK3). In our experiments simulating increasing genetic distance, Input-Output Kernel Regression proved to be the most robust prediction approach. We also show that the MKL approaches improve the predictions compared to uniform combination of the kernels. We evaluate the methods on the task of predicting protein-protein-interactions in the secretion pathways in fungi, S.cerevisiae, baker's yeast, being the source, T. reesei being the target of the inter-species transfer learning. We identify completely novel candidate secretion proteins conserved in filamentous fungi. These proteins could contribute to their unique secretion capabilities. PMID:27441920

  17. Machine Learning of Protein Interactions in Fungal Secretory Pathways

    PubMed Central

    Kludas, Jana; Arvas, Mikko; Castillo, Sandra; Pakula, Tiina; Oja, Merja; Brouard, Céline; Jäntti, Jussi; Penttilä, Merja

    2016-01-01

    In this paper we apply machine learning methods for predicting protein interactions in fungal secretion pathways. We assume an inter-species transfer setting, where training data is obtained from a single species and the objective is to predict protein interactions in other, related species. In our methodology, we combine several state of the art machine learning approaches, namely, multiple kernel learning (MKL), pairwise kernels and kernelized structured output prediction in the supervised graph inference framework. For MKL, we apply recently proposed centered kernel alignment and p-norm path following approaches to integrate several feature sets describing the proteins, demonstrating improved performance. For graph inference, we apply input-output kernel regression (IOKR) in supervised and semi-supervised modes as well as output kernel trees (OK3). In our experiments simulating increasing genetic distance, Input-Output Kernel Regression proved to be the most robust prediction approach. We also show that the MKL approaches improve the predictions compared to uniform combination of the kernels. We evaluate the methods on the task of predicting protein-protein-interactions in the secretion pathways in fungi, S.cerevisiae, baker’s yeast, being the source, T. reesei being the target of the inter-species transfer learning. We identify completely novel candidate secretion proteins conserved in filamentous fungi. These proteins could contribute to their unique secretion capabilities. PMID:27441920

  18. Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

    PubMed Central

    Srinivasan, Lalitha; Ahlbrand, Sarah; Briken, Volker

    2014-01-01

    Mycobacterium tuberculosis (Mtb) has coevolved with humans for tens of thousands of years. It is thus highly adapted to its human host and has evolved multiple mechanisms to manipulate host immune responses to its advantage. One central host pathogen interaction modality is host cell death pathways. Host cell apoptosis is associated with a protective response to Mtb infection, whereas a necrotic response favors the pathogen. Consistently, Mtb inhibits host cell apoptosis signaling but promotes induction of programmed necrosis. The molecular mechanisms involved in Mtb-mediated host cell death manipulation, the consequences for host immunity, and the potential for therapeutic and preventive approaches will be discussed. PMID:24968864

  19. Elucidation of functional consequences of signalling pathway interactions

    PubMed Central

    2009-01-01

    Background A great deal of data has accumulated on signalling pathways. These large datasets are thought to contain much implicit information on their molecular structure, interaction and activity information, which provides a picture of intricate molecular networks believed to underlie biological functions. While tremendous advances have been made in trying to understand these systems, how information is transmitted within them is still poorly understood. This ever growing amount of data demands we adopt powerful computational techniques that will play a pivotal role in the conversion of mined data to knowledge, and in elucidating the topological and functional properties of protein - protein interactions. Results A computational framework is presented which allows for the description of embedded networks, and identification of common shared components thought to assist in the transmission of information within the systems studied. By employing the graph theories of network biology - such as degree distribution, clustering coefficient, vertex betweenness and shortest path measures - topological features of protein-protein interactions for published datasets of the p53, nuclear factor kappa B (NF-κB) and G1/S phase of the cell cycle systems were ascertained. Highly ranked nodes which in some cases were identified as connecting proteins most likely responsible for propagation of transduction signals across the networks were determined. The functional consequences of these nodes in the context of their network environment were also determined. These findings highlight the usefulness of the framework in identifying possible combination or links as targets for therapeutic responses; and put forward the idea of using retrieved knowledge on the shared components in constructing better organised and structured models of signalling networks. Conclusion It is hoped that through the data mined reconstructed signal transduction networks, well developed models of the

  20. Signalling pathway impact analysis based on the strength of interaction between genes.

    PubMed

    Bao, Zhenshen; Li, Xianbin; Zan, Xiangzhen; Shen, Liangzhong; Ma, Runnian; Liu, Wenbin

    2016-08-01

    Signalling pathway analysis is a popular approach that is used to identify significant cancer-related pathways based on differentially expressed genes (DEGs) from biological experiments. The main advantage of signalling pathway analysis lies in the fact that it assesses both the number of DEGs and the propagation of signal perturbation in signalling pathways. However, this method simplifies the interactions between genes by categorising them only as activation (+1) and suppression (-1), which does not encompass the range of interactions in real pathways, where interaction strength between genes may vary. In this study, the authors used newly developed signalling pathway impact analysis (SPIA) methods, SPIA based on Pearson correlation coefficient (PSPIA), and mutual information (MSPIA), to measure the interaction strength between pairs of genes. In analyses of a colorectal cancer dataset, a lung cancer dataset, and a pancreatic cancer dataset, PSPIA and MSPIA identified more candidate cancer-related pathways than were identified by SPIA. Generally, MSPIA performed better than PSPIA. PMID:27444024

  1. Structural activation pathways from dynamic olfactory receptor-odorant interactions.

    PubMed

    Lai, Peter C; Singer, Michael S; Crasto, Chiquito J

    2005-11-01

    We have simulated an odor ligand's dynamic behavior in the binding region of an olfactory receptor (OR). Our short timescale computational studies (up to 200 ps) have helped identify unprecedented postdocking ligand behavior of ligands. From in vacuo molecular dynamics simulations of interactions between models of rat OR I7 and 10 aldehyde ligands, we have identified a dissociative pathway along which the ligand exits and enters the OR-binding pocket--a transit event. The ligand's transit through the receptor's binding region may mark the beginning of a signal transduction cascade leading to odor recognition. We have graphically traced the rotameric changes in key OR amino acid side chains during the transit. Our results have helped substantiate or refute previously held notions of amino acid contribution to ligand stability in the binding pocket. Our observations of ligand activity when compared to those of experimental (electroolfactogram response) OR-activation studies provide a view to predicting the stability of ligands in the binding pocket as a precursor to OR activation by the ligand. PMID:16243965

  2. Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data

    PubMed Central

    Li, Donghui

    2014-01-01

    Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing Genome-wide association study (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2028 cases and 2109 controls to examine gene–smoking interactions at pathway/gene/single nucleotide polymorphism (SNP) level. Using the likelihood ratio test nested in logistic regression models and ingenuity pathway analysis (IPA), we examined 172 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, 3 manually curated gene sets, 3 nicotine dependency gene ontology pathways, 17 912 genes and 468 114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P < 0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB and ATXN2 had P interaction < 0.0005. Five intergenic region SNPs and two SNPs of the EVC and KCNIP4 genes had P interaction < 0.00003. In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling (P=2.12×10−7) and α-adrenergic signaling (P=2.52×10−5) genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional data set. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer. PMID:24419231

  3. Interactions between Trypanosoma cruzi Secreted Proteins and Host Cell Signaling Pathways

    PubMed Central

    Watanabe Costa, Renata; da Silveira, Jose F.; Bahia, Diana

    2016-01-01

    Chagas disease is one of the prevalent neglected tropical diseases, affecting at least 6–7 million individuals in Latin America. It is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted to vertebrate hosts by blood-sucking insects. After infection, the parasite invades and multiplies in the myocardium, leading to acute myocarditis that kills around 5% of untreated individuals. T. cruzi secretes proteins that manipulate multiple host cell signaling pathways to promote host cell invasion. The primary secreted lysosomal peptidase in T. cruzi is cruzipain, which has been shown to modulate the host immune response. Cruzipain hinders macrophage activation during the early stages of infection by interrupting the NF-kB P65 mediated signaling pathway. This allows the parasite to survive and replicate, and may contribute to the spread of infection in acute Chagas disease. Another secreted protein P21, which is expressed in all of the developmental stages of T. cruzi, has been shown to modulate host phagocytosis signaling pathways. The parasite also secretes soluble factors that exert effects on host extracellular matrix, such as proteolytic degradation of collagens. Finally, secreted phospholipase A from T. cruzi contributes to lipid modifications on host cells and concomitantly activates the PKC signaling pathway. Here, we present a brief review of the interaction between secreted proteins from T. cruzi and the host cells, emphasizing the manipulation of host signaling pathways during invasion. PMID:27065960

  4. Using the Biochemical Pathway Model To Teach the Concepts of Gene Interaction and Epistasis.

    ERIC Educational Resources Information Center

    Chinnici, Joseph P.

    1999-01-01

    Describes the successful use of giving examples of genes affecting various steps in biochemical pathways to teach gene interaction. Finds that once students grasp the notion that genes can interact because they control different steps within biochemical pathways, the reason why phenotypic ratios appear to be non-Mendelian becomes more obvious and…

  5. Progesterone in pregnancy; receptor-ligand interaction and signaling pathways.

    PubMed

    Szekeres-Bartho, Julia; Halasz, Melinda; Palkovics, Tamas

    2009-12-01

    Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an appropriate maternal immune response to the fetus. Along with its endocrine effects, progesterone also acts as an "immunosteroid", by contributing to the establishment of a pregnancy protective immune milieu. Progesterone plays a role in uterine homing of NK cells and upregulates HLA-G gene expression, the ligand for NK inhibitory and activating receptors. At high concentrations, progesterone is a potent inducer of Th2-type cytokines as well as of LIF and M-CSF production by T cells. A protein called progesterone-induced blocking factor (PIBF), by inducing a Th2-dominant cytokine production mediates the immunological effects of progesterone. PIBF binds to a novel type of the IL-4 receptor and signals via the Jak/STAT pathway, to induce a number of genes, that not only affect the immune response, but might also play a role in trophoblast invasiveness. PMID:19880194

  6. Defining the Protein–Protein Interaction Network of the Human Hippo Pathway*

    PubMed Central

    Wang, Wenqi; Li, Xu; Huang, Jun; Feng, Lin; Dolinta, Keithlee G.; Chen, Junjie

    2014-01-01

    The Hippo pathway, which is conserved from Drosophila to mammals, has been recognized as a tumor suppressor signaling pathway governing cell proliferation and apoptosis, two key events involved in organ size control and tumorigenesis. Although several upstream regulators, the conserved kinase cascade and key downstream effectors including nuclear transcriptional factors have been defined, the global organization of this signaling pathway is not been fully understood. Thus, we conducted a proteomic analysis of human Hippo pathway, which revealed the involvement of an extensive protein–protein interaction network in this pathway. The mass spectrometry data were deposited to ProteomeXchange with identifier PXD000415. Our data suggest that 550 interactions within 343 unique protein components constitute the central protein–protein interaction landscape of human Hippo pathway. Our study provides a glimpse into the global organization of Hippo pathway, reveals previously unknown interactions within this pathway, and uncovers new potential components involved in the regulation of this pathway. Understanding these interactions will help us further dissect the Hippo signaling-pathway and extend our knowledge of organ size control. PMID:24126142

  7. The multiple pathways for itch and their interactions with pain

    PubMed Central

    Davidson, Steve; Giesler, Glenn J

    2010-01-01

    Multiple neural pathways and molecular mechanisms responsible for producing the sensation of itch have recently been identified, including histamine-independent pathways. Physiological, molecular, behavioral and brain imaging studies are converging to describe these pathways and their close association with pain processing. Some conflicting results have arisen, and the precise relationship between itch and pain remains controversial. A better understanding of the generation of itch and of the intrinsic mechanisms that inhibit itch after scratching should facilitate the search for new methods to alleviate clinical pruritus (itch). In this review, we describe the current understanding of the production and inhibition of itch. A model of itch processing within the central nervous system (CNS) is proposed. PMID:21056479

  8. Interaction of key pathways in sorafenib-treated hepatocellular carcinoma based on a PCR-array

    PubMed Central

    Liu, Yan; Wang, Ping; Li, Shijie; Yin, Linan; Shen, Haiyang; Liu, Ruibao

    2015-01-01

    This study aimed to identify the key pathways and to explore the mechanism of sorafenib in inhibiting hepatocellular carcinoma (HCC). The gene expression profile of GSE33621, including 6 sorafenib treated group and 6 control samples, was downloaded from the GEO (Gene Expression Omnibus) database. The differentially expressed genes (DEGs) in HCC samples were screened using the ΔΔCt method with the homogenized internal GAPDH. Also, the functions and pathways of DEGs were analyzed using the DAVID. Moreover, the significant pathways of DEGs that involved in HCC were analyzed based on the Latent pathway identification analysis (LPIA). A total of 44 down-regulated DEGs were selected in HCC samples. Also, there were 84 biological pathways that these 44 DEGs involved in. Also, LPIA showed that Osteoclast differentiation and hsa04664-Fc epsilon RI signaling pathway was the most significant interaction pathways. Moreover, Apoptosis, Toll-like receptor signaling pathway, Chagas disease, and T cell receptor signaling pathway were the significant pathways that interacted with hsa04664. In addition, DEGs such as AKT1 (v-akt murine thymoma viral oncogene homolog 1), TNF (tumor necrosis factor), SYK (spleen tyrosine kinase), and PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha)) were the common genes that involved in the significant pathways. Several pathway interaction pairs that caused by several downregulated genes such as SYK, PI3K, AKT1, and TNF, were identified play curial role in sorafenib treated HCC. Sorafenib played important inhibition roles in HCC by affecting a complicate pathway interaction network. PMID:26045814

  9. BDNF-estrogen interactions in hippocampal mossy fiber pathway: implications for normal brain function and disease

    PubMed Central

    Harte-Hargrove, Lauren; MacLusky, Neil J.; Scharfman, Helen E.

    2013-01-01

    The neurotrophin BDNF and the steroid hormone estrogen exhibit potent effects on hippocampal neurons during development and in adulthood. BDNF and estrogen have also been implicated in the etiology of diverse types of neurological disorders or psychiatric illnesses, or have been discussed as potentially important in treatment. Although both are typically studied independently, it has been suggested that BDNF mediates several of the effects of estrogen in hippocampus, and that these interactions play a role in the normal brain as well as disease. Here we focus on the mossy fiber (MF) pathway of the hippocampus, a critical pathway in normal hippocampal function, and a prime example of a location where numerous studies support an interaction between BDNF and estrogen in the rodent brain. We first review the temporal and spatially-regulated expression of BDNF and estrogen in the MFs, as well as their receptors. Then we consider the results of studies that suggest that 17β-estradiol alters hippocampal function by its influence on BDNF expression in the MF pathway. We also address the hypothesis that estrogen influences hippocampus by mechanisms related not only to the mature form of BDNF, acting at trkB receptors, but also by regulating the precursor, proBDNF, acting at p75NTR. We suggest that the interactions between BDNF and 17β-estradiol in the MFs are potentially important in the normal function of the hippocampus, and have implications for sex differences in functions that depend on the MFs and in diseases where MF plasticity has been suggested to play an important role, Alzheimer’s disease, epilepsy and addiction. PMID:23276673

  10. The Arginine Decarboxylase Pathways of Host and Pathogen Interact to Impact Inflammatory Pathways in the Lung

    PubMed Central

    Dalluge, Joseph J.; Welchlin, Cole W.; Hughes, John; Han, Wei; Blackwell, Timothy S.; Laguna, Theresa A.; Williams, Bryan J.

    2014-01-01

    The arginine decarboxylase pathway, which converts arginine to agmatine, is present in both humans and most bacterial pathogens. In humans agmatine is a neurotransmitter with affinities towards α2-adrenoreceptors, serotonin receptors, and may inhibit nitric oxide synthase. In bacteria agmatine serves as a precursor to polyamine synthesis and was recently shown to enhance biofilm development in some strains of the respiratory pathogen Pseudomonas aeruginosa. We determined agmatine is at the center of a competing metabolism in the human lung during airways infections and is influenced by the metabolic phenotypes of the infecting pathogens. Ultra performance liquid chromatography with mass spectrometry detection was used to measure agmatine in human sputum samples from patients with cystic fibrosis, spent supernatant from clinical sputum isolates, and from bronchoalvelolar lavage fluid from mice infected with P. aeruginosa agmatine mutants. Agmatine in human sputum peaks during illness, decreased with treatment and is positively correlated with inflammatory cytokines. Analysis of the agmatine metabolic phenotype in clinical sputum isolates revealed most deplete agmatine when grown in its presence; however a minority appeared to generate large amounts of agmatine presumably driving sputum agmatine to high levels. Agmatine exposure to inflammatory cells and in mice demonstrated its role as a direct immune activator with effects on TNF-α production, likely through NF-κB activation. P. aeruginosa mutants for agmatine detection and metabolism were constructed and show the real-time evolution of host-derived agmatine in the airways during acute lung infection. These experiments also demonstrated pathogen agmatine production can upregulate the inflammatory response. As some clinical isolates have adapted to hypersecrete agmatine, these combined data would suggest agmatine is a novel target for immune modulation in the host-pathogen dynamic. PMID:25350753

  11. Interaction between ICOS-B7RP1 and B7-CD28 costimulatory pathways in alloimmune responses in vivo.

    PubMed

    Salama, Alan D; Yuan, Xueli; Nayer, Ali; Chandraker, Anil; Inobe, Manabu; Uede, Toshimutsu; Sayegh, Mohamed H

    2003-04-01

    The B7-CD28 pathway is one of the foremost costimulatory pathways involved in T-cell activation. Recently, a number of additional costimulatory pathways have been described and preliminary data suggest that they play important roles in alloimmunity. However, the interactions between these different pathways are not well understood. We studied the effect of targeting ICOS ligand, B7RP1, in a rat cardiac transplant model, with and without concomitant blockade of the B7 pathway using CTLA4Ig. In a fully mismatched WF to LEW vascularized cardiac allograft model, without therapy, grafts were acutely rejected (MST 10.8 +/- 1.6 days). Early (day of transplant) B7RP1 blockade with ICOSIg alone had little effect on graft survival and rather than being additive with B7 blockade, ICOSIg abrogated the prolonged graft survival induced by CTLA4Ig treatment. By contrast, delayed (day 2 post-transplant) blockade of B7RP1 did not have such an effect. These findings were not related to cytokine deviation but may be in part related to the pattern of down-regulation of B7.2 expression following early B7RP1 blockade. This is the first report describing the complex interactions between ICOS-B7RP1 and B7-CD28 costimulatory pathways in alloimmunity in vivo. PMID:12694060

  12. PathPPI: an integrated dataset of human pathways and protein-protein interactions.

    PubMed

    Tang, HaiLin; Zhong, Fan; Liu, Wei; He, FuChu; Xie, HongWei

    2015-06-01

    Integration of pathway and protein-protein interaction (PPI) data can provide more information that could lead to new biological insights. PPIs are usually represented by a simple binary model, whereas pathways are represented by more complicated models. We developed a series of rules for transforming protein interactions from pathway to binary model, and the protein interactions from seven pathway databases, including PID, BioCarta, Reactome, NetPath, INOH, SPIKE and KEGG, were transformed based on these rules. These pathway-derived binary protein interactions were integrated with PPIs from other five PPI databases including HPRD, IntAct, BioGRID, MINT and DIP, to develop integrated dataset (named PathPPI). More detailed interaction type and modification information on protein interactions can be preserved in PathPPI than other existing datasets. Comparison analysis results indicate that most of the interaction overlaps values (O AB) among these pathway databases were less than 5%, and these databases must be used conjunctively. The PathPPI data was provided at http://proteomeview.hupo.org.cn/PathPPI/PathPPI.html. PMID:25591449

  13. Receptor interactions through phosphorylation and methylation pathways in bacterial chemotaxis.

    PubMed Central

    Sanders, D A; Koshland, D E

    1988-01-01

    The effects of messages initiated by one receptor on the covalent modification of a second receptor were studied by use of a technique for rapidly separating the receptors. Methylation of the bacterial-chemotactic serine receptor increases as a result of aspartate binding to the aspartate receptor. The aspartate-induced methylation on the serine receptor is absent in a strain that lacks cheA and cheW genes and is not the result of physical interaction, such as the formation of heterodimers between the aspartate and serine receptors, or of alterations in the affinity of the serine receptor for the methyltransferase and the methylesterase. Serine-induced methylation of the serine receptor did not require cheA and cheW. A model is presented in which the receptor methylation level depends on the combination of (i) a ligand-induced conformational change on the receptor substrate of the methylation enzymes and (ii) an indirect cytoplasmic signal that operates through the methylesterase. PMID:2847160

  14. Linear effects models of signaling pathways from combinatorial perturbation data

    PubMed Central

    Szczurek, Ewa; Beerenwinkel, Niko

    2016-01-01

    Motivation: Perturbations constitute the central means to study signaling pathways. Interrupting components of the pathway and analyzing observed effects of those interruptions can give insight into unknown connections within the signaling pathway itself, as well as the link from the pathway to the effects. Different pathway components may have different individual contributions to the measured perturbation effects, such as gene expression changes. Those effects will be observed in combination when the pathway components are perturbed. Extant approaches focus either on the reconstruction of pathway structure or on resolving how the pathway components control the downstream effects. Results: Here, we propose a linear effects model, which can be applied to solve both these problems from combinatorial perturbation data. We use simulated data to demonstrate the accuracy of learning the pathway structure as well as estimation of the individual contributions of pathway components to the perturbation effects. The practical utility of our approach is illustrated by an application to perturbations of the mitogen-activated protein kinase pathway in Saccharomyces cerevisiae. Availability and Implementation: lem is available as a R package at http://www.mimuw.edu.pl/∼szczurek/lem. Contact: szczurek@mimuw.edu.pl; niko.beerenwinkel@bsse.ethz.ch Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307630

  15. Protein/Protein Interactions in the Mammalian Heme Degradation Pathway

    PubMed Central

    Spencer, Andrea L. M.; Bagai, Ireena; Becker, Donald F.; Zuiderweg, Erik R. P.; Ragsdale, Stephen W.

    2014-01-01

    Heme oxygenase (HO) catalyzes the rate-limiting step in the O2-dependent degradation of heme to biliverdin, CO, and iron with electrons delivered from NADPH via cytochrome P450 reductase (CPR). Biliverdin reductase (BVR) then catalyzes conversion of biliverdin to bilirubin. We describe mutagenesis combined with kinetic, spectroscopic (fluorescence and NMR), surface plasmon resonance, cross-linking, gel filtration, and analytical ultracentrifugation studies aimed at evaluating interactions of HO-2 with CPR and BVR. Based on these results, we propose a model in which HO-2 and CPR form a dynamic ensemble of complex(es) that precede formation of the productive electron transfer complex. The 1H-15N TROSY NMR spectrum of HO-2 reveals specific residues, including Leu-201, near the heme face of HO-2 that are affected by the addition of CPR, implicating these residues at the HO/CPR interface. Alanine substitutions at HO-2 residues Leu-201 and Lys-169 cause a respective 3- and 22-fold increase in Km values for CPR, consistent with a role for these residues in CPR binding. Sedimentation velocity experiments confirm the transient nature of the HO-2·CPR complex (Kd = 15.1 μm). Our results also indicate that HO-2 and BVR form a very weak complex that is only captured by cross-linking. For example, under conditions where CPR affects the 1H-15N TROSY NMR spectrum of HO-2, BVR has no effect. Fluorescence quenching experiments also suggest that BVR binds HO-2 weakly, if at all, and that the previously reported high affinity of BVR for HO is artifactual, resulting from the effects of free heme (dissociated from HO) on BVR fluorescence. PMID:25196843

  16. From pathways to networks: connecting dots by establishing protein-protein interaction networks in signaling pathways using affinity purification and mass spectrometry

    PubMed Central

    Li, Xu; Wang, Wenqi; Chen, Junjie

    2015-01-01

    Signal transductions are the basis of biological activities in all living organisms. Studying the signaling pathways, especially under physiological conditions, has become one of the most important facets of modern biological research. During the last decade, mass spectrometry has been used extensively in biological research and is proven to be effective in addressing important biological questions. Here, we review the current progress in the understanding of signaling networks using mass spectrometry approaches. We will focus on studies of protein-protein interactions that use affinity purification followed by mass spectrometry approach. We discuss obstacles to affinity purification, data processing, functional validation, and identification of transient interactions and provide potential solutions for pathway-specific proteomics analysis, which we hope one day will lead to a comprehensive understanding of signaling networks in humans. PMID:25137225

  17. From pathways to networks: connecting dots by establishing protein-protein interaction networks in signaling pathways using affinity purification and mass spectrometry.

    PubMed

    Li, Xu; Wang, Wenqi; Chen, Junjie

    2015-01-01

    Signal transductions are the basis of biological activities in all living organisms. Studying the signaling pathways, especially under physiological conditions, has become one of the most important facets of modern biological research. During the last decade, MS has been used extensively in biological research and is proven to be effective in addressing important biological questions. Here, we review the current progress in the understanding of signaling networks using MS approaches. We will focus on studies of protein-protein interactions that use affinity purification followed by MS approach. We discuss obstacles to affinity purification, data processing, functional validation, and identification of transient interactions and provide potential solutions for pathway-specific proteomics analysis, which we hope one day will lead to a comprehensive understanding of signaling networks in humans. PMID:25137225

  18. Wolbachia-induced paternal defect in Drosophila is likely by interaction with the juvenile hormone pathway.

    PubMed

    Liu, Chen; Wang, Jia-Lin; Zheng, Ya; Xiong, En-Juan; Li, Jing-Jing; Yuan, Lin-Ling; Yu, Xiao-Qiang; Wang, Yu-Feng

    2014-06-01

    Wolbachia are endosymbionts that infect many insect species. They can manipulate the host's reproduction to increase their own maternal transmission. Cytoplasmic incompatibility (CI) is one such manipulation, which is expressed as embryonic lethality when Wolbachia-infected males mate with uninfected females. However, matings between males and females carrying the same Wolbachia strain result in viable progeny. The molecular mechanisms of CI are currently not clear. We have previously reported that the gene Juvenile hormone-inducible protein 26 (JhI-26) exhibited the highest upregulation in the 3rd instar larval testes of Drosophila melanogaster when infected by Wolbachia. This is reminiscent of an interaction between Wolbachia and juvenile hormone (JH) pathway in flies. Considering that Jhamt gene encodes JH acid methyltransferase, a key regulatory enzyme of JH biosynthesis, and that methoprene-tolerant (Met) has been regarded as the best JH receptor candidate, we first compared the expression of Jhamt and Met between Wolbachia-infected and uninfected fly testes to investigate whether Wolbachia infection influence the JH signaling pathway. We found that the expressions of Jhamt and Met were significantly increased in the presence of Wolbachia, suggesting an interaction of Wolbachia with the JH signaling pathway. Then, we found that overexpression of JhI-26 in Wolbachia-free transgenic male flies caused paternal-effect lethality that mimics the defects associated with CI. JhI-26 overexpressing males resulted in significantly decrease in hatch rate. Surprisingly, Wolbachia-infected females could rescue the egg hatch. In addition, we showed that overexpression of JhI-26 caused upregulation of the male accessory gland protein (Acp) gene CG10433, but not vice versa. This result suggests that JhI-26 may function at the upstream of CG10433. Likewise, overexpression of CG10433 also resulted in paternal-effect lethality. Both JhI-26 and CG10433 overexpressing males

  19. Hodgkin Lymphoma Risk: Role of Genetic Polymorphisms and Gene-Gene Interactions in DNA repair pathways

    PubMed Central

    Monroy, Claudia M.; Cortes, Andrea C.; Lopez, Mirtha; Rourke, Elizabeth; Etzel, Carol J.; Younes, Anas; Strom, Sara S.; El-Zein, Randa

    2011-01-01

    DNA repair variants may play a potentially important role in an individual’s susceptibility to developing cancer. Numerous studies have reported the association between genetic single nucleotide polymorphisms (SNPs) in DNA repair genes and different types of hematologic cancers. However, to date, the effects of such SNPs on modulating Hodgkin Lymphoma (HL) risk have not yet been investigated. We hypothesized that gene-gene interaction between candidate genes in Direct Reversal, Nucleotide excision repair (NER), Base excision repair (BER) and Double strand break (DSB) pathways may contribute to susceptibility to HL. To test this hypothesis, we conducted a study on 200 HL cases and 220 controls to assess associations between HL risk and 21 functional SNPs in DNA repair genes. We evaluated potential gene-gene interactions and the association of multiple polymorphisms in a chromosome region using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction and classification and regression tree approaches. We observed that, in combination, allelic variants in the XPC Ala499Val, NBN Glu185Gln, XRCC3 Thr241Me, XRCC1 Arg194Trp and XRCC1 399Gln polymorphisms modify the risk for developing HL. Moreover, the cumulative genetic risk score revealed a significant trend where the risk for developing HL increases as the number of adverse alleles in BER and DSB genes increase. These findings suggest that DNA repair variants in BER and DSB pathways may play an important role in the development of HL. PMID:21374732

  20. Nonlinear Scale Interactions and Energy Pathways in the Ocean

    NASA Astrophysics Data System (ADS)

    Aluie, Hussein; Hecht, Matthew; Vallis, Geoffrey; Bryan, Kirk; Maltrud, Mathew; Ecke, Robert; Wingate, Beth

    2013-03-01

    Large-scale currents and eddies pervade the ocean and play a prime role in the general circulation and climate. The coupling between scales ranging from O (104) km down to O (1) mm presents a major difficulty in understanding, modeling, and predicting oceanic circulation and mixing, where the energy budget is uncertain within a factor possibly as large as ten. Identifying the energy sources and sinks at various scales can reduce such uncertainty and yield insight into new parameterizations. To this end, we refine a novel coarse-graining framework to directly analyze the coupling between scales. The approach is very general, allows for probing the dynamics simultaneously in scale and in space, and is not restricted by usual assumptions of homogeneity or isotropy. We apply these tools to study the energy pathways from high-resolution ocean simulations using LANL's Parallel Ocean Program. We examine the extent to which the traditional paradigm for such pathways is valid at various locations such as in western boundary currents, near the equator, and in the deep ocean. We investigate the contribution of various nonlinear mechanisms to the transfer of energy across scales such as baroclinic and barotropic instabilities, barotropization, and Rossby wave generation.

  1. Energy Pathways and Scale Interactions in the Ocean

    NASA Astrophysics Data System (ADS)

    Aluie, H.; Hecht, M. W.; Vallis, G. K.; Bryan, K.; Ecke, R. E.; Maltrud, M. E.; Wingate, B. A.

    2012-12-01

    Large-scale currents and eddies pervade the ocean and play a prime role in the general circulation and climate. The coupling between scales ranging from O(104) km down to O(1) mm presents a major difficulty in understanding, modeling, and predicting oceanic circulation and mixing, where the energy budget is uncertain within a factor possibly as large as ten. Identifying the energy sources and sinks at various scales can reduce such uncertainty and yield insight into new parameterizations. To this end, we refine a novel coarse-graining framework to directly analyze the coupling between scales. The approach is very general, allows for probing the dynamics simultaneously in scale and in space, and is not restricted by usual assumptions of homogeneity or isotropy. We apply these tools to study the energy pathways from high-resolution ocean simulations using LANL's Parallel Ocean Program. We examine the extent to which the traditional paradigm for such pathways is valid at various locations such as in western boundary currents, near the equator, and in the deep ocean. We investigate the contribution of various nonlinear mechanisms to the transfer of energy across scales such as baroclinic and barotropic instabilities, barotropization, and Rossby wave generation.

  2. Nonlinear Scale Interactions and Energy Pathways in the Ocean

    NASA Astrophysics Data System (ADS)

    Aluie, Hussein; Hecht, Matthew; Vallis, Geoffrey

    2013-11-01

    Large-scale currents and eddies pervade the ocean and play a prime role in the general circulation and climate. The coupling between scales ranging from O (104) km down to O (1) mm presents a major difficulty in understanding, modeling, and predicting oceanic circulation and mixing, where the energy budget is uncertain within a factor possibly as large as ten. Identifying the energy sources and sinks at various scales can reduce such uncertainty and yield insight into new parameterizations. To this end, we refine a novel coarse-graining framework to directly analyze the coupling between scales. The approach is very general, allows for probing the dynamics simultaneously in scale and in space, and is not restricted by usual assumptions of homogeneity or isotropy. We apply these tools to study the energy pathways from high-resolution ocean simulations using LANL's Parallel Ocean Program. We examine the extent to which the traditional paradigm for such pathways is valid at various locations such as in western boundary currents, near the equator, and in the deep ocean. We investigate the contribution of various nonlinear mechanisms to the transfer of energy across scales such as baroclinic and barotropic instabilities.

  3. LKB1 and Notch Pathways Interact and Control Biliary Morphogenesis

    PubMed Central

    Just, Pierre-Alexandre; Poncy, Alexis; Charawi, Sara; Dahmani, Rajae; Traore, Massiré; Dumontet, Typhanie; Drouet, Valérie; Dumont, Florent; Gilgenkrantz, Hélène; Colnot, Sabine; Terris, Benoit; Coulouarn, Cédric; Lemaigre, Frédéric; Perret, Christine

    2015-01-01

    Background LKB1 is an evolutionary conserved kinase implicated in a wide range of cellular functions including inhibition of cell proliferation, regulation of cell polarity and metabolism. When Lkb1 is inactivated in the liver, glucose homeostasis is perturbed, cellular polarity is affected and cholestasis develops. Cholestasis occurs as a result from deficient bile duct development, yet how LKB1 impacts on biliary morphogenesis is unknown. Methodology/Principal Findings We characterized the phenotype of mice in which deletion of the Lkb1 gene has been specifically targeted to the hepatoblasts. Our results confirmed that lack of LKB1 in the liver results in bile duct paucity leading to cholestasis. Immunostaining analysis at a prenatal stage showed that LKB1 is not required for differentiation of hepatoblasts to cholangiocyte precursors but promotes maturation of the primitive ductal structures to mature bile ducts. This phenotype is similar to that obtained upon inactivation of Notch signaling in the liver. We tested the hypothesis of a functional overlap between the LKB1 and Notch pathways by gene expression profiling of livers deficient in Lkb1 or in the Notch mediator RbpJκ and identified a mutual cross-talk between LKB1 and Notch signaling. In vitro experiments confirmed that Notch activity was deficient upon LKB1 loss. Conclusion LKB1 and Notch share a common genetic program in the liver, and regulate bile duct morphogenesis. PMID:26689699

  4. Peptides interfering with protein-protein interactions in the ethylene signaling pathway delay tomato fruit ripening

    PubMed Central

    Bisson, Melanie M. A.; Kessenbrock, Mareike; Müller, Lena; Hofmann, Alexander; Schmitz, Florian; Cristescu, Simona M.; Groth, Georg

    2016-01-01

    The plant hormone ethylene is involved in the regulation of several processes with high importance for agricultural applications, e.g. ripening, aging and senescence. Previous work in our group has identified a small peptide (NOP-1) derived from the nuclear localization signal of the Arabidopsis ethylene regulator ETHYLENE INSENSITIVE-2 (EIN2) C-terminal part as efficient inhibitor of ethylene responses. Here, we show that NOP-1 is also able to efficiently disrupt EIN2-ETR1 complex formation in tomato, indicating that the NOP-1 inhibition mode is conserved across plant species. Surface application of NOP-1 on green tomato fruits delays ripening similar to known inhibitors of ethylene perception (MCP) and ethylene biosynthesis (AVG). Fruits treated with NOP-1 showed similar ethylene production as untreated controls underlining that NOP-1 blocks ethylene signaling by targeting an essential interaction in this pathway, while having no effect on ethylene biosynthesis. PMID:27477591

  5. Localization and interactions between Arabidopsis auxin biosynthetic enzymes in the TAA/YUC-dependent pathway.

    PubMed

    Kriechbaumer, Verena; Botchway, Stanley W; Hawes, Chris

    2016-07-01

    The growth regulator auxin is involved in all key developmental processes in plants. A complex network of a multiplicity of potential biosynthetic pathways as well as transport, signalling plus conjugation and deconjugation lead to a complex and multifaceted system system for auxin function. This raises the question how such a system can be effectively organized and controlled. Here we report that a subset of auxin biosynthetic enzymes in the TAA/YUC route of auxin biosynthesis is localized to the endoplasmic reticulum (ER). ER microsomal fractions also contain a significant percentage of auxin biosynthetic activity. This could point toward a model of auxin function using ER membrane location and subcellular compartmentation for supplementary layers of regulation. Additionally we show specific protein-protein interactions between some of the enzymes in the TAA/YUC route of auxin biosynthesis. PMID:27208541

  6. Peptides interfering with protein-protein interactions in the ethylene signaling pathway delay tomato fruit ripening.

    PubMed

    Bisson, Melanie M A; Kessenbrock, Mareike; Müller, Lena; Hofmann, Alexander; Schmitz, Florian; Cristescu, Simona M; Groth, Georg

    2016-01-01

    The plant hormone ethylene is involved in the regulation of several processes with high importance for agricultural applications, e.g. ripening, aging and senescence. Previous work in our group has identified a small peptide (NOP-1) derived from the nuclear localization signal of the Arabidopsis ethylene regulator ETHYLENE INSENSITIVE-2 (EIN2) C-terminal part as efficient inhibitor of ethylene responses. Here, we show that NOP-1 is also able to efficiently disrupt EIN2-ETR1 complex formation in tomato, indicating that the NOP-1 inhibition mode is conserved across plant species. Surface application of NOP-1 on green tomato fruits delays ripening similar to known inhibitors of ethylene perception (MCP) and ethylene biosynthesis (AVG). Fruits treated with NOP-1 showed similar ethylene production as untreated controls underlining that NOP-1 blocks ethylene signaling by targeting an essential interaction in this pathway, while having no effect on ethylene biosynthesis. PMID:27477591

  7. [Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

    PubMed

    Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

    2015-01-01

    Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. PMID:25986976

  8. Pedigree-based random effect tests to screen gene pathways.

    PubMed

    Almeida, Marcio; Peralta, Juan M; Farook, Vidya; Puppala, Sobha; Kent, John W; Duggirala, Ravindranath; Blangero, John

    2014-01-01

    The new generation of sequencing platforms opens new horizons in the genetics field. It is possible to exhaustively assay all genetic variants in an individual and search for phenotypic associations. The whole genome sequencing approach, when applied to a large human sample like the San Antonio Family Study, detects a very large number (>25 million) of single nucleotide variants along with other more complex variants. The analytical challenges imposed by this number of variants are formidable, suggesting that methods are needed to reduce the overall number of statistical tests. In this study, we develop a single degree-of-freedom test of variants in a gene pathway employing a random effect model that uses an empirical pathway-specific genetic relationship matrix as the focal covariance kernel. The empirical pathway-specific genetic relationship uses all variants (or a chosen subset) from gene members of a given biological pathway. Using SOLAR's pedigree-based variance components modeling, which also allows for arbitrary fixed effects, such as principal components, to deal with latent population structure, we employ a likelihood ratio test of the pathway-specific genetic relationship matrix model. We examine all gene pathways in KEGG database gene pathways using our method in the first replicate of the Genetic Analysis Workshop 18 simulation of systolic blood pressure. Our random effect approach was able to detect true association signals in causal gene pathways. Those pathways could be easily be further dissected by the independent analysis of all markers. PMID:25519354

  9. An Effective Method to Identify Shared Pathways and Common Factors among Neurodegenerative Diseases

    PubMed Central

    Li, Ping; Nie, Yaling; Yu, Jingkai

    2015-01-01

    Groups of distinct but related diseases often share common symptoms, which suggest likely overlaps in underlying pathogenic mechanisms. Identifying the shared pathways and common factors among those disorders can be expected to deepen our understanding for them and help designing new treatment strategies effected on those diseases. Neurodegeneration diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), were taken as a case study in this research. Reported susceptibility genes for AD, PD and HD were collected and human protein-protein interaction network (hPPIN) was used to identify biological pathways related to neurodegeneration. 81 KEGG pathways were found to be correlated with neurodegenerative disorders. 36 out of the 81 are human disease pathways, and the remaining ones are involved in miscellaneous human functional pathways. Cancers and infectious diseases are two major subclasses within the disease group. Apoptosis is one of the most significant functional pathways. Most of those pathways found here are actually consistent with prior knowledge of neurodegenerative diseases except two cell communication pathways: adherens and tight junctions. Gene expression analysis showed a high probability that the two pathways were related to neurodegenerative diseases. A combination of common susceptibility genes and hPPIN is an effective method to study shared pathways involved in a group of closely related disorders. Common modules, which might play a bridging role in linking neurodegenerative disorders and the enriched pathways, were identified by clustering analysis. The identified shared pathways and common modules can be expected to yield clues for effective target discovery efforts on neurodegeneration. PMID:26575483

  10. Bioinformatics Annotation of Human Y Chromosome-Encoded Protein Pathways and Interactions.

    PubMed

    Rengaraj, Deivendran; Kwon, Woo-Sung; Pang, Myung-Geol

    2015-09-01

    We performed a comprehensive analysis of human Y chromosome-encoded proteins, their pathways, and their interactions using bioinformatics tools. From the NCBI annotation release 107 of human genome, we retrieved a total of 66 proteins encoded on Y chromosome. Most of the retrieved proteins were also matched with the proteins listed in the core databases of the Human Proteome Project including neXtProt, PeptideAtlas, and the Human Protein Atlas. When we examined the pathways of human Y-encoded proteins through KEGG database and Pathway Studio software, many of proteins fall into the categories related to cell signaling pathways. Using the STRING program, we found a total of 49 human Y-encoded proteins showing strong/medium interaction with each other. While using the Pathway studio software, we found that a total of 16 proteins interact with other chromosome-encoded proteins. In particular, the SRY protein interacted with 17 proteins encoded on other chromosomes. Additionally, we aligned the sequences of human Y-encoded proteins with the sequences of chimpanzee and mouse Y-encoded proteins using the NCBI BLAST program. This analysis resulted in a significant number of orthologous proteins between human, chimpanzee, and mouse. Collectively, our findings provide the scientific community with additional information on the human Y chromosome-encoded proteins. PMID:26279084

  11. Interactions between the jasmonic and salicylic acid pathway modulate the plant metabolome and affect herbivores of different feeding types.

    PubMed

    Schweiger, R; Heise, A-M; Persicke, M; Müller, C

    2014-07-01

    The phytohormones jasmonic acid (JA) and salicylic acid (SA) mediate induced plant defences and the corresponding pathways interact in a complex manner as has been shown on the transcript and proteine level. Downstream, metabolic changes are important for plant-herbivore interactions. This study investigated metabolic changes in leaf tissue and phloem exudates of Plantago lanceolata after single and combined JA and SA applications as well as consequences on chewing-biting (Heliothis virescens) and piercing-sucking (Myzus persicae) herbivores. Targeted metabolite profiling and untargeted metabolic fingerprinting uncovered different categories of plant metabolites, which were influenced in a specific manner, indicating points of divergence, convergence, positive crosstalk and pronounced mutual antagonism between the signaling pathways. Phytohormone-specific decreases of primary metabolite pool sizes in the phloem exudates may indicate shifts in sink-source relations, resource allocation, nutrient uptake or photosynthesis. Survival of both herbivore species was significantly reduced by JA and SA treatments. However, the combined application of JA and SA attenuated the negative effects at least against H. virescens suggesting that mutual antagonism between the JA and SA pathway may be responsible. Pathway interactions provide a great regulatory potential for the plant that allows triggering of appropriate defences when attacked by different antagonist species. PMID:24372400

  12. Interactions between the juvenile Batten disease gene, CLN3, and the Notch and JNK signalling pathways

    PubMed Central

    Tuxworth, Richard I.; Vivancos, Valérie; O'Hare, Megan B.; Tear, Guy

    2009-01-01

    Mutations in the gene CLN3 are responsible for the neurodegenerative disorder juvenile neuronal ceroid lipofuscinosis or Batten disease. CLN3 encodes a multi-spanning and hydrophobic transmembrane protein whose function is unclear. As a consequence, the cell biology that underlies the pathology of the disease is not well understood. We have developed a genetic gain-of-function system in Drosophila to identify functional pathways and interactions for CLN3. We have identified previously unknown interactions between CLN3 and the Notch and Jun N-terminal kinase signalling pathways and have uncovered a potential role for the RNA splicing and localization machinery in regulating CLN3 function. PMID:19028667

  13. Organelle interactions and possible degradation pathways visualized in high-pressure frozen algal cells.

    PubMed

    Aichinger, N; Lütz-Meindl, U

    2005-08-01

    Summary Organelle interactions, although essential for both anabolic and catabolic pathways in plant cells have not been examined in detail so far. In the present study the structure of different organelle-organelle, organelle-vesicle and organelle-membrane interactions were investigated in growing and nongrowing cells of the green alga Micrasterias denticulata by use of high pressure freeze fixation and energy filtering transmission electron microscopy. It became clear that contacts between mitochondria always occur by formation of a cone-shaped protuberance of one of the mitochondria which penetrates into its fusion partner. In the same way, structural interactions between mitochondria and mucilage vesicles and between microbodies and mucilage vesicles are achieved. Lytic compartments contact mitochondria or mucilage vesicles again by forming protuberances and by extending their contents into the respective compartment. Detached portions of mitochondria are found inside lytic compartments as a consequence of such interactions. Mitochondria found in contact with the plasma membrane reveal structural disintegration. Our study shows that interactions of organelles and vesicles are frequent events in Micrasterias cells of different ages. The interactive contacts between lytic compartments and organelles or vesicles suggest a degradation pathway different from autophagy processes described in the literature. Both the interactions between vesicles and organelles and the degradation pathways occur independently from cytoskeleton function as demonstrated by use of cytochalasin D and the microtubule inhibitor amiprophos-methyl. PMID:16159344

  14. Clozapine Interaction with Phosphatidyl Inositol 3-Kinase (PI3K)/Insulin Signaling Pathway in Caenorhabditis elegans

    PubMed Central

    Karmacharya, Rakesh; Sliwoski, Gregory R.; Lundy, Miriam Y.; Suckow, Raymond F.; Cohen, Bruce M.; Buttner, Edgar A.

    2012-01-01

    Clozapine has superior and unique effects as an antipsychotic agent, but the mediators of these effects are not known. We studied behavioral and developmental effects of clozapine in Caenorhabditis elegans, as a model system to identify previously undiscovered mechanisms of drug action. Clozapine induced early larval arrest, a phenotype that was also seen with the clozapine metabolite N-desmethyl clozapine but not with any other typical or atypical antipsychotic drug tested. Mutations in the insulin receptor/daf-2 and the phosphatidyl inositol 3-kinase (PI3K)/age-1 suppressed clozapine-induced larval arrest, suggesting that clozapine may activate the insulin signaling pathway. Consistent with this notion, clozapine also increased expression of an age-1::GFP reporter. Activation of the insulin signaling pathway leads to cytoplasmic localization of the fork head transcription factor FOXO/daf-16. Clozapine produced cytoplasmic localization of DAF-16::GFP in arrested L1 larvae, in contrast to stressors such as starvation or high temperature which produce nuclear localization of DAF-16::GFP in arrested L1 larvae. Clozapine also inhibited pharyngeal pumping in C. elegans, an effect that may contribute to but did not explain clozapine-induced larval arrest. Our findings demonstrate a drug-specific interaction between clozapine and the PI3K/insulin signaling pathway in C. elegans. As this pathway is conserved across species, the results may have implications for understanding the unique effects of clozapine in humans. PMID:19322168

  15. Uniform and Complementary Social Interaction: Distinct Pathways to Solidarity.

    PubMed

    Koudenburg, Namkje; Postmes, Tom; Gordijn, Ernestine H; van Mourik Broekman, Aafke

    2015-01-01

    We examine how different forms of co-action give rise to feelings of solidarity. We propose that (a) coordinated action elicits a sense of solidarity, and (b) the process through which such solidarity emerges differs for different forms of co-action. We suggest that whether solidarity within groups emerges from uniform action (e.g. synchronizing, as when people speak in unison) or from more complementary forms of action (e.g. alternating, when speaking in turns) has important consequences for the emergent position of individuals within the group. Uniform action relies on commonality, leaving little scope for individuality. In complementary action each individual makes a distinctive contribution to the group, thereby increasing a sense of personal value to the group, which should contribute to the emergence of solidarity. The predictions receive support from five studies, in which we study groups in laboratory and field settings. Results show that both complementary and uniform co-action increase a sense of solidarity compared to control conditions. However, in the complementary action condition, but not in the uniform action (or synchrony) condition, the effect on feelings of solidarity is mediated by a sense of personal value to the group. PMID:26047131

  16. Uniform and Complementary Social Interaction: Distinct Pathways to Solidarity

    PubMed Central

    Koudenburg, Namkje; Postmes, Tom; Gordijn, Ernestine H.; van Mourik Broekman, Aafke

    2015-01-01

    We examine how different forms of co-action give rise to feelings of solidarity. We propose that (a) coordinated action elicits a sense of solidarity, and (b) the process through which such solidarity emerges differs for different forms of co-action. We suggest that whether solidarity within groups emerges from uniform action (e.g. synchronizing, as when people speak in unison) or from more complementary forms of action (e.g. alternating, when speaking in turns) has important consequences for the emergent position of individuals within the group. Uniform action relies on commonality, leaving little scope for individuality. In complementary action each individual makes a distinctive contribution to the group, thereby increasing a sense of personal value to the group, which should contribute to the emergence of solidarity. The predictions receive support from five studies, in which we study groups in laboratory and field settings. Results show that both complementary and uniform co-action increase a sense of solidarity compared to control conditions. However, in the complementary action condition, but not in the uniform action (or synchrony) condition, the effect on feelings of solidarity is mediated by a sense of personal value to the group. PMID:26047131

  17. Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells

    PubMed Central

    Miller, Aaron L; Garza, Anna S; Johnson, Betty H; Thompson, E Brad

    2007-01-01

    CEM cells. Forskolin, which activates the cAMP pathway, and rapamycin, which inhibits mTOR, also inhibit JNK. Further, the sensitizing treatments result in a largely dexamethasone-dependent increase in the total pool of glucocorticoid receptor phosphorylated at serine 211. The phospho-serine 211 receptor is known to be more potent in activating gene transcription and apoptosis. The interactive effects demonstrated here in reverting resistant cells to corticoid sensitivity could provide therapeutic clinical potential in the treatment of lymphoid malignancies. PMID:17391526

  18. The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis

    PubMed Central

    Thomas, Duncan C.; Zhang, Junfeng; Kipen, Howard M.; Rich, David Q.; Zhu, Tong; Huang, Wei; Hu, Min; Wang, Guangfa; Wang, Yuedan; Zhu, Ping; Lu, Shou-En; Ohman-Strickland, Pamela; Diehl, Scott R.; Eckel, Sandrah P.

    2014-01-01

    Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system. PMID:25502951

  19. A novel interaction linking the FAS-II and phthiocerol dimycocerosate (PDIM) biosynthetic pathways.

    PubMed

    Kruh, Nicole A; Borgaro, Janine G; Ruzsicska, Béla P; Xu, Hua; Tonge, Peter J

    2008-11-14

    The fatty acid biosynthesis (FAS-II) pathway in Mycobacterium tuberculosis generates long chain fatty acids that serve as the precursors to mycolic acids, essential components of the mycobacterial cell wall. Enzymes in the FAS-II pathway are thought to form one or more noncovalent multi-enzyme complexes within the cell, and a bacterial two-hybrid screen was used to search for missing components of the pathway and to furnish additional data on interactions involving these enzymes in vivo. Using the FAS-II beta-ketoacyl synthase, KasA, as bait, an extensive bacterial two-hybrid screen of a M. tuberculosis genome fragment library unexpectedly revealed a novel interaction between KasA and PpsB as well as PpsD, two polyketide modules involved in the biosynthesis of the virulence lipid phthiocerol dimycocerosate (PDIM). Sequence analysis revealed that KasA interacts with PpsB and PpsD in the region of the acyl carrier domain of each protein, raising the possibility that lipids could be transferred between the FAS-II and PDIM biosynthetic pathways. Subsequent studies utilizing purified proteins and radiolabeled lipids revealed that fatty acids loaded onto PpsB were transferred to KasA and also incorporated into long chain fatty acids synthesized using a Mycobacterium smegmatis lysate. These data suggest that in addition to producing PDIMs, the growing phthiocerol product can also be shuttled into the FAS-II pathway via KasA as an entry point for further elongation. Interactions between these biosynthetic pathways may exist as a simple means to increase mycobacterial lipid diversity, enhancing functionality and the overall complexity of the cell wall. PMID:18703500

  20. Genetic interactions within inositol-related pathways are associated with longitudinal changes in ventricle size

    PubMed Central

    Koran, Mary Ellen I.; Hohman, Timothy J.; Meda, Shashwath A.; Thornton-Wells, Tricia A.

    2013-01-01

    The genetic etiology of late onset Alzheimer disease (LOAD) has proven complex, involving clinical and genetic heterogeneity and gene-gene interactions. Recent genome wide association studies (GWAS) in LOAD have led to the discovery of novel genetic risk factors; however, the investigation of gene-gene interactions has been limited. Conventional genetic studies often use binary disease status as the primary phenotype, but for complex brain-based diseases, neuroimaging data can serve as quantitative endophenotypes that correlate with disease status and closely reflect pathological changes. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, we tested for association of genetic interactions with longitudinal MRI measurements of the inferior lateral ventricles (ILVs), which have repeatedly shown a relationship to LOAD status and progression. We performed linear regression to evaluate the ability of pathway-derived SNP-SNP pairs to predict the slope of change in volume of the ILVs. After Bonferroni correction, we identified four significant interactions in the right ILV (RILV) corresponding to gene-gene pairs SYNJ2-PI4KA, PARD3-MYH2, PDE3A-ABHD12B and OR2L13-PRKG1 and one significant interaction in the left ILV (LILV) corresponding to SYNJ2-PI4KA. The SNP-SNP interaction corresponding to SYNJ2-PI4KA was identical in the RILV and LILV and was the most significant interaction in each (RILV: p=9.10×10−12; LILV: p=8.20×10−13). Both genes belong to the inositol phosphate signaling pathway which has been previously associated with neurodegeneration in AD and we discuss the possibility that perturbation of this pathway results in a down-regulation of the Akt cell survival pathway and, thereby, decreased neuronal survival, as reflected by increased volume of the ventricles. PMID:24077433

  1. Unified theory of effective interaction

    NASA Astrophysics Data System (ADS)

    Takayanagi, Kazuo

    2016-09-01

    We present a unified description of effective interaction theories in both algebraic and graphic representations. In our previous work, we have presented the Rayleigh-Schrödinger and Bloch perturbation theories in a unified fashion by introducing the main frame expansion of the effective interaction. In this work, we start also from the main frame expansion, and present various nonperturbative theories in a coherent manner, which include generalizations of the Brandow, Brillouin-Wigner, and Bloch-Horowitz theories on the formal side, and the extended Krenciglowa-Kuo and the extended Lee-Suzuki methods on the practical side. We thus establish a coherent and comprehensive description of both perturbative and nonperturbative theories on the basis of the main frame expansion.

  2. Molecular mechanism for the interaction between gibberellin and brassinosteroid signaling pathways in Arabidopsis

    PubMed Central

    Gallego-Bartolomé, Javier; Minguet, Eugenio G.; Grau-Enguix, Federico; Abbas, Mohamad; Locascio, Antonella; Thomas, Stephen G.; Alabadí, David; Blázquez, Miguel A.

    2012-01-01

    Plant development is modulated by the convergence of multiple environmental and endogenous signals, and the mechanisms that allow the integration of different signaling pathways is currently being unveiled. A paradigmatic case is the concurrence of brassinosteroid (BR) and gibberellin (GA) signaling in the control of cell expansion during photomorphogenesis, which is supported by physiological observations in several plants but for which no molecular mechanism has been proposed. In this work, we show that the integration of these two signaling pathways occurs through the physical interaction between the DELLA protein GAI, which is a major negative regulator of the GA pathway, and BRASSINAZOLE RESISTANT1 (BZR1), a transcription factor that broadly regulates gene expression in response to BRs. We provide biochemical evidence, both in vitro and in vivo, indicating that GAI inactivates the transcriptional regulatory activity of BZR1 upon their interaction by inhibiting the ability of BZR1 to bind to target promoters. The physiological relevance of this interaction was confirmed by the observation that the dominant gai-1 allele interferes with BR-regulated gene expression, whereas the bzr1-1D allele displays enhanced resistance to DELLA accumulation during hypocotyl elongation. Because DELLA proteins mediate the response to multiple environmental signals, our results provide an initial molecular framework for the integration with BRs of additional pathways that control plant development. PMID:22847438

  3. Effective interactions between fluid membranes

    NASA Astrophysics Data System (ADS)

    Lu, Bing-Sui; Podgornik, Rudolf

    2015-08-01

    A self-consistent theory is proposed for the general problem of interacting undulating fluid membranes subject to the constraint that they do not interpenetrate. We implement the steric constraint via an exact functional integral representation and, through the use of a saddle-point approximation, transform it into a novel effective steric potential. The steric potential is found to consist of two contributions: one generated by zero-mode fluctuations of the membranes and the other by thermal bending fluctuations. For membranes of cross-sectional area S , we find that the bending fluctuation part scales with the intermembrane separation d as d-2 for d ≪√{S } but crosses over to d-4 scaling for d ≫√{S } , whereas the zero-mode part of the steric potential always scales as d-2. For membranes interacting exclusively via the steric potential, we obtain closed-form expressions for the effective interaction potential and for the rms undulation amplitude σ , which becomes small at low temperatures T and/or large bending stiffnesses κ . Moreover, σ scales as d for d ≪√{S } but saturates at √{kBT S /κ } for d ≫√{S } . In addition, using variational Gaussian theory, we apply our self-consistent treatment to study intermembrane interactions subject to different types of potentials: (i) the Moreira-Netz potential for a pair of strongly charged membranes with an intervening solution of multivalent counterions, (ii) an attractive square well, (iii) the Morse potential, and (iv) a combination of hydration and van der Waals interactions.

  4. Effective interactions between fluid membranes.

    PubMed

    Lu, Bing-Sui; Podgornik, Rudolf

    2015-08-01

    A self-consistent theory is proposed for the general problem of interacting undulating fluid membranes subject to the constraint that they do not interpenetrate. We implement the steric constraint via an exact functional integral representation and, through the use of a saddle-point approximation, transform it into a novel effective steric potential. The steric potential is found to consist of two contributions: one generated by zero-mode fluctuations of the membranes and the other by thermal bending fluctuations. For membranes of cross-sectional area S, we find that the bending fluctuation part scales with the intermembrane separation d as d-2 for d≪√S but crosses over to d-4 scaling for d≫√S, whereas the zero-mode part of the steric potential always scales as d-2. For membranes interacting exclusively via the steric potential, we obtain closed-form expressions for the effective interaction potential and for the rms undulation amplitude σ, which becomes small at low temperatures T and/or large bending stiffnesses κ. Moreover, σ scales as d for d≪√S but saturates at √kBTS/κ for d≫√S. In addition, using variational Gaussian theory, we apply our self-consistent treatment to study intermembrane interactions subject to different types of potentials: (i) the Moreira-Netz potential for a pair of strongly charged membranes with an intervening solution of multivalent counterions, (ii) an attractive square well, (iii) the Morse potential, and (iv) a combination of hydration and van der Waals interactions. PMID:26382349

  5. Differential Interactions of Sex Pheromone and Plant Odour in the Olfactory Pathway of a Male Moth

    PubMed Central

    Deisig, Nina; Kropf, Jan; Vitecek, Simon; Pevergne, Delphine; Rouyar, Angela; Sandoz, Jean-Christophe; Lucas, Philippe; Gadenne, Christophe

    2012-01-01

    Most animals rely on olfaction to find sexual partners, food or a habitat. The olfactory system faces the challenge of extracting meaningful information from a noisy odorous environment. In most moth species, males respond to sex pheromone emitted by females in an environment with abundant plant volatiles. Plant odours could either facilitate the localization of females (females calling on host plants), mask the female pheromone or they could be neutral without any effect on the pheromone. Here we studied how mixtures of a behaviourally-attractive floral odour, heptanal, and the sex pheromone are encoded at different levels of the olfactory pathway in males of the noctuid moth Agrotis ipsilon. In addition, we asked how interactions between the two odorants change as a function of the males' mating status. We investigated mixture detection in both the pheromone-specific and in the general odorant pathway. We used a) recordings from individual sensilla to study responses of olfactory receptor neurons, b) in vivo calcium imaging with a bath-applied dye to characterize the global input response in the primary olfactory centre, the antennal lobe and c) intracellular recordings of antennal lobe output neurons, projection neurons, in virgin and newly-mated males. Our results show that heptanal reduces pheromone sensitivity at the peripheral and central olfactory level independently of the mating status. Contrarily, heptanal-responding olfactory receptor neurons are not influenced by pheromone in a mixture, although some post-mating modulation occurs at the input of the sexually isomorphic ordinary glomeruli, where general odours are processed within the antennal lobe. The results are discussed in the context of mate localization. PMID:22427979

  6. Ehrlichia chaffeensis Exploits Host SUMOylation Pathways To Mediate Effector-Host Interactions and Promote Intracellular Survival

    PubMed Central

    Dunphy, Paige Selvy; Luo, Tian

    2014-01-01

    Ehrlichia chaffeensis is an obligately intracellular Gram-negative bacterium that selectively infects mononuclear phagocytes. We recently reported that E. chaffeensis utilizes a type 1 secretion (T1S) system to export tandem repeat protein (TRP) effectors and demonstrated that these effectors interact with a functionally diverse array of host proteins. By way of these interactions, TRP effectors modulate host cell functions; however, the molecular basis of these interactions and their roles in ehrlichial pathobiology are not well defined. In this study, we describe the first bacterial protein posttranslational modification (PTM) by the small ubiquitin-like modifier (SUMO). The E. chaffeensis T1S effector TRP120 is conjugated to SUMO at a carboxy-terminal canonical consensus SUMO conjugation motif in vitro and in human cells. In human cells, TRP120 was selectively conjugated with SUMO2/3 isoforms. Disruption of TRP120 SUMOylation perturbed interactions with known host proteins, through predicted SUMO interaction motif-dependent and -independent mechanisms. E. chaffeensis infection did not result in dramatic changes in the global host SUMOylated protein profile, but a robust colocalization of predominately SUMO1 with ehrlichial inclusions was observed. Inhibiting the SUMO pathway with a small-molecule inhibitor had a significant impact on E. chaffeensis replication and recruitment of the TRP120-interacting protein polycomb group ring finger protein 5 (PCGF5) to the inclusion, indicating that the SUMO pathway is critical for intracellular survival. This study reveals the novel exploitation of the SUMO pathway by Ehrlichia, which facilitates effector-eukaryote interactions necessary to usurp the host and create a permissive intracellular niche. PMID:25047847

  7. Vasoactive Intestinal Peptide modulates trophoblast-derived cell line function and interaction with phagocytic cells through autocrine pathways.

    PubMed

    Vota, Daiana; Paparini, Daniel; Hauk, Vanesa; Toro, Ayelén; Merech, Fatima; Varone, Cecilia; Ramhorst, Rosanna; Pérez Leirós, Claudia

    2016-01-01

    Trophoblast cells migrate and invade the decidual stroma in a tightly regulated process to maintain immune homeostasis at the maternal-placental interface during the first weeks of pregnancy. Locally synthesized factors modulate trophoblast cell function and their interaction with maternal leukocytes to promote the silent clearance of apoptotic cells. The vasoactive intestinal peptide (VIP) is a pleiotropic polypeptide with trophic and anti-inflammatory effects in murine pregnancy models. We explored the effect of VIP on two human first trimester trophoblast cell lines, particularly on their migration, invasiveness and interaction with phagocytic cells, and the signalling and regulatory pathways involved. We found that VIP enhanced trophoblast cell migration and invasion through the activation of high affinity VPAC receptors and PKA-CRE signalling pathways. VIP knocked-down trophoblast cells showed reduced migration in basal and leukemic inhibitor factor (LIF)-elicited conditions. In parallel, VIP-silenced trophoblast cells failed to induce the phagocytosis of apoptotic bodies and the expression of immunosuppressant markers by human monocytes. Our results suggest that VIP-mediated autocrine pathways regulate trophoblast cell function and contribute to immune homeostasis maintenance at placentation and may provide new clues for therapeutic intervention in pregnancies complicated by defective deep placentation. PMID:27212399

  8. Vasoactive Intestinal Peptide modulates trophoblast-derived cell line function and interaction with phagocytic cells through autocrine pathways

    PubMed Central

    Vota, Daiana; Paparini, Daniel; Hauk, Vanesa; Toro, Ayelén; Merech, Fatima; Varone, Cecilia; Ramhorst, Rosanna; Pérez Leirós, Claudia

    2016-01-01

    Trophoblast cells migrate and invade the decidual stroma in a tightly regulated process to maintain immune homeostasis at the maternal-placental interface during the first weeks of pregnancy. Locally synthesized factors modulate trophoblast cell function and their interaction with maternal leukocytes to promote the silent clearance of apoptotic cells. The vasoactive intestinal peptide (VIP) is a pleiotropic polypeptide with trophic and anti-inflammatory effects in murine pregnancy models. We explored the effect of VIP on two human first trimester trophoblast cell lines, particularly on their migration, invasiveness and interaction with phagocytic cells, and the signalling and regulatory pathways involved. We found that VIP enhanced trophoblast cell migration and invasion through the activation of high affinity VPAC receptors and PKA-CRE signalling pathways. VIP knocked-down trophoblast cells showed reduced migration in basal and leukemic inhibitor factor (LIF)-elicited conditions. In parallel, VIP-silenced trophoblast cells failed to induce the phagocytosis of apoptotic bodies and the expression of immunosuppressant markers by human monocytes. Our results suggest that VIP-mediated autocrine pathways regulate trophoblast cell function and contribute to immune homeostasis maintenance at placentation and may provide new clues for therapeutic intervention in pregnancies complicated by defective deep placentation. PMID:27212399

  9. Angiogenin interacts with ribonuclease inhibitor regulating PI3K/AKT/mTOR signaling pathway in bladder cancer cells.

    PubMed

    Peng, Yuan; Li, Lin; Huang, Mengge; Duan, Changzhu; Zhang, Luyu; Chen, Junxia

    2014-12-01

    Angiogenin (ANG), a member of RNase A superfamily, is the only angiogenic factor that possesses ribonucleolytic activity. Recent studies showed that the expression of ANG was elevated in various types of cancers. Accumulating evidence indicates that ANG plays an essential role in cancer progression by stimulating both cancer cell proliferation and tumor angiogenesis. Human ribonuclease inhibitor (RI), a cytoplasmic protein, is constructed almost entirely of leucine rich repeats (LRRs), which are present in a large family of proteins that are distinguished by their display of vast surface areas to foster protein-protein interactions. RI might be involved in unknown biological effects except inhibiting RNase A activity. The experiment demonstrated that RI also could suppress activity of angiogenin (ANG) through closely combining with it in vitro. PI3K/AKT/mTOR signaling pathway exerts a key role in cell growth, survival, proliferation, apoptosis and angiogenesis. We recently reported that up-regulating RI inhibited the growth and induced apoptosis of murine melanoma cells through repression of angiogenin and PI3K/AKT signaling pathway. However, ANG receptors have not yet been identified to date, its related signal transduction pathways are not fully clear and underlying interacting mechanisms between RI and ANG remain largely unknown. Therefore, we hypothesize that RI might combine with intracellular ANG to block its nuclear translocation and regulate PI3K/AKT/mTOR signaling pathway to inhibit biological functions of ANG. Here, we reported for the first time that ANG could interact with RI endogenously and exogenously by using co-immunoprecipitation (Co-IP) and GST pull-down. Furthermore, we observed the colocalization of ANG and RI in cells with immunofluorescence staining under laser confocal microscope. Moreover, through fluorescence resonance energy transfer (FRET) assay, we further confirmed that these two proteins have a physical interaction in living cells

  10. Methods for Investigating Gene-Environment Interactions in Candidate Pathway and Genome-Wide Association Studies

    PubMed Central

    Thomas, Duncan

    2010-01-01

    Despite the considerable enthusiasm about the yield of novel and replicated discoveries of genetic associations from the new generation of genome-wide association studies (GWAS), the proportion of the heritability of most complex diseases that have been studied to date remains small. Some of this “dark matter” could be due to gene-environment (G×E) interactions or more complex pathways involving multiple genes and exposures. We review the basic epidemiologic study design and statistical analysis approaches to studying G×E interactions individually and then consider more comprehensive approaches to studying entire pathways or GWAS data. In addition to the usual issues in genetic association studies, particular care is needed in exposure assessment and very large sample sizes are required. Although hypothesis-driven pathway-based and “agnostic” GWAS approaches are generally viewed as opposite poles, we suggest that the two can be usefully married using hierarchical modeling strategies that exploit external pathway knowledge in mining genome-wide data. PMID:20070199

  11. O/S-1/ interactions - The product channels. [collisional electron quenching and chemical reaction pathway frequencies

    NASA Technical Reports Server (NTRS)

    Slanger, T. G.; Black, G.

    1978-01-01

    The first measurements are reported of the reaction pathways for the interaction between oxygen atoms in the 4.19 eV S-1 state, and four molecules, N2O, CO2, H2O, and NO. Distinction is made between three possible paths - quenching to O(D-1), quenching to O(P-3), and chemical reaction. With N2O, the most reasonable interpretation of the data indicates that there no reaction, in sharp contrast with the interaction between O(D-1) and N2O, which proceeds entirely by reaction. Similarly, there is no reaction with CO2. With H2O, the reactive pathway is the dominant one, although electronic quenching is not negligible. With NO, O(D-1) is the preferred product.

  12. Effects of radiation on the epidermal growth factor receptor pathway in the heart

    PubMed Central

    Sridharan, Vijayalakshmi; Sharma, Sunil K.; Moros, Eduardo G.; Corry, Peter M.; Tripathi, Preeti; Lieblong, Benjamin J.; Guha, Chandan; Hauer-Jensen, Martin; Boerma, Marjan

    2013-01-01

    Purpose Radiation-induced heart disease (RIHD) is a serious side effect of thoracic radiotherapy. The epidermal growth factor receptor (EGFR) pathway is essential for the function and survival of cardiomyocytes. Hence, agents that target the EGFR pathway are cardiotoxic. Tocotrienols protect from radiation injury, but may also enhance the therapeutic effects of EGFR pathway inhibitors in cancer treatment. This study investigates the effects of local irradiation on the EGFR pathway in the heart and tests whether tocotrienols may modify radiation-induced changes in this pathway. Methods Male Sprague-Dawley rats received image-guided localized heart irradiation with 21 Gy. Twenty four hours before irradiation, rats received a single dose of tocotrienol-enriched formulation or vehicle by oral gavage. At time points from 2 hours to 9 months after irradiation, left ventricular expression of EGFR pathway mediators was studied. Results Irradiation caused a decrease in the expression of epidermal growth factor (EGF) and neuregulin-1 (Nrg-1) mRNA from 6 hours up to 10 weeks, followed by an upregulation of these ligands and the receptor erythroblastic leukemia viral oncogene homolog (ErbB)4 at 6 months. In addition, the upregulation of Nrg-1 was statistically significant up to 9 months after irradiation. A long-term upregulation of ErbB2 protein did not coincide with changes in transcription or post-translational interaction with the chaperone heat shock protein 90 (HSP90). Pretreatment with tocotrienols prevented radiation-induced changes at 2 weeks. Conclusions Local heart irradiation causes long-term changes in the EGFR pathway. Studies have to address how radiation may interact with cardiotoxic effects of EGFR inhibitors. PMID:23488537

  13. Interaction between glutamate dehydrogenase (GDH) and L-leucine catabolic enzymes: intersecting metabolic pathways.

    PubMed

    Hutson, Susan M; Islam, Mohammad Mainul; Zaganas, Ioannis

    2011-09-01

    Branched-chain amino acids (BCAAs) catabolism follows sequential reactions and their metabolites intersect with other metabolic pathways. The initial enzymes in BCAA metabolism, the mitochondrial branched-chain aminotransferase (BCATm), which deaminates the BCAAs to branched-chain α-keto acids (BCKAs); and the branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC), which oxidatively decarboxylates the BCKAs, are organized in a supramolecular complex termed metabolon. Glutamate dehydrogenase (GDH1) is found in the metabolon in rat tissues. Bovine GDH1 binds to the pyridoxamine 5'-phosphate (PMP)-form of human BCATm (PMP-BCATm) but not to pyridoxal 5'-phosphate (PLP)-BCATm in vitro. This protein interaction facilitates reamination of the α-ketoglutarate (αKG) product of the GDH1 oxidative deamination reaction. Human GDH1 appears to act like bovine GDH1 but human GDH2 does not show the same enhancement of BCKDC enzyme activities. Another metabolic enzyme is also found in the metabolon is pyruvate carboxylase (PC). Kinetic results suggest that PC binds to the E1 decarboxylase of BCKDC but does not effect BCAA catabolism. The protein interaction of BCATm and GDH1 promotes regeneration of PLP-BCATm which then binds to BCKDC resulting in channeling of the BCKA products from BCATm first half reaction to E1 and promoting BCAA oxidation and net nitrogen transfer from BCAAs. The cycling of nitrogen through glutamate via the actions of BCATm and GDH1 releases free ammonia. Formation of ammonia may be important for astrocyte glutamine synthesis in the central nervous system. In peripheral tissue association of BCATm and GDH1 would promote BCAA oxidation at physiologically relevant BCAA concentrations. PMID:21621574

  14. Glutamate, Ornithine, Arginine, Proline, and Polyamine Metabolic Interactions: The Pathway Is Regulated at the Post-Transcriptional Level

    PubMed Central

    Majumdar, Rajtilak; Barchi, Boubker; Turlapati, Swathi A.; Gagne, Maegan; Minocha, Rakesh; Long, Stephanie; Minocha, Subhash C.

    2016-01-01

    The metabolism of glutamate into ornithine, arginine, proline, and polyamines is a major network of nitrogen-metabolizing pathways in plants, which also produces intermediates like nitric oxide, and γ-aminobutyric acid (GABA) that play critical roles in plant development and stress. While the accumulations of intermediates and the products of this network depend primarily on nitrogen assimilation, the overall regulation of the interacting sub-pathways is not well understood. We tested the hypothesis that diversion of ornithine into polyamine biosynthesis (by transgenic approach) not only plays a role in regulating its own biosynthesis from glutamate but also affects arginine and proline biosynthesis. Using two high putrescine producing lines of Arabidopsis thaliana (containing a transgenic mouse ornithine decarboxylase gene), we studied the: (1) effects of exogenous supply of carbon and nitrogen on polyamines and pools of soluble amino acids; and, (2) expression of genes encoding key enzymes in the interactive pathways of arginine, proline and GABA biosynthesis as well as the catabolism of polyamines. Our findings suggest that: (1) the overall conversion of glutamate to arginine and polyamines is enhanced by increased utilization of ornithine for polyamine biosynthesis by the transgene product; (2) proline and arginine biosynthesis are regulated independently of polyamines and GABA biosynthesis; (3) the expression of most genes (28 that were studied) that encode enzymes of the interacting sub-pathways of arginine and GABA biosynthesis does not change even though overall biosynthesis of Orn from glutamate is increased several fold; and (4) increased polyamine biosynthesis results in increased assimilation of both nitrogen and carbon by the cells. PMID:26909083

  15. Graph-theoretical identification of dissociation pathways on free energy landscapes of biomolecular interaction.

    PubMed

    Wang, Ling; Stumm, Boris; Helms, Volkhard

    2010-03-01

    Biomolecular association and dissociation reactions take place on complicated interaction free energy landscapes that are still very hard to characterize computationally. For large enough distances, though, it often suffices to consider the six relative translational and rotational degrees of freedom of the two particles treated as rigid bodies. Here, we computed the six-dimensional free energy surface of a dimer of water-soluble alpha-helices by scanning these six degrees of freedom in about one million grid points. In each point, the relative free energy difference was computed as the sum of the polar and nonpolar solvation free energies of the helix dimer and of the intermolecular coulombic interaction energy. The Dijkstra graph algorithm was then applied to search for the lowest cost dissociation pathways based on a weighted, directed graph, where the vertices represent the grid points, the edges connect the grid points and their neighbors, and the weights are the reaction costs between adjacent pairs of grid points. As an example, the configuration of the bound state was chosen as the source node, and the eight corners of the translational cube were chosen as the destination nodes. With the strong electrostatic interaction of the two helices giving rise to a clearly funnel-shaped energy landscape, the eight lowest-energy cost pathways coming from different orientations converge into a well-defined pathway for association. We believe that the methodology presented here will prove useful for identifying low-energy association and dissociation pathways in future studies of complicated free energy landscapes for biomolecular interaction. PMID:19603501

  16. Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction.

    PubMed

    Amil-Ruiz, Francisco; Garrido-Gala, José; Gadea, José; Blanco-Portales, Rosario; Muñoz-Mérida, Antonio; Trelles, Oswaldo; de Los Santos, Berta; Arroyo, Francisco T; Aguado-Puig, Ana; Romero, Fernando; Mercado, José-Ángel; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L

    2016-01-01

    Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen. PMID:27471515

  17. Partial Activation of SA- and JA-Defensive Pathways in Strawberry upon Colletotrichum acutatum Interaction

    PubMed Central

    Amil-Ruiz, Francisco; Garrido-Gala, José; Gadea, José; Blanco-Portales, Rosario; Muñoz-Mérida, Antonio; Trelles, Oswaldo; de los Santos, Berta; Arroyo, Francisco T.; Aguado-Puig, Ana; Romero, Fernando; Mercado, José-Ángel; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L.

    2016-01-01

    Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa) cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5, and FaPR10) were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen. PMID:27471515

  18. A systems biology approach using metabolomic data reveals genes and pathways interacting to modulate divergent growth in cattle

    PubMed Central

    2013-01-01

    Background Systems biology enables the identification of gene networks that modulate complex traits. Comprehensive metabolomic analyses provide innovative phenotypes that are intermediate between the initiator of genetic variability, the genome, and raw phenotypes that are influenced by a large number of environmental effects. The present study combines two concepts, systems biology and metabolic analyses, in an approach without prior functional hypothesis in order to dissect genes and molecular pathways that modulate differential growth at the onset of puberty in male cattle. Furthermore, this integrative strategy was applied to specifically explore distinctive gene interactions of non-SMC condensin I complex, subunit G (NCAPG) and myostatin (GDF8), known modulators of pre- and postnatal growth that are only partially understood for their molecular pathways affecting differential body weight. Results Our study successfully established gene networks and interacting partners affecting growth at the onset of puberty in cattle. We demonstrated the biological relevance of the created networks by comparison to randomly created networks. Our data showed that GnRH (Gonadotropin-releasing hormone) signaling is associated with divergent growth at the onset of puberty and revealed two highly connected hubs, BTC and DGKH, within the network. Both genes are known to directly interact with the GnRH signaling pathway. Furthermore, a gene interaction network for NCAPG containing 14 densely connected genes revealed novel information concerning the functional role of NCAPG in divergent growth. Conclusions Merging both concepts, systems biology and metabolomic analyses, successfully yielded new insights into gene networks and interacting partners affecting growth at the onset of puberty in cattle. Genetic modulation in GnRH signaling was identified as key modifier of differential cattle growth at the onset of puberty. In addition, the benefit of our innovative concept without prior

  19. Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: multilocus interaction in the mTOR pathway.

    PubMed

    Mas, S; Gassó, P; Ritter, M A; Malagelada, C; Bernardo, M; Lafuente, A

    2015-01-01

    Antipsychotic (AP) treatment-emergent extrapyramidal symptoms (EPS) are acute adverse reactions of APs. The aim of the present study is to analyze gene-gene interactions in nine genes related to the mTOR pathway, in order to develop genetic predictors of the appearance of EPS. 243 subjects (78 presenting EPS: 165 not) from three cohorts participated in the present study: Cohort 1, patients treated with risperidone, (n=114); Cohort 2, patients treated with APs other than risperidone (n=102); Cohort 3, AP-naïve patients with first-episode psychosis treated with risperidone, paliperidone or amisulpride, n=27. We analyzed gene-gene interactions by multifactor dimensionality reduction assay (MDR). In Cohort 1, we identified a four-way interaction, including the rs1130214 (AKT1), rs456998 (FCHSD1), rs7211818 (Raptor) and rs1053639 (DDIT4), that correctly predicted 97 of the 114 patients (85% accuracy). We validated the predictive power of the four-way interaction in Cohort 2 and in Cohort 3 with 86% and 88% accuracy respectively. We develop and validate a powerful pharmacogenetic predictor of AP-induced EPS. For the first time, the mTOR pathway has been related to EPS susceptibility and AP response. However, validation in larger and independent populations will be necessary for optimal generalization. PMID:25499605

  20. [Cognition-Emotion Interactions and Psychopathic Personality: Distinct Pathways to Antisocial and Violent Behavior].

    PubMed

    Verona, Edelyn

    2016-01-01

    Researchers have long acknowledged heterogeneity among persons who exhibit antisocial and violent behaviours. The study of psychopathic personality or psychopathy can help elucidate this heterogeneity through examination of the different facets that constitute this disorder. In particular, the distinct correlates of the interpersonal-affective traits (Factor 1) and the impulsive-antisocial traits (Factor 2) of psychopathy suggest at least two possible pathways to antisocial behaviours. Building on basic studies in cognitive and affective neuroscience, we provide a focused, non-comprehensive review of work identifying the biopsychological mechanisms involved in these two pathways, with special attention to studies using event-related potential (ERP) methods. In specific, a series of studies are discussed which examined affective and cognitive processes that may distinguish offenders high on psychopathic traits from other offenders, with emphasis on alterations in emotion-cognition interactions related to each factor of psychopathy. The set of findings reviewed highlight a central conclusion: Factor 1 represents a pathway involving reduced emotional responding, exacerbated by attentional abnormalities, that make for a more deliberate and emotionally insensitive offender profile. In contrast, Factor 2 characterizes a pathway marked by emotional and behavioural dysregulation and cognitive control dysfunctions, particularly in emotional contexts. Implications for identifying etiological processes and the further understanding of antisocial and violent behaviours are discussed. PMID:27570952

  1. Synergistic interaction between the fibroblast growth factor and bone morphogenetic protein signaling pathways in lens cells

    PubMed Central

    Boswell, Bruce A.; Musil, Linda S.

    2015-01-01

    Fibroblast growth factors (FGFs) play a central role in two processes essential for lens transparency—fiber cell differentiation and gap junction–mediated intercellular communication (GJIC). Using serum-free primary cultures of chick lens epithelial cells (DCDMLs), we investigated how the FGF and bone morphogenetic protein (BMP) signaling pathways positively cooperate to regulate lens development and function. We found that culturing DCDMLs for 6 d with the BMP blocker noggin inhibits the canonical FGF-to-ERK pathway upstream of FRS2 activation and also prevents FGF from stimulating FRS2- and ERK-independent gene expression, indicating that BMP signaling is required at the level of FGF receptors. Other experiments revealed a second type of BMP/FGF interaction by which FGF promotes expression of BMP target genes as well as of BMP4. Together these studies reveal a novel mode of cooperation between the FGF and BMP pathways in which BMP keeps lens cells in an optimally FGF-responsive state and, reciprocally, FGF enhances BMP-mediated gene expression. This interaction provides a mechanistic explanation for why disruption of either FGF or BMP signaling in the lens leads to defects in lens development and function. PMID:25947138

  2. SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival.

    PubMed

    Jamshidi, Maral; Fagerholm, Rainer; Khan, Sofia; Aittomäki, Kristiina; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Andrulis, Irene L; Chang-Claude, Jenny; Devilee, Peter; Fasching, Peter A; Michailidou, Kyriaki; Bolla, Manjeet K; Dennis, Joe; Wang, Qin; Guo, Qi; Rhenius, Valerie; Cornelissen, Sten; Rudolph, Anja; Knight, Julia A; Loehberg, Christian R; Burwinkel, Barbara; Marme, Frederik; Hopper, John L; Southey, Melissa C; Bojesen, Stig E; Flyger, Henrik; Brenner, Hermann; Holleczek, Bernd; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Van Dyck, Laurien; Nevelsteen, Ines; Couch, Fergus J; Olson, Janet E; Giles, Graham G; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Winqvist, Robert; Pylkäs, Katri; Tollenaar, Rob A E M; García-Closas, Montserrat; Figueroa, Jonine; Hooning, Maartje J; Martens, John W M; Cox, Angela; Cross, Simon S; Simard, Jacques; Dunning, Alison M; Easton, Douglas F; Pharoah, Paul D P; Hall, Per; Blomqvist, Carl; Schmidt, Marjanka K; Nevanlinna, Heli

    2015-11-10

    In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses. PMID:26317411

  3. SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

    PubMed Central

    Jamshidi, Maral; Fagerholm, Rainer; Khan, Sofia; Aittomäki, Kristiina; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Andrulis, Irene L.; Chang-Claude, Jenny; Devilee, Peter; Fasching, Peter A.; Michailidou, Kyriaki; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Guo, Qi; Rhenius, Valerie; Cornelissen, Sten; Rudolph, Anja; Knight, Julia A.; Loehberg, Christian R.; Burwinkel, Barbara; Marme, Frederik; Hopper, John L.; Southey, Melissa C.; Bojesen, Stig E.; Flyger, Henrik; Brenner, Hermann; Holleczek, Bernd; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Dyck, Laurien Van; Nevelsteen, Ines; Couch, Fergus J.; Olson, Janet E.; Giles, Graham G.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Winqvist, Robert; Pylkäs, Katri; Tollenaar, Rob A.E.M.; García-Closas, Montserrat; Figueroa, Jonine; Hooning, Maartje J.; Martens, John W.M.; Cox, Angela; Cross, Simon S.; Simard, Jacques; Dunning, Alison M.; Easton, Douglas F.; Pharoah, Paul D.P.; Hall, Per; Blomqvist, Carl; Schmidt, Marjanka K.; Nevanlinna, Heli

    2015-01-01

    In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox’ regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P = 1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses. PMID:26317411

  4. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

    PubMed Central

    Kelemen, Linda E.; Terry, Kathryn L.; Goodman, Marc T.; Webb, Penelope M.; Bandera, Elisa V.; McGuire, Valerie; Rossing, Mary Anne; Wang, Qinggang; Dicks, Ed; Tyrer, Jonathan P.; Song, Honglin; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Timorek, Agnieszka; Menon, Usha; Gentry-Maharaj, Aleksandra; Gayther, Simon A.; Ramus, Susan J.; Narod, Steven A.; Risch, Harvey A.; McLaughlin, John R.; Siddiqui, Nadeem; Glasspool, Rosalind; Paul, James; Carty, Karen; Gronwald, Jacek; Lubiński, Jan; Jakubowska, Anna; Cybulski, Cezary; Kiemeney, Lambertus A.; Massuger, Leon F. A. G.; van Altena, Anne M.; Aben, Katja K. H.; Olson, Sara H.; Orlow, Irene; Cramer, Daniel W.; Levine, Douglas A.; Bisogna, Maria; Giles, Graham G.; Southey, Melissa C.; Bruinsma, Fiona; Kjær, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Høgdall, Claus K.; Lundvall, Lene; Engelholm, Svend-Aage; Heitz, Florian; du Bois, Andreas; Harter, Philipp; Schwaab, Ira; Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.; Leminen, Arto; Thompson, Pamela J.; Lurie, Galina; Wilkens, Lynne R.; Lambrechts, Diether; Van Nieuwenhuysen, Els; Lambrechts, Sandrina; Vergote, Ignace; Beesley, Jonathan; Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander; Ekici, Arif B.; Doherty, Jennifer A.; Wu, Anna H.; Pearce, Celeste L.; Pike, Malcolm C.; Stram, Daniel; Chang-Claude, Jenny; Rudolph, Anja; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B.; Bogdanova, Natalia; Antonenkova, Natalia; Odunsi, Kunle; Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary; Ness, Roberta B.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Fridley, Brooke L.; Vierkant, Robert A.; Cunningham, Julie M.; Wu, Xifeng; Lu, Karen; Liang, Dong; Hildebrandt, Michelle A.T.; Weber, Rachel Palmieri; Iversen, Edwin S.; Tworoger, Shelley S.; Poole, Elizabeth M.; Salvesen, Helga B.; Krakstad, Camilla; Bjorge, Line; Tangen, Ingvild L.; Pejovic, Tanja; Bean, Yukie; Kellar, Melissa; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Garcia-Closas, Montserrat; Campbell, Ian G.; Eccles, Diana; Whittemore, Alice S.; Sieh, Weiva; Rothstein, Joseph H.; Anton-Culver, Hoda; Ziogas, Argyrios; Phelan, Catherine M.; Moysich, Kirsten B.; Goode, Ellen L.; Schildkraut, Joellen M.; Berchuck, Andrew; Pharoah, Paul D.P.; Sellers, Thomas A.; Brooks-Wilson, Angela; Cook, Linda S.; Le, Nhu D.

    2014-01-01

    Scope We re-evaluated previously reported associations between variants in pathways of one-carbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and Results Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10−5) and rs828054 (OR=1.06, P=1x10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (Pinteraction=0.03-0.006). Conclusions Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC. PMID:25066213

  5. Final State Interactions Effects in Neutrino-Nucleus Interactions

    SciTech Connect

    Golan, Tomasz; Juszczak, Cezary; Sobczyk, Jan T.

    2012-07-01

    Final State Interactions effects are discussed in the context of Monte Carlo simulations of neutrino-nucleus interactions. A role of Formation Time is explained and several models describing this effect are compared. Various observables which are sensitive to FSI effects are reviewed including pion-nucleus interaction and hadron yields in backward hemisphere. NuWro Monte Carlo neutrino event generator is described and its ability to understand neutral current $\\pi^0$ production data in $\\sim 1$ GeV neutrino flux experiments is demonstrated.

  6. Modeling of the dorsal gradient across species reveals interaction between embryo morphology and Toll signaling pathway during evolution.

    PubMed

    Ambrosi, Priscilla; Chahda, Juan Sebastian; Koslen, Hannah R; Chiel, Hillel J; Mizutani, Claudia Mieko

    2014-08-01

    Morphogenetic gradients are essential to allocate cell fates in embryos of varying sizes within and across closely related species. We previously showed that the maternal NF-κB/Dorsal (Dl) gradient has acquired different shapes in Drosophila species, which result in unequally scaled germ layers along the dorso-ventral axis and the repositioning of the neuroectodermal borders. Here we combined experimentation and mathematical modeling to investigate which factors might have contributed to the fast evolutionary changes of this gradient. To this end, we modified a previously developed model that employs differential equations of the main biochemical interactions of the Toll (Tl) signaling pathway, which regulates Dl nuclear transport. The original model simulations fit well the D. melanogaster wild type, but not mutant conditions. To broaden the applicability of this model and probe evolutionary changes in gradient distributions, we adjusted a set of 19 independent parameters to reproduce three quantified experimental conditions (i.e. Dl levels lowered, nuclear size and density increased or decreased). We next searched for the most relevant parameters that reproduce the species-specific Dl gradients. We show that adjusting parameters relative to morphological traits (i.e. embryo diameter, nuclear size and density) alone is not sufficient to reproduce the species Dl gradients. Since components of the Tl pathway simulated by the model are fast-evolving, we next asked which parameters related to Tl would most effectively reproduce these gradients and identified a particular subset. A sensitivity analysis reveals the existence of nonlinear interactions between the two fast-evolving traits tested above, namely the embryonic morphological changes and Tl pathway components. Our modeling further suggests that distinct Dl gradient shapes observed in closely related melanogaster sub-group lineages may be caused by similar sequence modifications in Tl pathway components, which

  7. Modeling of the Dorsal Gradient across Species Reveals Interaction between Embryo Morphology and Toll Signaling Pathway during Evolution

    PubMed Central

    Koslen, Hannah R.; Chiel, Hillel J.; Mizutani, Claudia Mieko

    2014-01-01

    Morphogenetic gradients are essential to allocate cell fates in embryos of varying sizes within and across closely related species. We previously showed that the maternal NF-κB/Dorsal (Dl) gradient has acquired different shapes in Drosophila species, which result in unequally scaled germ layers along the dorso-ventral axis and the repositioning of the neuroectodermal borders. Here we combined experimentation and mathematical modeling to investigate which factors might have contributed to the fast evolutionary changes of this gradient. To this end, we modified a previously developed model that employs differential equations of the main biochemical interactions of the Toll (Tl) signaling pathway, which regulates Dl nuclear transport. The original model simulations fit well the D. melanogaster wild type, but not mutant conditions. To broaden the applicability of this model and probe evolutionary changes in gradient distributions, we adjusted a set of 19 independent parameters to reproduce three quantified experimental conditions (i.e. Dl levels lowered, nuclear size and density increased or decreased). We next searched for the most relevant parameters that reproduce the species-specific Dl gradients. We show that adjusting parameters relative to morphological traits (i.e. embryo diameter, nuclear size and density) alone is not sufficient to reproduce the species Dl gradients. Since components of the Tl pathway simulated by the model are fast-evolving, we next asked which parameters related to Tl would most effectively reproduce these gradients and identified a particular subset. A sensitivity analysis reveals the existence of nonlinear interactions between the two fast-evolving traits tested above, namely the embryonic morphological changes and Tl pathway components. Our modeling further suggests that distinct Dl gradient shapes observed in closely related melanogaster sub-group lineages may be caused by similar sequence modifications in Tl pathway components, which

  8. Magnetoelectric effects via pentalinear interactions

    NASA Astrophysics Data System (ADS)

    Zhao, Hong Jian; Grisolia, M. N.; Yang, Yurong; Íñiguez, Jorge; Bibes, M.; Chen, Xiang Ming; Bellaiche, L.

    2015-12-01

    Magnetoelectric multiferroic materials, particularly with the perovskite structure, are receiving a lot of attention because of their inherent coupling between electrical polarization and magnetic ordering. However, very few types of direct coupling between polarization and magnetization are known, and it is unclear whether they can be useful to the design of spintronic devices exploiting the control of magnetization by electric fields. For instance, the typical biquadratic coupling only allows changing the magnitude of the magnetization by an electric field, but it does not permit an electric-field-induced switching of the magnetization. Similarly, the so-called Lifshitz invariants allow an electric-field control of complicated magnetic orderings, but not of the magnetization. Here, we report on original direct couplings between polarization and magnetization in epitaxial perovskite films, via the use of first-principles methods and the development of an original Landau-type phenomenological theory. Our results feature pentalinear interactions involving the ferromagnetic and antiferromagnetic vectors as well as the polar distortions and oxygen octahedral tilting, and permit a number of striking effects. Examples include a continuous electric-field control of the magnetization magnitude and sign, and the discrete switching of the magnetization magnitude. Thus, the high-order, pentalinear couplings demonstrated in this work may open paths towards specific magnetoelectric effects, as well as spintronic and magnonic devices.

  9. Structural and Functional Characterization of a Caenorhabditis elegans Genetic Interaction Network within Pathways

    PubMed Central

    Boucher, Benjamin; Lee, Anna Y.; Hallett, Michael; Jenna, Sarah

    2016-01-01

    A genetic interaction (GI) is defined when the mutation of one gene modifies the phenotypic expression associated with the mutation of a second gene. Genome-wide efforts to map GIs in yeast revealed structural and functional properties of a GI network. This provided insights into the mechanisms underlying the robustness of yeast to genetic and environmental insults, and also into the link existing between genotype and phenotype. While a significant conservation of GIs and GI network structure has been reported between distant yeast species, such a conservation is not clear between unicellular and multicellular organisms. Structural and functional characterization of a GI network in these latter organisms is consequently of high interest. In this study, we present an in-depth characterization of ~1.5K GIs in the nematode Caenorhabditis elegans. We identify and characterize six distinct classes of GIs by examining a wide-range of structural and functional properties of genes and network, including co-expression, phenotypical manifestations, relationship with protein-protein interaction dense subnetworks (PDS) and pathways, molecular and biological functions, gene essentiality and pleiotropy. Our study shows that GI classes link genes within pathways and display distinctive properties, specifically towards PDS. It suggests a model in which pathways are composed of PDS-centric and PDS-independent GIs coordinating molecular machines through two specific classes of GIs involving pleiotropic and non-pleiotropic connectors. Our study provides the first in-depth characterization of a GI network within pathways of a multicellular organism. It also suggests a model to understand better how GIs control system robustness and evolution. PMID:26871911

  10. NEMix: single-cell nested effects models for probabilistic pathway stimulation.

    PubMed

    Siebourg-Polster, Juliane; Mudrak, Daria; Emmenlauer, Mario; Rämö, Pauli; Dehio, Christoph; Greber, Urs; Fröhlich, Holger; Beerenwinkel, Niko

    2015-04-01

    Nested effects models have been used successfully for learning subcellular networks from high-dimensional perturbation effects that result from RNA interference (RNAi) experiments. Here, we further develop the basic nested effects model using high-content single-cell imaging data from RNAi screens of cultured cells infected with human rhinovirus. RNAi screens with single-cell readouts are becoming increasingly common, and they often reveal high cell-to-cell variation. As a consequence of this cellular heterogeneity, knock-downs result in variable effects among cells and lead to weak average phenotypes on the cell population level. To address this confounding factor in network inference, we explicitly model the stimulation status of a signaling pathway in individual cells. We extend the framework of nested effects models to probabilistic combinatorial knock-downs and propose NEMix, a nested effects mixture model that accounts for unobserved pathway activation. We analyzed the identifiability of NEMix and developed a parameter inference scheme based on the Expectation Maximization algorithm. In an extensive simulation study, we show that NEMix improves learning of pathway structures over classical NEMs significantly in the presence of hidden pathway stimulation. We applied our model to single-cell imaging data from RNAi screens monitoring human rhinovirus infection, where limited infection efficiency of the assay results in uncertain pathway stimulation. Using a subset of genes with known interactions, we show that the inferred NEMix network has high accuracy and outperforms the classical nested effects model without hidden pathway activity. NEMix is implemented as part of the R/Bioconductor package 'nem' and available at www.cbg.ethz.ch/software/NEMix. PMID:25879530

  11. NEMix: Single-cell Nested Effects Models for Probabilistic Pathway Stimulation

    PubMed Central

    Siebourg-Polster, Juliane; Mudrak, Daria; Emmenlauer, Mario; Rämö, Pauli; Dehio, Christoph; Greber, Urs; Fröhlich, Holger; Beerenwinkel, Niko

    2015-01-01

    Nested effects models have been used successfully for learning subcellular networks from high-dimensional perturbation effects that result from RNA interference (RNAi) experiments. Here, we further develop the basic nested effects model using high-content single-cell imaging data from RNAi screens of cultured cells infected with human rhinovirus. RNAi screens with single-cell readouts are becoming increasingly common, and they often reveal high cell-to-cell variation. As a consequence of this cellular heterogeneity, knock-downs result in variable effects among cells and lead to weak average phenotypes on the cell population level. To address this confounding factor in network inference, we explicitly model the stimulation status of a signaling pathway in individual cells. We extend the framework of nested effects models to probabilistic combinatorial knock-downs and propose NEMix, a nested effects mixture model that accounts for unobserved pathway activation. We analyzed the identifiability of NEMix and developed a parameter inference scheme based on the Expectation Maximization algorithm. In an extensive simulation study, we show that NEMix improves learning of pathway structures over classical NEMs significantly in the presence of hidden pathway stimulation. We applied our model to single-cell imaging data from RNAi screens monitoring human rhinovirus infection, where limited infection efficiency of the assay results in uncertain pathway stimulation. Using a subset of genes with known interactions, we show that the inferred NEMix network has high accuracy and outperforms the classical nested effects model without hidden pathway activity. NEMix is implemented as part of the R/Bioconductor package ‘nem’ and available at www.cbg.ethz.ch/software/NEMix. PMID:25879530

  12. Deciphering the biological effects of acupuncture treatment modulating multiple metabolism pathways

    PubMed Central

    Zhang, Aihua; Yan, Guangli; Sun, Hui; Cheng, Weiping; Meng, Xiangcai; Liu, Li; Xie, Ning; Wang, Xijun

    2016-01-01

    Acupuncture is an alternative therapy that is widely used to treat various diseases. However, detailed biological interpretation of the acupuncture stimulations is limited. We here used metabolomics and proteomics technology, thereby identifying the serum small molecular metabolites into the effect and mechanism pathways of standardized acupuncture treatments at ‘Zusanli’ acupoint which was the most often used acupoint in previous reports. Comprehensive overview of serum metabolic profiles during acupuncture stimulation was investigated. Thirty-four differential metabolites were identified in serum metabolome and associated with ten metabolism pathways. Importantly, we have found that high impact glycerophospholipid metabolism, fatty acid metabolism, ether lipid metabolism were acutely perturbed by acupuncture stimulation. As such, these alterations may be useful to clarify the biological mechanism of acupuncture stimulation. A series of differentially expressed proteins were identified and such effects of acupuncture stimulation were found to play a role in transport, enzymatic activity, signaling pathway or receptor interaction. Pathway analysis further revealed that most of these proteins were found to play a pivotal role in the regulation of multiple metabolism pathways. It demonstrated that the metabolomics coupled with proteomics as a powerful approach for potential applications in understanding the biological effects of acupuncture stimulation. PMID:26879284

  13. Forest disturbance interactions and successional pathways in the Southern Rocky Mountains

    USGS Publications Warehouse

    Lu Liang; Hawbaker, Todd J.; Zhu, Zhiliang; Xuecao Li; Peng Gong

    2016-01-01

    The pine forests in the southern portion of the Rocky Mountains are a heterogeneous mosaic of disturbance and recovery. The most extensive and intensive stress and mortality are received from human activity, fire, and mountain pine beetles (MPB;Dendroctonus ponderosae). Understanding disturbance interactions and disturbance-succession pathways are crucial for adapting management strategies to mitigate their impacts and anticipate future ecosystem change. Driven by this goal, we assessed the forest disturbance and recovery history in the Southern Rocky Mountains Ecoregion using a 13-year time series of Landsat image stacks. An automated classification workflow that integrates temporal segmentation techniques and a random forest classifier was used to examine disturbance patterns. To enhance efficiency in selecting representative samples at the ecoregion scale, a new sampling strategy that takes advantage of the scene-overlap among adjacent Landsat images was designed. The segment-based assessment revealed that the overall accuracy for all 14 scenes varied from 73.6% to 92.5%, with a mean of 83.1%. A design-based inference indicated the average producer’s and user’s accuracies for MPB mortality were 85.4% and 82.5% respectively. We found that burn severity was largely unrelated to the severity of pre-fire beetle outbreaks in this region, where the severity of post-fire beetle outbreaks generally decreased in relation to burn severity. Approximately half the clear-cut and burned areas were in various stages of recovery, but the regeneration rate was much slower for MPB-disturbed sites. Pre-fire beetle outbreaks and subsequent fire produced positive compound effects on seedling reestablishment in this ecoregion. Taken together, these results emphasize that although multiple disturbances do play a role in the resilience mechanism of the serotinous lodgepole pine, the overall recovery could be slow due to the vast area of beetle mortality.

  14. Zebrafish Mutants calamity and catastrophe Define Critical Pathways of Gene–Nutrient Interactions in Developmental Copper Metabolism

    PubMed Central

    Madsen, Erik C.; Gitlin, Jonathan D.

    2008-01-01

    Nutrient availability is an important environmental variable during development that has significant effects on the metabolism, health, and viability of an organism. To understand these interactions for the nutrient copper, we used a chemical genetic screen for zebrafish mutants sensitive to developmental copper deficiency. In this screen, we isolated two mutants that define subtleties of copper metabolism. The first contains a viable hypomorphic allele of atp7a and results in a loss of pigmentation when exposed to mild nutritional copper deficiency. This mutant displays incompletely penetrant skeletal defects affected by developmental copper availability. The second carries an inactivating mutation in the vacuolar ATPase that causes punctate melanocytes and embryonic lethality. This mutant, catastrophe, is sensitive to copper deprivation revealing overlap between ion metabolic pathways. Together, the two mutants illustrate the utility of chemical genetic screens in zebrafish to elucidate the interaction of nutrient availability and genetic polymorphisms in cellular metabolism. PMID:19008952

  15. Extracting Between-Pathway Models from E-MAP Interactions Using Expected Graph Compression

    NASA Astrophysics Data System (ADS)

    Kelley, David R.; Kingsford, Carl

    Genetic interactions (such as synthetic lethal interactions) have become quantifiable on a large-scale using the epistatic miniarray profile (E-MAP) method. An E-MAP allows the construction of a large, weighted network of both aggravating and alleviating genetic interactions between genes. By clustering genes into modules and establishing relationships between those modules, we can discover compensatory pathways. We introduce a general framework for applying greedy clustering heuristics to probabilistic graphs. We use this framework to apply a graph clustering method called graph summarization to an E-MAP that targets yeast chromosome biology. This results in a new method for clustering E-MAP data that we call Expected Graph Compression (EGC). We validate modules and compensatory pathways using enriched Gene Ontology annotations and a novel method based on correlated gene expression. EGC finds a number of modules that are not found by any previous methods to cluster E-MAP data. EGC also uncovers core submodules contained within several previously found modules, suggesting that EGC can reveal the finer structure of E-MAP networks.

  16. Constructing a molecular interaction network for thyroid cancer via large-scale text mining of gene and pathway events

    PubMed Central

    2015-01-01

    Background Biomedical studies need assistance from automated tools and easily accessible data to address the problem of the rapidly accumulating literature. Text-mining tools and curated databases have been developed to address such needs and they can be applied to improve the understanding of molecular pathogenesis of complex diseases like thyroid cancer. Results We have developed a system, PWTEES, which extracts pathway interactions from the literature utilizing an existing event extraction tool (TEES) and pathway named entity recognition (PathNER). We then applied the system on a thyroid cancer corpus and systematically extracted molecular interactions involving either genes or pathways. With the extracted information, we constructed a molecular interaction network taking genes and pathways as nodes. Using curated pathway information and network topological analyses, we highlight key genes and pathways involved in thyroid carcinogenesis. Conclusions Mining events involving genes and pathways from the literature and integrating curated pathway knowledge can help improve the understanding of molecular interactions of complex diseases. The system developed for this study can be applied in studies other than thyroid cancer. The source code is freely available online at https://github.com/chengkun-wu/PWTEES. PMID:26679379

  17. An additive interaction between the NFκB and estrogen receptor signalling pathways in human endometrial epithelial cells

    PubMed Central

    King, A.E.; Collins, F.; Klonisch, T.; Sallenave, J.-M.; Critchley, H.O.D.; Saunders, P.T.K.

    2010-01-01

    BACKGROUND Human embryo implantation is regulated by estradiol (E2), progesterone and locally produced mediators including interleukin-1β (IL-1β). Interactions between the estrogen receptor (ER) and NF kappa B (NFκB) signalling pathways have been reported in other systems but have not been detailed in human endometrium. METHODS AND RESULTS Real-time PCR showed that mRNA for the p65 and p105 NFκB subunits is maximally expressed in endometrium from the putative implantation window. Both subunits are localized in the endometrial epithelium throughout the menstrual cycle. Reporter assays for estrogen response element (ERE) activity were used to examine functional interactions between ER and NFκB in telomerase immortalized endometrial epithelial cells (TERT-EEC). E2 and IL-1β treatment of TERT-EECs enhances ERE activity by a NFκB and ER dependent mechanism; this effect could be mediated by ERα or ERβ. E2 and IL-1β also positively interact to increase endogenous gene expression of prostaglandin E synthase and c-myc. This is a gene-dependent action as there is no additive effect on cyclin D1 or progesterone receptor expression. CONCLUSION In summary, we have established that NFκB signalling proteins are expressed in normal endometrium and report that IL-1β can enhance the actions of E2 in a cell line derived from healthy endometrium. This mechanism may allow IL-1β, possibly from the developing embryo, to modulate the function of the endometrial epithelium to promote successful implantation, for example by regulating prostaglandin production. Aberrations in the interaction between the ER and NFκB signalling pathways may have a negative impact on implantation contributing to pathologies such as early pregnancy loss and infertility. PMID:19955102

  18. Special issue: redox active natural products and their interaction with cellular signalling pathways.

    PubMed

    Jacob, Claus

    2014-01-01

    During the last decade, research into natural products has experienced a certain renaissance. The urgent need for more and more effective antibiotics in medicine, the demand for ecologically friendly plant protectants in agriculture, "natural" cosmetics and the issue of a sustainable and healthy nutrition in an ageing society have fuelled research into Nature's treasure chest of "green gold". Here, redox active secondary metabolites from plants, fungi, bacteria and other (micro-)organisms often have been at the forefront of the most interesting developments. These agents provide powerful means to interfere with many, probably most cellular signaling pathways in humans, animals and lower organisms, and therefore can be used to protect, i.e., in form of antioxidants, and to frighten off or even kill, i.e., in form of repellants, antibiotics, fungicides and selective, often catalytic "sensor/effector" anticancer agents. Interestingly, whilst natural product research dates back many decades, in some cases even centuries, and compounds such as allicin and various flavonoids have been investigated thoroughly in the past, it has only recently become possible to investigate their precise interactions and mode(s) of action inside living cells. Here, fluorescent staining and labelling on the one side, and appropriate detection, either qualitatively under the microscope or quantitatively in flow cytometers and plate readers, on the other, enable researchers to obtain the various pieces of information necessary to construct a fairly complete puzzle of how such compounds act and interact in living cells. Complemented by the more traditional activity assays and Western Blots, and increasingly joined by techniques such as proteomics, chemogenetic screening and mRNA profiling, these cell based bioanalytical techniques form a powerful platform for "intracellular diagnostics". In the case of redox active compounds, especially of Reactive Sulfur Species (RSS), such techniques have

  19. Investigation of Protein-Protein Interactions and Conformational Changes in Hedgehog Signaling Pathway by FRET.

    PubMed

    Fu, Lin; Lv, Xiangdong; Xiong, Yue; Zhao, Yun

    2015-01-01

    Protein-protein interactions and signal-induced protein conformational changes are fundamental molecular events that are considered as essential in modern life sciences. Among various techniques developed to study such phenomena, fluorescence resonance energy transfer (FRET) is a widely used method with many advantages in detecting these molecular events. Here, we describe the application of FRET in the mechanistic investigation of cell signal transduction, taking the example of the Hh signaling pathway, which plays a critical role in embryonic development and tissue homeostasis. A number of general guidelines as well as some key notes have been summarized as a protocol for reader's reference. PMID:26179039

  20. Solar wind-magnetosphere interaction: energy transfer pathways and their predictability

    NASA Astrophysics Data System (ADS)

    Vassiliadis, D.

    2001-09-01

    The coupling of the solar wind to planets has been studied for several decades now. Much of the recent progress in understanding the complexity of the interaction is due to the variability of the magnetospheres in the solar system. The interaction with the terrestrial system is evidently the best known, although by far not the simplest one. The geospace and the surrounding solar wind constitute an input-output system where the various parts of the energy budget are measured simultaneously by a fleet of spacecraft. We integrate these measurements by combining plasma physics and simulation models with system analysis methods. The large-scale energy transfer is dominated by magnetic reconnection and its effects which supply electromagnetic and kinetic energy at the rate of ~10^15 W to the magnetosphere with part of it eventually dissipating at the ionospheric boundary. The storage-release of magnetic energy and its transformation to kinetic energy takes place continually through convection and more explosively during magnetospheric substorms. Long known from its effects, ranging from auroral displays to the more recent disruptions of electric power grid operation, this interaction involves many spatial and temporal pathways: The overall disturbance levels are represented by regional and global magnetic indices. Index time series were the first to be reproduced accurately by nonlinear dynamical systems driven by solar wind parameter data. The models have subsequently been used in prediction of the indices based on real-time interplanetary field and plasma parameters from the ACE and WIND spacecraft (http://lep694.gsfc.nasa.gov/RTSM/). The model time scales represent the physical responses, namely the directly driven convection and the less predictable substorm. Currently the approach has been extended to modeling the spatial distribution as well as temporal variations. Data from ground magnetometer arrays have replaced the scalar indices to provide magnetic field maps

  1. Cost-Effectiveness of Interactive Courseware.

    ERIC Educational Resources Information Center

    Fletcher, J. D.

    What is known about the cost effectiveness of interactive courseware (ICW) is reviewed, and issues that remain are summarized. Effect size is used for reporting the effectiveness of ICW programs. Two ICW media are considered: computer-based instruction and interactive videodisc instruction. Effect sizes for computer-based instruction have been…

  2. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice.

    PubMed

    Bermudez-Silva, Francisco J; Romero-Zerbo, Silvana Y; Haissaguerre, Magalie; Ruz-Maldonado, Inmaculada; Lhamyani, Said; El Bekay, Rajaa; Tabarin, Antoine; Marsicano, Giovanni; Cota, Daniela

    2016-01-01

    The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases. PMID:26563389

  3. The cannabinoid CB1 receptor and mTORC1 signalling pathways interact to modulate glucose homeostasis in mice

    PubMed Central

    Bermudez-Silva, Francisco J.; Romero-Zerbo, Silvana Y.; Haissaguerre, Magalie; Ruz-Maldonado, Inmaculada; Lhamyani, Said; El Bekay, Rajaa; Tabarin, Antoine; Marsicano, Giovanni; Cota, Daniela

    2016-01-01

    ABSTRACT The endocannabinoid system (ECS) is an intercellular signalling mechanism that is present in the islets of Langerhans and plays a role in the modulation of insulin secretion and expansion of the β-cell mass. The downstream signalling pathways mediating these effects are poorly understood. Mammalian target of rapamycin complex 1 (mTORC1) signalling is a key intracellular pathway involved in energy homeostasis and is known to importantly affect the physiology of pancreatic islets. We investigated the possible relationship between cannabinoid type 1 (CB1) receptor signalling and the mTORC1 pathway in the endocrine pancreas of mice by using pharmacological analysis as well as mice genetically lacking the CB1 receptor or the downstream target of mTORC1, the kinase p70S6K1. In vitro static secretion experiments on islets, western blotting, and in vivo glucose and insulin tolerance tests were performed. The CB1 receptor antagonist rimonabant decreased glucose-stimulated insulin secretion (GSIS) at 0.1 µM while increasing phosphorylation of p70S6K1 and ribosomal protein S6 (rpS6) within the islets. Specific pharmacological blockade of mTORC1 by 3 nM rapamycin, as well as genetic deletion of p70S6K1, impaired the CB1-antagonist-mediated decrease in GSIS. In vivo experiments showed that 3 mg/kg body weight rimonabant decreased insulin levels and induced glucose intolerance in lean mice without altering peripheral insulin sensitivity; this effect was prevented by peripheral administration of low doses of rapamycin (0.1 mg/kg body weight), which increased insulin sensitivity. These findings suggest a functional interaction between the ECS and the mTORC1 pathway within the endocrine pancreas and at the whole-organism level, which could have implications for the development of new therapeutic approaches for pancreatic β-cell diseases. PMID:26563389

  4. Sharing, liking, commenting, and distressed? The pathway between Facebook interaction and psychological distress.

    PubMed

    Chen, Wenhong; Lee, Kye-Hyoung

    2013-10-01

    Studies on the mental health implications of social media have generated mixed results. Drawing on a survey of college students (N=513), this research uses structural equation modeling to assess the relationship between Facebook interaction and psychological distress and two underlying mechanisms: communication overload and self-esteem. It is the first study, to our knowledge, that examines how communication overload mediates the mental health implications of social media. Frequent Facebook interaction is associated with greater distress directly and indirectly via a two-step pathway that increases communication overload and reduces self-esteem. The research sheds light on new directions for understanding psychological well-being in an increasingly mediated social world as users share, like, and comment more and more. PMID:23745614

  5. Conditional Epistatic Interaction Maps Reveal Global Functional Rewiring of Genome Integrity Pathways in Escherichia coli.

    PubMed

    Kumar, Ashwani; Beloglazova, Natalia; Bundalovic-Torma, Cedoljub; Phanse, Sadhna; Deineko, Viktor; Gagarinova, Alla; Musso, Gabriel; Vlasblom, James; Lemak, Sofia; Hooshyar, Mohsen; Minic, Zoran; Wagih, Omar; Mosca, Roberto; Aloy, Patrick; Golshani, Ashkan; Parkinson, John; Emili, Andrew; Yakunin, Alexander F; Babu, Mohan

    2016-01-26

    As antibiotic resistance is increasingly becoming a public health concern, an improved understanding of the bacterial DNA damage response (DDR), which is commonly targeted by antibiotics, could be of tremendous therapeutic value. Although the genetic components of the bacterial DDR have been studied extensively in isolation, how the underlying biological pathways interact functionally remains unclear. Here, we address this by performing systematic, unbiased, quantitative synthetic genetic interaction (GI) screens and uncover widespread changes in the GI network of the entire genomic integrity apparatus of Escherichia coli under standard and DNA-damaging growth conditions. The GI patterns of untreated cultures implicated two previously uncharacterized proteins (YhbQ and YqgF) as nucleases, whereas reorganization of the GI network after DNA damage revealed DDR roles for both annotated and uncharacterized genes. Analyses of pan-bacterial conservation patterns suggest that DDR mechanisms and functional relationships are near universal, highlighting a modular and highly adaptive genomic stress response. PMID:26774489

  6. Interaction of SecB with intermediates along the folding pathway of maltose-binding protein.

    PubMed Central

    Diamond, D. L.; Strobel, S.; Chun, S. Y.; Randall, L. L.

    1995-01-01

    SecB, a molecular chaperone involved in protein export in Escherichia coli, displays the remarkable ability to selectively bind many different polypeptide ligands whose only common feature is that of being nonnative. The selectivity is explained in part by a kinetic partitioning between the folding of a polypeptide and its association with SecB. SecB has no affinity for native, stably folded polypeptides but interacts tightly with polypeptides that are nonnative. In order to better understand the nature of the binding, we have examined the interaction of SecB with intermediates along the folding pathway of maltose-binding protein. Taking advantage of forms of maltose-binding protein that are altered in their folding properties, we show that the first intermediate in folding, represented by the collapsed state, binds to SecB, and that the polypeptide remains active as a ligand until it crosses the final energy barrier to attain the native state. PMID:7549876

  7. Triple SILAC to determine stimulus specific interactions in the Wnt pathway.

    PubMed

    Hilger, Maximiliane; Mann, Matthias

    2012-02-01

    Many important regulatory functions are performed by dynamic multiprotein complexes that adapt their composition and activity in response to different stimuli. Here we employ quantitative affinity purification coupled with mass spectrometry to efficiently separate background from specific interactors but add an additional quantitative dimension to explicitly characterize stimulus-dependent interactions. This is accomplished by SILAC in a triple-labeling format, in which pull-downs with bait, with bait and stimulus, and without bait are quantified against each other. As baits, we use full-length proteins fused to the green fluorescent protein and expressed under endogenous control. We applied this technology to Wnt signaling, which is important in development, tissue homeostasis, and cancer, and investigated interactions of the key components APC, Axin-1, DVL2, and CtBP2 with differential pathway activation. Our screens identify many known Wnt signaling complex components and link novel candidates to Wnt signaling, including FAM83B and Girdin, which we found as interactors to multiple Wnt pathway players. Girdin binds to DVL2 independent of stimulation with the ligand Wnt3a but to Axin-1 and APC in a stimulus-dependent manner. The core destruction complex itself, which regulates beta-catenin stability as the key step in canonical Wnt signaling, remained essentially unchanged. PMID:22011079

  8. Non-equilibrium colloidal assembly pathways via synergistic dipolar, depletion, and hydrodynamic interactions

    NASA Astrophysics Data System (ADS)

    Coughlan, Anna; Bevan, Michael

    The ability to assemble nano- and micro- colloidal particles into ordered materials and controllable devices provides the basis for emerging technologies. However, current capabilities for manipulating colloidal assembly are limited by the degree of order, time to generate/reconfigure structures, and scalability to large areas. These limitations are due to problems with designing, controlling, and optimizing the thermodynamics and kinetics of colloidal assembly. Our approach is to provide viable non-equilibrium pathways for rapid assembly of defect free colloidal crystals using combinations of magnetic field and depletion mediated assembly. Results include video microscopy experiments and Stokesian Dynamic computer simulations of superparamagnetic colloidal particles experiencing depletion attraction in time varying magnetic fields. Findings show multi-body hydrodynamic interactions and magnetic dipole relaxation mechanisms are essential to capture assembly and annealing of attractive colloidal crystals. With the ability to measure, model and tune colloidal interactions and dynamics, we demonstrate the use of time varying fields to manipulate non-equilibrium pathways for the assembly, disassembly, and repair of colloidal microstructures.

  9. Confirmation of a Protein-Protein Interaction in the Pantothenate Biosynthetic Pathway by Using Sortase-Mediated Labelling.

    PubMed

    Morrison, Philip M; Balmforth, Matthew R; Ness, Samuel W; Williamson, Daniel J; Rugen, Michael D; Turnbull, W Bruce; Webb, Michael E

    2016-04-15

    High-throughput studies have been widely used to identify protein-protein interactions; however, few of these candidate interactions have been confirmed in vitro. We have used a combination of isothermal titration calorimetry and fluorescence anisotropy to screen candidate interactions within the pantothenate biosynthetic pathway. In particular, we observed no interaction between the next enzyme in the pathway, pantothenate synthetase (PS), and aspartate decarboxylase, but did observe an interaction between PS and the putative Nudix hydrolase, YfcD. Confirmation of the interaction by fluorescence anisotropy was dependent upon labelling an adventitiously formed glycine on the protein N-terminal affinity purification tag by using Sortase. Subsequent formation of the protein-protein complex led to apparent restriction of the dynamics of this tag, thus suggesting that this approach could be generally applied to a subset of other protein-protein interaction complexes. PMID:26818742

  10. [Low-dose radiation effects and intracellular signaling pathways].

    PubMed

    Suzuki, Keiji; Kodama, Seiji; Watanabe, Masami

    2006-10-01

    Accumulated evidence has shown that exposure to low-dose radiation, especially doses less than 0.1 Gy, induces observable effects on mammalian cells. However, the underlying molecular mechanisms have not yet been clarified. Recently, it has been shown that low-dose radiation stimulates growth factor receptor, which results in a sequential activation of the mitogen-activated protein kinase pathway. In addition to the activation of the membrane-bound pathways, it is becoming evident that nuclear pathways are also activated by low-dose radiation. Ionizing radiation has detrimental effects on chromatin structure, since radiation-induced DNA double-strand breaks result in discontinuity of nucleosomes. Recently, it has been shown that ATM protein, the product of the ATM gene mutated in ataxia-telangiectasia, recognizes alteration in the chromatin structure, and it is activated through intermolecular autophosphorylation at serine 1981. Using antibodies against phosphorylated ATM, we found that the activated and phosphorylated ATM protein is detected as discrete foci in the nucleus between doses of 10 mGy and 1 Gy. Interestingly, the size of the foci induced by low-dose radiation was equivalent to the foci induced by high-dose radiation. These results indicate that the initial signal is amplified through foci growth, and cells evolve a system by which they can respond to a small number of DNA double-strand breaks. From these results, it can be concluded that low-dose radiation is sensed both in the membrane and in the nucleus, and activation of multiple signal transduction pathways could be involved in manifestations of low-dose effects. PMID:17016017

  11. Partitioning the effects of an ecosystem engineer: kangaroo rats control community structure via multiple pathways.

    PubMed

    Prugh, Laura R; Brashares, Justin S

    2012-05-01

    1. Ecosystem engineers impact communities by altering habitat conditions, but they can also have strong effects through consumptive, competitive and other non-engineering pathways. 2. Engineering effects can lead to fundamentally different community dynamics than non-engineering effects, but the relative strengths of these interactions are seldom quantified. 3. We combined structural equation modelling and exclosure experiments to partition the effects of a keystone engineer, the giant kangaroo rat (Dipodomys ingens), on plants, invertebrates and vertebrates in a semi-arid California grassland. 4. We separated the effects of burrow creation from kangaroo rat density and found that kangaroo rats increased the diversity and abundance of other species via both engineering and non-engineering pathways. 5. Engineering was the primary factor structuring plant and small mammal communities, whereas non-engineering effects structured invertebrate communities and increased lizard abundance. 6. These results highlight the importance of the non-engineering effects of ecosystem engineers and shed new light on the multiple pathways by which strong-interactors shape communities. PMID:22098534

  12. Pathway-Dependent Effectiveness of Network Algorithms for Gene Prioritization

    PubMed Central

    Shim, Jung Eun; Hwang, Sohyun; Lee, Insuk

    2015-01-01

    A network-based approach has proven useful for the identification of novel genes associated with complex phenotypes, including human diseases. Because network-based gene prioritization algorithms are based on propagating information of known phenotype-associated genes through networks, the pathway structure of each phenotype might significantly affect the effectiveness of algorithms. We systematically compared two popular network algorithms with distinct mechanisms – direct neighborhood which propagates information to only direct network neighbors, and network diffusion which diffuses information throughout the entire network – in prioritization of genes for worm and human phenotypes. Previous studies reported that network diffusion generally outperforms direct neighborhood for human diseases. Although prioritization power is generally measured for all ranked genes, only the top candidates are significant for subsequent functional analysis. We found that high prioritizing power of a network algorithm for all genes cannot guarantee successful prioritization of top ranked candidates for a given phenotype. Indeed, the majority of the phenotypes that were more efficiently prioritized by network diffusion showed higher prioritizing power for top candidates by direct neighborhood. We also found that connectivity among pathway genes for each phenotype largely determines which network algorithm is more effective, suggesting that the network algorithm used for each phenotype should be chosen with consideration of pathway gene connectivity. PMID:26091506

  13. Algorithms for effective querying of compound graph-based pathway databases

    PubMed Central

    2009-01-01

    Background Graph-based pathway ontologies and databases are widely used to represent data about cellular processes. This representation makes it possible to programmatically integrate cellular networks and to investigate them using the well-understood concepts of graph theory in order to predict their structural and dynamic properties. An extension of this graph representation, namely hierarchically structured or compound graphs, in which a member of a biological network may recursively contain a sub-network of a somehow logically similar group of biological objects, provides many additional benefits for analysis of biological pathways, including reduction of complexity by decomposition into distinct components or modules. In this regard, it is essential to effectively query such integrated large compound networks to extract the sub-networks of interest with the help of efficient algorithms and software tools. Results Towards this goal, we developed a querying framework, along with a number of graph-theoretic algorithms from simple neighborhood queries to shortest paths to feedback loops, that is applicable to all sorts of graph-based pathway databases, from PPIs (protein-protein interactions) to metabolic and signaling pathways. The framework is unique in that it can account for compound or nested structures and ubiquitous entities present in the pathway data. In addition, the queries may be related to each other through "AND" and "OR" operators, and can be recursively organized into a tree, in which the result of one query might be a source and/or target for another, to form more complex queries. The algorithms were implemented within the querying component of a new version of the software tool PATIKAweb (Pathway Analysis Tool for Integration and Knowledge Acquisition) and have proven useful for answering a number of biologically significant questions for large graph-based pathway databases. Conclusion The PATIKA Project Web site is http

  14. Effects of Prostaglandin Analogues on Aqueous Humor Outflow Pathways

    PubMed Central

    Winkler, Nelson S.

    2014-01-01

    Abstract Elevated intraocular pressure (IOP) is the most prevalent risk factor for glaucoma. All treatments, whether surgical or pharmaceutical, are aimed at lowering IOP. Prostaglandin analogues are a first line therapy for glaucoma due to their ability to reduce IOP, once-daily dosing, efficacy, and minimal side-effect profile. Whereas prostaglandin analogues have been known to alter aqueous humor outflow through the unconventional (uveoscleral) pathway, more recent evidence suggests their action also occurs through the conventional (trabecular) pathway. Understanding how prostaglandin analogues successfully lower IOP is important, as this information may lead to the discovery of new molecular targets for future therapeutic intervention. This review explores the current understanding of prostaglandin analogue biology as it pertains to IOP reduction and improved aqueous humor outflow facility. PMID:24359106

  15. Regulation of Candida albicans Interaction with Macrophages through the Activation of HOG Pathway by Genistein.

    PubMed

    Cui, Shuna; Hassan, Rabeay Y A; Heintz-Buschart, Anna; Bilitewski, Ursula

    2016-01-01

    The severity of infections caused by Candida albicans, the most common opportunistic human fungal pathogen, needs rapid and effective antifungal treatments. One of the effective ways is to control the virulence factors of the pathogen. Therefore, the current study examined the effects of genistein, a natural isoflavone present in soybeans, on C. albicans. The genistein-treated C. albicans cells were then exposed to macrophages. Although no inhibition effect on the growth rates of C. albicans was noted an enhancement of the immune response to macrophages has been observed, indicated by phagocytosis and release of cytokines TNF-α and IL-10. The effect of genistein on the enhanced phagocytosis can be mimicked by the fungicides fludioxonil or iprodione, which inhibit the histidine kinase Cos1p and lead to activation of HOG pathway. The western blot results showed a clear phosphorylation of Hog1p in the wild type strain of C. albicans after incubation with genistein. In addition, effects of genistein on the phosphorylation of Hog1p in the histidine kinase mutants Δcos1 and Δsln1 were also observed. Our results thus indicate a new bio-activity of genistein on C. albicans by activation of the HOG pathway of the human pathogen C. albicans. PMID:26828477

  16. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila.

    PubMed

    Jackson, George R; Wiedau-Pazos, Martina; Sang, Tzu-Kang; Wagle, Naveed; Brown, Carlos A; Massachi, Sasan; Geschwind, Daniel H

    2002-05-16

    Pathologic alterations in the microtubule-associated protein tau have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD). Here, we show that tau overexpression, in combination with phosphorylation by the Drosophila glycogen synthase kinase-3 (GSK-3) homolog and wingless pathway component (Shaggy), exacerbated neurodegeneration induced by tau overexpression alone, leading to neurofibrillary pathology in the fly. Furthermore, manipulation of other wingless signaling molecules downstream from shaggy demonstrated that components of the Wnt signaling pathway modulate neurodegeneration induced by tau pathology in vivo but suggested that tau phosphorylation by GSK-3beta differs from canonical Wnt effects on beta-catenin stability and TCF activity. The genetic system we have established provides a powerful reagent for identification of novel modifiers of tau-induced neurodegeneration that may serve as future therapeutic targets. PMID:12062036

  17. The Clickable Guard Cell, Version II: Interactive Model of Guard Cell Signal Transduction Mechanisms and Pathways.

    PubMed

    Kwak, June M; Mäser, Pascal; Schroeder, Julian I

    2008-01-01

    Guard cells are located in the leaf epidermis and pairs of guard cells surround and form stomatal pores, which regulate CO(2) influx from the atmosphere into leaves for photosynthetic carbon fixation. Stomatal guard cells also regulate water loss of plants via transpiration to the atmosphere. Signal transduction mechanisms in guard cells integrate a multitude of different stimuli to modulate stomatal apertures. Stomata open in response to light. Stomata close in response to drought stress, elevated CO(2), ozone and low humidity. In response to drought, plants synthesize the hormone abscisic acid (ABA) that triggers closing of stomatal pores. Guard cells have become a highly developed model system for dissecting signal transduction mechanisms in plants and for elucidating how individual signaling mechanisms can interact within a network in a single cell. Many new findings have been made in the last few years. This chapter is an update of an electronic interactive chapter in the previous edition of The Arabidopsis Book (Mäser et al. 2003). Here we focus on mechanisms for which genes and mutations have been characterized, including signaling components for which there is substantial signaling, biochemical and genetic evidence. Ion channels have been shown to represent targets of early signal transduction mechanisms and provide functional signaling and quantitative analysis points to determine where and how mutations affect branches within the guard cell signaling network. Although a substantial number of genes and proteins that function in guard cell signaling have been identified in recent years, there are many more left to be identified and the protein-protein interactions within this network will be an important subject of future research. A fully interactive clickable electronic version of this publication can be accessed at the following web site: http://www-biology.ucsd.edu/labs/schroeder/clickablegc2/. The interactive clickable version includes the following

  18. Gene-environment interactions in male reproductive health: Special reference to the aryl hydrocarbon receptor signaling pathway

    PubMed Central

    Brokken, Leon J S; Giwercman, Yvonne Lundberg

    2014-01-01

    Over the last few decades, there have been numerous reports of adverse effects on the reproductive health of wildlife and laboratory animals caused by exposure to endocrine disrupting chemicals (EDCs). The increasing trends in human male reproductive disorders and the mounting evidence for causative environmental factors have therefore sparked growing interest in the health threat posed to humans by EDCs, which are substances in our food, environment and consumer items that interfere with hormone action, biosynthesis or metabolism, resulting in disrupted tissue homeostasis or reproductive function. The mechanisms of EDCs involve a wide array of actions and pathways. Examples include the estrogenic, androgenic, thyroid and retinoid pathways, in which the EDCs may act directly as agonists or antagonists, or indirectly via other nuclear receptors. Dioxins and dioxin-like EDCs exert their biological and toxicological actions through activation of the aryl hydrocarbon-receptor, which besides inducing transcription of detoxifying enzymes also regulates transcriptional activity of other nuclear receptors. There is increasing evidence that genetic predispositions may modify the susceptibility to adverse effects of toxic chemicals. In this review, potential consequences of hereditary predisposition and EDCs are discussed, with a special focus on the currently available publications on interactions between dioxin and androgen signaling. PMID:24369137

  19. Uncertainty quantification of effective nuclear interactions

    NASA Astrophysics Data System (ADS)

    Pérez, R. Navarro; Amaro, J. E.; Arriola, E. Ruiz

    2016-03-01

    We give a brief review on the development of phenomenological NN interactions and the corresponding quantification of statistical uncertainties. We look into the uncertainty of effective interactions broadly used in mean field calculations through the Skyrme parameters and effective field theory counterterms by estimating both statistical and systematic uncertainties stemming from the NN interaction. We also comment on the role played by different fitting strategies on the light of recent developments.

  20. Improved Protein Arrays for Quantitative Systems Analysis of the Dynamics of Signaling Pathway Interactions

    SciTech Connect

    YANG, CHIN-RANG

    2013-12-11

    Astronauts and workers in nuclear plants who repeatedly exposed to low doses of ionizing radiation (IR, <10 cGy) are likely to incur specific changes in signal transduction and gene expression in various tissues of their body. Remarkable advances in high throughput genomics and proteomics technologies enable researchers to broaden their focus from examining single gene/protein kinetics to better understanding global gene/protein expression profiling and biological pathway analyses, namely Systems Biology. An ultimate goal of systems biology is to develop dynamic mathematical models of interacting biological systems capable of simulating living systems in a computer. This Glue Grant is to complement Dr. Boothman’s existing DOE grant (No. DE-FG02-06ER64186) entitled “The IGF1/IGF-1R-MAPK-Secretory Clusterin (sCLU) Pathway: Mediator of a Low Dose IR-Inducible Bystander Effect” to develop sensitive and quantitative proteomic technology that suitable for low dose radiobiology researches. An improved version of quantitative protein array platform utilizing linear Quantum dot signaling for systematically measuring protein levels and phosphorylation states for systems biology modeling is presented. The signals are amplified by a confocal laser Quantum dot scanner resulting in ~1000-fold more sensitivity than traditional Western blots and show the good linearity that is impossible for the signals of HRP-amplification. Therefore this improved protein array technology is suitable to detect weak responses of low dose radiation. Software is developed to facilitate the quantitative readout of signaling network activities. Kinetics of EGFRvIII mutant signaling was analyzed to quantify cross-talks between EGFR and other signaling pathways.

  1. gigantea suppresses immutans variegation by interactions with cytokinin and gibberellin signaling pathways.

    PubMed

    Putarjunan, Aarthi; Rodermel, Steve

    2014-12-01

    The immutans (im) variegation mutant of Arabidopsis (Arabidopsis thaliana) is an ideal model to gain insight into factors that control chloroplast biogenesis. im defines the gene for PTOX, a plastoquinol terminal oxidase that participates in the control of thylakoid redox. Here, we report that the im defect can be suppressed during the late stages of plant development by gigantea (gi2), which defines the gene for GI, a central component of the circadian clock that plays a poorly understood role in diverse plant developmental processes. imgi2 mutants are late flowering and display other well-known phenotypes associated with gi2, such as starch accumulation and resistance to oxidative stress. We show that the restoration of chloroplast biogenesis in imgi2 is caused by a development-specific derepression of cytokinin signaling that involves cross talk with signaling pathways mediated by gibberellin (GA) and SPINDLY (SPY), a GA response inhibitor. Suppression of the plastid defect in imgi2 is likely caused by a relaxation of excitation pressures in developing plastids by factors contributed by gi2, including enhanced rates of photosynthesis and increased resistance to oxidative stress. Interestingly, the suppression phenotype of imgi can be mimicked by crossing im with the starch accumulation mutant, starch excess1 (sex1), perhaps because sex1 utilizes pathways similar to gi. We conclude that our studies provide a direct genetic linkage between GI and chloroplast biogenesis, and we construct a model of interactions between signaling pathways mediated by gi, GA, SPY, cytokinins, and sex1 that are required for chloroplast biogenesis. PMID:25349324

  2. gigantea Suppresses immutans Variegation by Interactions with Cytokinin and Gibberellin Signaling Pathways1[W][OPEN

    PubMed Central

    Putarjunan, Aarthi; Rodermel, Steve

    2014-01-01

    The immutans (im) variegation mutant of Arabidopsis (Arabidopsis thaliana) is an ideal model to gain insight into factors that control chloroplast biogenesis. im defines the gene for PTOX, a plastoquinol terminal oxidase that participates in the control of thylakoid redox. Here, we report that the im defect can be suppressed during the late stages of plant development by gigantea (gi2), which defines the gene for GI, a central component of the circadian clock that plays a poorly understood role in diverse plant developmental processes. imgi2 mutants are late flowering and display other well-known phenotypes associated with gi2, such as starch accumulation and resistance to oxidative stress. We show that the restoration of chloroplast biogenesis in imgi2 is caused by a development-specific derepression of cytokinin signaling that involves cross talk with signaling pathways mediated by gibberellin (GA) and SPINDLY (SPY), a GA response inhibitor. Suppression of the plastid defect in imgi2 is likely caused by a relaxation of excitation pressures in developing plastids by factors contributed by gi2, including enhanced rates of photosynthesis and increased resistance to oxidative stress. Interestingly, the suppression phenotype of imgi can be mimicked by crossing im with the starch accumulation mutant, starch excess1 (sex1), perhaps because sex1 utilizes pathways similar to gi. We conclude that our studies provide a direct genetic linkage between GI and chloroplast biogenesis, and we construct a model of interactions between signaling pathways mediated by gi, GA, SPY, cytokinins, and sex1 that are required for chloroplast biogenesis. PMID:25349324

  3. miRNA Influences in NRF2 Pathway Interactions within Cancer Models

    PubMed Central

    Ayers, Duncan; Baron, Byron; Hunter, Therese

    2015-01-01

    The NRF2 transcription factor (nuclear factor-erythroid 2 p45-related factor 2) has been identified as a key molecular player in orchestrating adaptive cellular interactions following a wide spectrum of cellular stress conditions that could be either extracellular or intracellular. Dysregulation of the NRF2 system is implicated in various disease states, including inflammatory conditions. The NRF2 transcription factor is also known to permit cross talk with several other essential cellular signaling pathways. Recent literature has also elucidated the potential influences of miRNA activity over modulations of the NRF2 signalling network. Consequently, further delving into the knowledge regarding the extent of miRNA-induced epigenetic gene regulatory control on key elements of the NRF2 signalling pathway and its cross talk, particularly within the context of cancer models, can prove to be of high clinical importance. This is so since such miRNAs, once identified and validated, can be potentially exploited as novel drug targets for emerging translational medicine-based therapies. PMID:26345522

  4. Applied neuroanatomy elective to reinforce and promote engagement with neurosensory pathways using interactive and artistic activities.

    PubMed

    Dao, Vinh; Yeh, Pon-Hsiu; Vogel, Kristine S; Moore, Charleen M

    2015-01-01

    One in six Americans is currently affected by neurologic disease. As the United States population ages, the number of neurologic complaints is expected to increase. Thus, there is a pressing need for more neurologists as well as more neurology training in other specialties. Often interest in neurology begins during medical school, so improving education in medical neural courses is a critical step toward producing more neurologists and better neurology training in other specialists. To this end, a novel applied neuroanatomy elective was designed at the University of Texas Health Science Center at San Antonio (UTHSCSA) to complement the traditional first-year medical neuroscience course and promote engagement and deep learning of the material with a focus on neurosensory pathways. The elective covered four neurosensory modalities (proprioception/balance, vision, auditory, and taste/olfaction) over four sessions, each with a short classroom component and a much longer activity component. At each session, students reviewed the neurosensory pathways through structured presentations and then applied them to preplanned interactive activities, many of which allowed students to utilize their artistic talents. Students were required to complete subjective pre-course and post-course surveys and reflections. The survey results and positive student comments suggest that the elective was a valuable tool when used in parallel with the traditional medical neuroscience course in promoting engagement and reinforcement of the neurosensory material. PMID:24920370

  5. Interaction of P-glycoprotein with anti-tumor drugs: the site, gate and pathway.

    PubMed

    Zhang, Junqiao; Li, Debing; Sun, Tianyang; Liang, Lijun; Wang, Qi

    2015-09-01

    Understanding the mechanism and pathway of anti-cancer drugs to be pumped out by P-glycoprotein (P-gp) in cancer cell is very important for the successful chemotherapy. P-gp is a member of ATP-binding cassette (ABC) transporters. In this study, random accelerated molecular dynamics (RAMD) simulation was used to explore the potential egress pathway of ligands from the binding pocket. This could be considered as a reverse process of drug binding. The most possible portal of drugs to dissociate is TM4/TM6, which is almost the same for different drugs, such as paclitaxel and doxorubicin. The interactions in the binding site are found to be remarkably stronger than that outside of the binding site. The results were suggested by the free energy calculation between P-gp and different drugs from metadynamics simulation. All the results indicate that the flexibility of inner residues, especially the residue Phe339, is very important for the drugs to access the binding site. PMID:26205623

  6. Genetic Interaction Maps in Escherichia coli Reveal Functional Crosstalk among Cell Envelope Biogenesis Pathways

    PubMed Central

    Vlasblom, James; Gagarinova, Alla; Phanse, Sadhna; Graham, Chris; Yousif, Fouad; Ding, Huiming; Xiong, Xuejian; Nazarians-Armavil, Anaies; Alamgir, Md; Ali, Mehrab; Pogoutse, Oxana; Pe'er, Asaf; Arnold, Roland; Michaut, Magali; Parkinson, John; Golshani, Ashkan; Whitfield, Chris; Wodak, Shoshana J.; Moreno-Hagelsieb, Gabriel; Greenblatt, Jack F.; Emili, Andrew

    2011-01-01

    As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among >235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target. PMID:22125496

  7. Cellular and molecular pathways of extremely-low-frequency electromagnetic field interactions with living systems

    NASA Astrophysics Data System (ADS)

    Tenforde, T. S.

    1992-06-01

    There is growing evidence that environmental electric and magnetic fields in the extremely-low-frequency (ELF) band below 300 Hz can influence biological functions by mechanisms that are only poorly understood at the present time. The primary objectives of this paper are to review the physical properties of ELF fields, their interactions with living systems at the tissue, cellular, and subcellular levels, and the key role of cell membranes in the transduction of signals from imposed ELF fields. Topics of discussion include signal-to-noise ratios for single cells and cell aggregates, resonance phenomena involving a combination of static and ELF magnetic fields, and the possible influence of ELF fields on molecular signaling pathways that involve membrane receptors and cytoplasmic second messengers.

  8. Cellular and molecular pathways of extremely-low-frequency electromagnetic field interactions with living systems

    SciTech Connect

    Tenforde, T.S.

    1992-06-01

    There is growing evidence that environmental electric and magnetic fields in the extremely-low-frequency (ELF) band below 300 Hz can influence biological functions by mechanisms that are only poorly understood at the present time. The primary objectives of this paper are to review the physical properties of ELF fields, their interactions with living systems at the tissue, cellular, and subcellular levels, and the key role of cell membranes ;in the transduction of signals from imposed ELF fields. Topics of discussion include signal-to-noise ratios for single cells and cell aggregates, resonance phenomena involving a combination of static and ELF magnetic fields, and the possible influence of ELF fields on molecular signaling pathways that involve membrane receptors and cytoplasmic second messengers.

  9. Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling

    PubMed Central

    Brai, Emanuele; Marathe, Swananda; Astori, Simone; Fredj, Naila Ben; Perry, Elisabeth; Lamy, Christophe; Scotti, Alessandra; Alberi, Lavinia

    2015-01-01

    Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia. Highlights In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation: Notch1 interacts with another important developmental pathway, the Reelin cascade. Notch1 regulates both NMDAR expression and composition. Notch1 influences a cascade of cellular events culminating in CREB activation. PMID:26635527

  10. Nodes with high centrality in protein interaction networks are responsible for driving signaling pathways in diabetic nephropathy

    PubMed Central

    Abedi, Maryam

    2015-01-01

    In spite of huge efforts, chronic diseases remain an unresolved problem in medicine. Systems biology could assist to develop more efficient therapies through providing quantitative holistic sights to these complex disorders. In this study, we have re-analyzed a microarray dataset to identify critical signaling pathways related to diabetic nephropathy. GSE1009 dataset was downloaded from Gene Expression Omnibus database and the gene expression profile of glomeruli from diabetic nephropathy patients and those from healthy individuals were compared. The protein-protein interaction network for differentially expressed genes was constructed and enriched. In addition, topology of the network was analyzed to identify the genes with high centrality parameters and then pathway enrichment analysis was performed. We found 49 genes to be variably expressed between the two groups. The network of these genes had few interactions so it was enriched and a network with 137 nodes was constructed. Based on different parameters, 34 nodes were considered to have high centrality in this network. Pathway enrichment analysis with these central genes identified 62 inter-connected signaling pathways related to diabetic nephropathy. Interestingly, the central nodes were more informative for pathway enrichment analysis compared to all network nodes and also 49 differentially expressed genes. In conclusion, we here show that central nodes in protein interaction networks tend to be present in pathways that co-occur in a biological state. Also, this study suggests a computational method for inferring underlying mechanisms of complex disorders from raw high-throughput data. PMID:26557424

  11. The Integration of Epistasis Network and Functional Interactions in a GWAS Implicates RXR Pathway Genes in the Immune Response to Smallpox Vaccine

    PubMed Central

    McKinney, Brett A.; Lareau, Caleb; Oberg, Ann L.; Kennedy, Richard B.; Ovsyannikova, Inna G.; Poland, Gregory A.

    2016-01-01

    Although many diseases and traits show large heritability, few genetic variants have been found to strongly separate phenotype groups by genotype. Complex regulatory networks of variants and expression of multiple genes lead to small individual-variant effects and difficulty replicating the effect of any single variant in an affected pathway. Interaction network modeling of GWAS identifies effects ignored by univariate models, but population differences may still cause specific genes to not replicate. Integrative network models may help detect indirect effects of variants in the underlying biological pathway. In this study, we used gene-level functional interaction information from the Integrative Multi-species Prediction (IMP) tool to reveal important genes associated with a complex phenotype through evidence from epistasis networks and pathway enrichment. We test this method for augmenting variant-based network analyses with functional interactions by applying it to a smallpox vaccine immune response GWAS. The integrative analysis spotlights the role of genes related to retinoid X receptor alpha (RXRA), which has been implicated in a previous epistasis network analysis of smallpox vaccine. PMID:27513748

  12. The Integration of Epistasis Network and Functional Interactions in a GWAS Implicates RXR Pathway Genes in the Immune Response to Smallpox Vaccine.

    PubMed

    McKinney, Brett A; Lareau, Caleb; Oberg, Ann L; Kennedy, Richard B; Ovsyannikova, Inna G; Poland, Gregory A

    2016-01-01

    Although many diseases and traits show large heritability, few genetic variants have been found to strongly separate phenotype groups by genotype. Complex regulatory networks of variants and expression of multiple genes lead to small individual-variant effects and difficulty replicating the effect of any single variant in an affected pathway. Interaction network modeling of GWAS identifies effects ignored by univariate models, but population differences may still cause specific genes to not replicate. Integrative network models may help detect indirect effects of variants in the underlying biological pathway. In this study, we used gene-level functional interaction information from the Integrative Multi-species Prediction (IMP) tool to reveal important genes associated with a complex phenotype through evidence from epistasis networks and pathway enrichment. We test this method for augmenting variant-based network analyses with functional interactions by applying it to a smallpox vaccine immune response GWAS. The integrative analysis spotlights the role of genes related to retinoid X receptor alpha (RXRA), which has been implicated in a previous epistasis network analysis of smallpox vaccine. PMID:27513748

  13. Technology Improvement Pathways to Cost-Effective Vehicle Electrification

    SciTech Connect

    Brooker, A.; Thornton, M.; Rugh, J. P.

    2010-04-01

    Electrifying transportation can reduce or eliminate dependence on foreign fuels, emission of green house gases, and emission of pollutants. One challenge is finding a pathway for vehicles that gains wide market acceptance to achieve a meaningful benefit. This paper evaluates several approaches aimed at making plug-in electric vehicles (EV) and plug-in hybrid electric vehicles (PHEVs) cost-effective including opportunity charging, replacing the battery over the vehicle life, improving battery life, reducing battery cost, and providing electric power directly to the vehicle during a portion of its travel. Many combinations of PHEV electric range and battery power are included. For each case, the model accounts for battery cycle life and the national distribution of driving distances to size the battery optimally. Using the current estimates of battery life and cost, only the dynamically plugged-in pathway was cost-effective to the consumer. Significant improvements in battery life and battery cost also made PHEVs more cost-effective than today's hybrid electric vehicles (HEVs) and conventional internal combustion engine vehicles (CVs).

  14. Postulated pathogenic pathway in triazole fungicide induced dysmorphogenic effects.

    PubMed

    Menegola, Elena; Broccia, Maria L; Di Renzo, Francesca; Giavini, Erminio

    2006-08-01

    Triazole fungicides are used in medicine as well as in agricultural treatment of mycoses. The pharmacological mechanism is related to the inhibition of CYP enzymes involved in the formation of the fungal walls. A similar inhibition of human CYP enzymes has been suggested as the cause of triazole side effects in humans. An important role of some CYP isoforms (CYP26 isoforms) expressed during mammalian development is the catabolism of retinoic acid, a known morphogen in vertebrates and invertebrates. The adverse effects on morphogenesis, observed after exposure of mammalian, amphibian and ascidiacea, are compared to the reported effects of triazole in humans. The possible pathogenic pathway in triazole-related teratogenesis is discussed on the basis of different experimental approaches. PMID:16781842

  15. The Vac14-interaction Network Is Linked to Regulators of the Endolysosomal and Autophagic Pathway*

    PubMed Central

    Schulze, Ulf; Vollenbröker, Beate; Braun, Daniela A.; Van Le, Truc; Granado, Daniel; Kremerskothen, Joachim; Fränzel, Benjamin; Klosowski, Rafael; Barth, Johannes; Fufezan, Christian; Wolters, Dirk A.; Pavenstädt, Hermann; Weide, Thomas

    2014-01-01

    The scaffold protein Vac14 acts in a complex with the lipid kinase PIKfyve and its counteracting phosphatase FIG4, regulating the interconversion of phosphatidylinositol-3-phosphate to phosphatidylinositol-3,5-bisphosphate. Dysfunctional Vac14 mutants, a deficiency of one of the Vac14 complex components, or inhibition of PIKfyve enzymatic activity results in the formation of large vacuoles in cells. How these vacuoles are generated and which processes are involved are only poorly understood. Here we show that ectopic overexpression of wild-type Vac14 as well as of the PIKfyve-binding deficient Vac14 L156R mutant causes vacuoles. Vac14-dependent vacuoles and PIKfyve inhibitor-dependent vacuoles resulted in elevated levels of late endosomal, lysosomal, and autophagy-associated proteins. However, only late endosomal marker proteins were bound to the membranes of these enlarged vacuoles. In order to decipher the linkage between the Vac14 complex and regulators of the endolysosomal pathway, a protein affinity approach combined with multidimensional protein identification technology was conducted, and novel molecular links were unraveled. We found and verified the interaction of Rab9 and the Rab7 GAP TBC1D15 with Vac14. The identified Rab-related interaction partners support the theory that the regulation of vesicular transport processes and phosphatidylinositol-modifying enzymes are tightly interconnected. PMID:24578385

  16. Interactive Big Data Resource to Elucidate Human Immune Pathways and Diseases.

    PubMed

    Gorenshteyn, Dmitriy; Zaslavsky, Elena; Fribourg, Miguel; Park, Christopher Y; Wong, Aaron K; Tadych, Alicja; Hartmann, Boris M; Albrecht, Randy A; García-Sastre, Adolfo; Kleinstein, Steven H; Troyanskaya, Olga G; Sealfon, Stuart C

    2015-09-15

    Many functionally important interactions between genes and proteins involved in immunological diseases and processes are unknown. The exponential growth in public high-throughput data offers an opportunity to expand this knowledge. To unlock human-immunology-relevant insight contained in the global biomedical research effort, including all public high-throughput datasets, we performed immunological-pathway-focused Bayesian integration of a comprehensive, heterogeneous compendium comprising 38,088 genome-scale experiments. The distillation of this knowledge into immunological networks of functional relationships between molecular entities (ImmuNet), and tools to mine this resource, are accessible to the public at http://immunet.princeton.edu. The predictive capacity of ImmuNet, established by rigorous statistical validation, is easily accessed by experimentalists to generate data-driven hypotheses. We demonstrate the power of this approach through the identification of unique host-virus interaction responses, and we show how ImmuNet complements genetic studies by predicting disease-associated genes. ImmuNet should be widely beneficial for investigating the mechanisms of the human immune system and immunological diseases. PMID:26362267

  17. Learning Communities: Pathways for Educational Success and Social Transformation through Interactive Groups in Mathematics

    ERIC Educational Resources Information Center

    García-Carrión, Rocío; Díez-Palomar, Javier

    2015-01-01

    Schools as learning communities have been recommended by the European Commission as an effective model to support school quality and development. Aiming at studying how these schools are achieving such positive results, this article focuses on the analysis of a particular classroom intervention called "interactive groups". A five-year…

  18. Effects of Nitrogen Fertilization on Tritrophic Interactions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant—herbivore—natural enemy interactions are basic components of nearly all ecosystems, and nitrogen can exert a variety of effects on plants which can significantly alter these interactions. We present a diagram illustrating the various ways that nitrogen can affect three trophic levels and revi...

  19. Effects of Noise on Small Group Interaction.

    ERIC Educational Resources Information Center

    Whitehead, Jack L.

    This study reports an analysis of the effects of moderate levels of noise on task performance of an interacting group. Groups of students first interacted in information-sharing discussions under varying conditions of noise and then responded to an objective test over the shared information and to a series of semantic differential scales designed…

  20. Interaction and multiband effects in the intrinsic spin-Hall effect of an interacting multiorbital metal

    NASA Astrophysics Data System (ADS)

    Arakawa, Naoya

    The spin-Hall effect is a spin-current version of the usual-Hall effect, and its potential for application may be great. For the efficient application utilizing the spin-Hall effect, an understanding of interaction effects may be helpful because the interaction effects sometimes become remarkable in transport phenomena (e.g., fractional-quantum-Hall effect). However, a lot of theoretical studies neglected the interaction effects, and the interaction effects in the spin-Hall effect had been little understood. To improve this situation, I developed a general formalism for the intrinsic spin-Hall effect including the interaction effects and multiband effects by using the linear-response theory with approximations appropriate for an interacting multiorbital metal (see arXiv:1510.03988). In this talk, I explain how the electron-electron interaction modifies the spin-Hall conductivity and show several new and remarkable interactions effects, new mechanisms of the damping dependence and a crossover of the damping dependence in a clean system and a temperature-dependent correction due to the spin-Coulomb drag. I also show guidelines useful for general formulations of other transport phenomena including the interaction effects and multiband effects.

  1. Interaction of Wnt pathway related variants with type 2 diabetes in a Chinese Han population.

    PubMed

    Zhou, Jian-Bo; Yang, Jin-Kui; Zhang, Bao-Hong; Lu, Jing

    2015-01-01

    Aims. Epistasis from gene set based on the function-related genes may confer to the susceptibility of type 2 diabetes (T2D). The Wnt pathway has been reported to play an important role in the pathogenesis of T2D. Here we applied tag SNPs to explore the association between epistasis among genes from Wnt and T2D in the Han Chinese population. Methods. Variants of fourteen genes selected from Wnt pathways were performed to analyze epistasis. Gene-gene interactions in case-control samples were identified by generalized multifactor dimensionality reduction (GMDR) method. We performed a case-controlled association analysis on a total of 1,026 individual with T2D and 1,157 controls via tag SNPs in Wnt pathway. Results. In single-locus analysis, SNPs in four genes were significantly associated with T2D adjusted for multiple testing (rs7903146(C) in TCF7L2, p = 3.21∗10(-3), OR = 1.39, 95% CI [1.31-1.47], rs12904944(G) in SMAD3, p = 2.51∗10(-3), OR = 1.39, 95% CI [1.31-1.47], rs2273368(C) in WNT2B, p = 4.46∗10(-3), OR = 1.23, 95% CI [1.11-1.32], rs6902123(C) in PPARD, p = 1.14∗10(-2), OR = 1.40, 95% CI [1.32-1.48]). The haplotype TGC constructed by TCF7L2 (rs7903146), DKK1 (rs2241529) and BTRC (rs4436485) showed a significant association with T2D (OR = 0.750, 95% CI [0.579-0.972], P = 0.03). For epistasis analysis, the optimized combination was the two locus model of WNT2B rs2273368 and TCF7L2rs7903146, which had the maximum cross-validation consistency. This was 9 out of 10 for the sign test at 0.0107 level. The best combination increased the risk of T2D by 1.47 times (95% CI [1.13-1.91], p = 0.0039). Conclusions. Epistasis between TCF7L2 and WNT2B is associated with the susceptibility of T2D in a Han Chinese population. Our results were compatible with the idea of the complex nature of T2D that would have been missed using conventional tools. PMID:26509107

  2. 3d-4f magnetic interaction with density functional theory plus u approach: local Coulomb correlation and exchange pathways.

    PubMed

    Zhang, Yachao; Yang, Yang; Jiang, Hong

    2013-12-12

    The 3d-4f exchange interaction plays an important role in many lanthanide based molecular magnetic materials such as single-molecule magnets and magnetic refrigerants. In this work, we study the 3d-4f magnetic exchange interactions in a series of Cu(II)-Gd(III) (3d(9)-4f(7)) dinuclear complexes based on the numerical atomic basis-norm-conserving pseudopotential method and density functional theory plus the Hubbard U correction approach (DFT+U). We obtain improved description of the 4f electrons by including the semicore 5s5p states in the valence part of the Gd-pseudopotential. The Hubbard U correction is employed to treat the strongly correlated Cu-3d and Gd-4f electrons, which significantly improve the agreement of the predicted exchange constants, J, with experiment, indicating the importance of accurate description of the local Coulomb correlation. The high efficiency of the DFT+U approach enables us to perform calculations with molecular crystals, which in general improve the agreement between theory and experiment, achieving a mean absolute error smaller than 2 cm(-1). In addition, through analyzing the physical effects of U, we identify two magnetic exchange pathways. One is ferromagnetic and involves an interaction between the Cu-3d, O-2p (bridge ligand), and the majority-spin Gd-5d orbitals. The other one is antiferromagnetic and involves Cu-3d, O-2p, and the empty minority-spin Gd-4f orbitals, which is suppressed by the planar Cu-O-O-Gd structure. This study demonstrates the accuracy of the DFT+U method for evaluating the 3d-4f exchange interactions, provides a better understanding of the exchange mechanism in the Cu(II)-Gd(III) complexes, and paves the way for exploiting the magnetic properties of the 3d-4f compounds containing lanthanides other than Gd. PMID:24274078

  3. Plasma interactions and surface/material effects

    NASA Technical Reports Server (NTRS)

    Mandel, M.; Chutjian, A.; Hall, W.; Leung, P.; Robinson, P.; Stevens, N. J.

    1986-01-01

    A discussion on plasma interactions and surface/material effects is summarized. The key issues in this area were: (1) the lack of data on the material properties of common spacecraft surface materials; (2) lack of understanding of the contamination and decontamination processes; and (3) insufficient analytical tools to model synergistic phenomena related to plasma interactions. Without an adequate database of material properties, accurate system performance predictions cannot be made. The interdisciplinary nature of the surface-plasma interactions area makes it difficult to plan and maintain a coherent theoretical and experimental program. The shuttle glow phenomenon is an excellent example of an unanticipated, complex interaction involving synergism between surface and plasma effects. Building an adequate technology base for understanding and predicting surface-plasma interactions will require the coordinated efforts of engineers, chemists, and physicists. An interdisciplinary R and D program should be organized to deal with similar problems that the space systems of the 21st century may encounter.

  4. Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase II metabolic pathways

    PubMed Central

    Jiang, Wen; Hu, Ming

    2014-01-01

    Flavonoids, existing mainly as glycosides in nature, have multiple “claimed” beneficial effects in humans. Flavonoids are extensively metabolized in enterocytes and hepatocytes by phase II enzymes such as UGTs and SULTs to form glucuronides and sulfates, respectively. These glucuronides and sulfates are subsequently excreted via ABC transporters (e.g., MRP2 or BCRP). Therefore, it is the interplay between phase II enzymes and efflux transporters that affects the disposition of flavonoids and leads to the low bioavailability of flavonoid aglycones. Flavonoids can also serve as chemical regulators that affect the activity or expression levels of phase II enzymes including UGTs, SULTs and GSTs, and transporters including P-gp, MRP2, BCRP, OATP and OAT. In general, flavonoids may exert the inhibitory or inductive effects on the phase II enzymes and transporters via multiple mechanisms that may involve different nuclear receptors. Since flavonoids may affect the metabolic pathways shared by many important clinical drugs, drug-flavonoid interaction is becoming an increasingly important concern. This review article focused on the disposition of flavonoids and effects of flavonoids on relevant enzymes (e.g. UGTs and SULTs) and transporters (e.g. MRP2 and BCRP) involved in the interplay between phase II enzymes and efflux transporters. The effects of flavonoids on other metabolic enzymes (e.g. GSTs) or transporters (e.g. P-gp, OATP and OAT) are also addressed but that is not the emphasis of this review. PMID:25400909

  5. From a Subtractive to Multiplicative Approach: A Concept-Driven Interactive Pathway on the Selective Absorption of Light

    ERIC Educational Resources Information Center

    Viennot, Laurence; de Hosson, Cécile

    2015-01-01

    This research documents the aims and the impact of a teaching experiment on how the absorption of light depends on the thickness of the absorbing medium. This teaching experiment is more specifically characterized as bringing to bear a "concept-driven interactive pathway". It is designed to make students analyse the absorption of light…

  6. Alcohol Effects on Stress Pathways: Impact on Craving and Relapse Risk.

    PubMed

    Blaine, Sara K; Milivojevic, Verica; Fox, Helen; Sinha, Rajita

    2016-03-01

    A significant amount of neurobiological research regarding the development of alcohol use disorders (AUDs) has focused on alcohol-related activation and long-term alterations in the mesocortical dopaminergic reward pathways. However, alcohol does not only interact with brain reward systems. Many of its acute and chronic effects may be related to allostatic adaptations in hypothalamic and extrahypothalamic stress regulation pathways. For example, acute binge intoxication is associated with hypothalamically driven increases in blood cortisol, norepinephrine, and sex steroid metabolite levels. This may contribute to the development of mesocortical sensitization to alcohol. Furthermore, chronic alcohol exposure is associated with systemic dysregulation of the hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and sex steroid systems. This dysregulation appears to manifest as neuroendocrine tolerance. In this review, we first summarize the literature suggesting that alcohol-induced alterations in these hypothalamic systems influence craving and contribute to the development of AUDs. We note that for women, the effects of alcohol on these neuroendocrine stress regulation systems may be influenced by the rhythmic variations of hormones and steroids across the menstrual cycle. Second, we discuss how changes in these systems may indicate progression of AUDs and increased risk of relapse in both sexes. Specifically, neuroendocrine tolerance may contribute to mesocortical sensitization, which in turn may lead to decreased prefrontal inhibitory control of the dopaminergic reward and hypothalamic stress systems. Thus, pharmacological strategies that counteract alcohol-associated changes in hypothalamic and extrahypothalamic stress regulation pathways may slow the development and progression of AUDs. PMID:27254089

  7. The centrosomal component CEP161 of Dictyostelium discoideum interacts with the Hippo signaling pathway

    PubMed Central

    Sukumaran, Salil K.; Blau-Wasser, Rosemarie; Rohlfs, Meino; Gallinger, Christoph; Schleicher, Michael; Noegel, Angelika A

    2015-01-01

    CEP161 is a novel component of the Dictyostelium discoideum centrosome which was identified as binding partner of the pericentriolar component CP250. Here we show that the amino acids 1-763 of the 1381 amino acids CEP161 are sufficient for CP250 binding, centrosomal targeting and centrosome association. Analysis of AX2 cells over-expressing truncated and full length CEP161 proteins revealed defects in growth and development. By immunoprecipitation experiments we identified the Hippo related kinase SvkA (Hrk-svk) as binding partner for CEP161. Both proteins colocalize at the centrosome. In in vitro kinase assays the N-terminal domain of CEP161 (residues 1-763) inhibited the kinase activity of Hrk-svk. A comparison of D. discoideum Hippo kinase mutants with mutants overexpressing CEP161 polypeptides revealed similar defects. We propose that the centrosomal component CEP161 is a novel player in the Hippo signaling pathway and affects various cellular properties through this interaction. PMID:25607232

  8. FOXP2 drives neuronal differentiation by interacting with retinoic acid signaling pathways

    PubMed Central

    Devanna, Paolo; Middelbeek, Jeroen; Vernes, Sonja C.

    2014-01-01

    FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells. PMID:25309332

  9. How does the Royal Family of Tudor rule the PIWI-interacting RNA pathway?

    PubMed Central

    Siomi, Mikiko C.; Mannen, Taro; Siomi, Haruhiko

    2010-01-01

    PIWI (P-element-induced wimpy testis) proteins are a subset of the Argonaute proteins and are expressed predominantly in the germlines of a variety of organisms, including Drosophila and mammals. PIWI proteins associate specifically with PIWI-interacting RNAs (piRNAs), small RNAs that are also expressed predominantly in germlines, and silence transposable DNA elements and other genes showing complementarities to the sequences of associated piRNAs. This mechanism helps to maintain the integrity of the genome and the development of gametes. PIWI proteins have been shown recently to contain symmetrical dimethyl arginines (sDMAs), and this modification is mediated by the methyltransferase PRMT5 (also known as Dart5 or Capsuleen). It was then demonstrated that multiple members of the Tudor (Tud) family of proteins, which are necessary for gametogenesis in both flies and mice, associate with PIWI proteins specifically through sDMAs in various but particular combinations. Although Tud domains in Tud family members are known to be sDMA-binding modules, involvement of the Tudor family at the molecular level in the piRNA pathway has only recently come into focus. PMID:20360382

  10. Different forms of effective connectivity in primate frontotemporal pathways

    PubMed Central

    Petkov, Christopher I.; Kikuchi, Yukiko; Milne, Alice E.; Mishkin, Mortimer; Rauschecker, Josef P.; Logothetis, Nikos K.

    2015-01-01

    It is generally held that non-primary sensory regions of the brain have a strong impact on frontal cortex. However, the effective connectivity of pathways to frontal cortex is poorly understood. Here we microstimulate sites in the superior temporal and ventral frontal cortex of monkeys and use functional magnetic resonance imaging to evaluate the functional activity resulting from the stimulation of interconnected regions. Surprisingly, we find that, although certain earlier stages of auditory cortical processing can strongly activate frontal cortex, downstream auditory regions, such as voice-sensitive cortex, appear to functionally engage primarily an ipsilateral temporal lobe network. Stimulating other sites within this activated temporal lobe network shows strong activation of frontal cortex. The results indicate that the relative stage of sensory processing does not predict the level of functional access to the frontal lobes. Rather, certain brain regions engage local networks, only parts of which have a strong functional impact on frontal cortex. PMID:25613079

  11. Different forms of effective connectivity in primate frontotemporal pathways.

    PubMed

    Petkov, Christopher I; Kikuchi, Yukiko; Milne, Alice E; Mishkin, Mortimer; Rauschecker, Josef P; Logothetis, Nikos K

    2015-01-01

    It is generally held that non-primary sensory regions of the brain have a strong impact on frontal cortex. However, the effective connectivity of pathways to frontal cortex is poorly understood. Here we microstimulate sites in the superior temporal and ventral frontal cortex of monkeys and use functional magnetic resonance imaging to evaluate the functional activity resulting from the stimulation of interconnected regions. Surprisingly, we find that, although certain earlier stages of auditory cortical processing can strongly activate frontal cortex, downstream auditory regions, such as voice-sensitive cortex, appear to functionally engage primarily an ipsilateral temporal lobe network. Stimulating other sites within this activated temporal lobe network shows strong activation of frontal cortex. The results indicate that the relative stage of sensory processing does not predict the level of functional access to the frontal lobes. Rather, certain brain regions engage local networks, only parts of which have a strong functional impact on frontal cortex. PMID:25613079

  12. Osmolyte Effects on the Unfolding Pathway of β-Lactoglobulin

    NASA Astrophysics Data System (ADS)

    Meng, Wei; Pan, Hai; Qin, Meng; Cao, Yi; Wang, Wei

    2013-10-01

    There are large amounts of osmolytes inside cells, which impact many physiological processes by complicated mechanisms. The osmolyte effects on the stability and folding of proteins have been studied in detail using simple two-state folding proteins. However, many important functional proteins fold in complex pathways involving various intermediates. Little is known about the osmolyte effects on the folding and unfolding of these proteins. It is noted that β-lactoglobulin (BLG) is an example of such proteins, whose unfolding involves an obvious intermediate state. Using equilibrium chemical denaturation and stopped-flow kinetics, we investigate the unfolding of BLG in the presence of different osmolytes, e.g., glycerol, ethylene glycol (EG) and poly(ethylene glycol)400 (PEG400). It is found that all these osmolytes can stabilize the unfolding intermediate by modulating the relative unfolding kinetics of the native and the intermediate states. The stabilization effects are similar for EG and PEG400 but distinct for glycerol. Since the unfolding intermediates of many proteins are directly related to protein misfolding diseases, evaluation of the osmolyte effects for the unfolding of these proteins in vitro should be beneficial for the understanding of the occurrence of the related diseases in vivo.

  13. Electrostatic interactions in the binding pathway of a transient protein complex studied by NMR and isothermal titration calorimetry.

    PubMed

    Meneses, Erick; Mittermaier, Anthony

    2014-10-01

    Much of our knowledge of protein binding pathways is derived from extremely stable complexes that interact very tightly, with lifetimes of hours to days. Much less is known about weaker interactions and transient complexes because these are challenging to characterize experimentally. Nevertheless, these types of interactions are ubiquitous in living systems. The combination of NMR relaxation dispersion Carr-Purcell-Meiboom-Gill (CPMG) experiments and isothermal titration calorimetry allows the quantification of rapid binding kinetics for complexes with submillisecond lifetimes that are difficult to study using conventional techniques. We have used this approach to investigate the binding pathway of the Src homology 3 (SH3) domain from the Fyn tyrosine kinase, which forms complexes with peptide targets whose lifetimes are on the order of about a millisecond. Long range electrostatic interactions have been shown to play a critical role in the binding pathways of tightly binding complexes. The role of electrostatics in the binding pathways of transient complexes is less well understood. Similarly to previously studied tight complexes, we find that SH3 domain association rates are enhanced by long range electrostatics, whereas short range interactions are formed late in the docking process. However, the extent of electrostatic association rate enhancement is several orders of magnitudes less, whereas the electrostatic-free basal association rate is significantly greater. Thus, the SH3 domain is far less reliant on electrostatic enhancement to achieve rapid association kinetics than are previously studied systems. This suggests that there may be overall differences in the role played by electrostatics in the binding pathways of extremely stable versus transient complexes. PMID:25122758

  14. Electrostatic Interactions in the Binding Pathway of a Transient Protein Complex Studied by NMR and Isothermal Titration Calorimetry*

    PubMed Central

    Meneses, Erick; Mittermaier, Anthony

    2014-01-01

    Much of our knowledge of protein binding pathways is derived from extremely stable complexes that interact very tightly, with lifetimes of hours to days. Much less is known about weaker interactions and transient complexes because these are challenging to characterize experimentally. Nevertheless, these types of interactions are ubiquitous in living systems. The combination of NMR relaxation dispersion Carr–Purcell–Meiboom–Gill (CPMG) experiments and isothermal titration calorimetry allows the quantification of rapid binding kinetics for complexes with submillisecond lifetimes that are difficult to study using conventional techniques. We have used this approach to investigate the binding pathway of the Src homology 3 (SH3) domain from the Fyn tyrosine kinase, which forms complexes with peptide targets whose lifetimes are on the order of about a millisecond. Long range electrostatic interactions have been shown to play a critical role in the binding pathways of tightly binding complexes. The role of electrostatics in the binding pathways of transient complexes is less well understood. Similarly to previously studied tight complexes, we find that SH3 domain association rates are enhanced by long range electrostatics, whereas short range interactions are formed late in the docking process. However, the extent of electrostatic association rate enhancement is several orders of magnitudes less, whereas the electrostatic-free basal association rate is significantly greater. Thus, the SH3 domain is far less reliant on electrostatic enhancement to achieve rapid association kinetics than are previously studied systems. This suggests that there may be overall differences in the role played by electrostatics in the binding pathways of extremely stable versus transient complexes. PMID:25122758

  15. Adhesion effects in contact interaction of solids

    NASA Astrophysics Data System (ADS)

    Goryacheva, Irina; Makhovskaya, Yulya

    2008-01-01

    An approach to solving problems of the interaction of axisymmetric elastic bodies in the presence of adhesion is developed. The different natures of adhesion, i.e. capillary adhesion, or molecular adhesion described by the Lennard-Jones potential are examined. The effect of additional loading of the interacting bodies outside the contact zone is also investigated. The approach is based on the representation of the pressure outside the contact zone arising from adhesion by a step function. The analytical solution is obtained and is used to analyze the influence of the form of the adhesion interaction potential, of the surface energy of interacting bodies or the films covering the bodies, their shapes (parabolic, higher power exponential function), volume of liquid in the meniscus, density of contact spots, of elastic modulus and the Poisson ratio on the characteristics of the interaction of the bodies in the presence of adhesion. To cite this article: I. Goryacheva, Y. Makhovskaya, C. R. Mecanique 336 (2008).

  16. Effects of photodynamic therapy on the endocytic pathway

    PubMed Central

    Kessel, David; Price, Michael; Caruso, Joseph; Reiners, John

    2011-01-01

    In this report, we describe an effect of photodynamic therapy (PDT) on membrane trafficking in murine 1c1c7 hepatoma cells. A brief exposure of 1c1c7 cells to a 20 nM concentration of the phosphatidylinositol kinase class-3 antagonist wortmannin led to the rapid appearance of cytoplasmic vacuoles. Fluorescence monitoring of plasma membrane-associated 1-[4-(trimethylamino)-phenyl]-6-phenylhexa-1,3,5-triene (TDPH) over time demonstrated that the wortmannin-induced vacuoles were derived from endocytosed plasma membrane. Low-dose photodamage catalyzed by the lysosomal photosensitizer NPe6, prior to the addition of wortmannin, prevented formation of these vacuoles. NPe6 was found to suppress for several hours the normal trafficking of TDPH-labeled plasma membrane to the cytosol, and the formation of punctate TDPH-labeled cytoplasmic vesicles. The ability of NPe6-induced photodamage to suppress wortmannin-induced vacuolization occurred under conditions that did not disrupt lysosomes and were at or below the threshold of cytostatic/cytotoxic effects. Furthermore, the suppressive effects of NPe6-PDT were not prevented by inclusion of an agent that stabilized lysosomal membranes, or by E64d, an inhibitor of lysosomal cathepsin proteases. Mitochondrial photodamage was less effective at preventing wortmannin-induced vacuole formation and PDT directed against the ER had no effect. The role of photodamage to the endocytic pathway may be a hitherto unexplored effect on cells that selectively accumulate photosensitizing agents. These results indicate that photodamage directed against endosomes/lysosomes has effects independent of the release of lysosomal proteases. PMID:21125114

  17. Effective Models for Electron Tansfer in Proteins - Connection Between Pathway and Detailed Hamiltonians

    NASA Astrophysics Data System (ADS)

    Balabin, I. A.; Onichic, J. N.

    1997-03-01

    Understanding how the protein molecular structure controls the electron transfer (ET) rate is critical for both achieving an insight into vital bioenergetic reactions and designing new ET proteins. We develop and test a new approach for computing ET tunneling matrix elements. Our goal is to provide quantitative results for large molecules with limited computer resources. This connection between simple models and more detailed atomistic models will also provide a better understanding of the basic features that control the ET mechanism. We introduce a series of simple Hamiltonians that incorporate effects of complex molecular structure on the ET rate. Electronic orbital interactions are categorized as classes, and only the most important of them are included. The remaining orbitals are incorporated by means of effective (dependent on the tunneling energy) interaction parameters. Calculations with these Hamiltonians are compared with ``exact'' extended Huckel-level results for several biological and chemically-designed systems. The suggested approach integrates quantum chemical and pathway-like methods. Quantitative calculations with limited computer resources and identification of the domains dominating ET are now in reach. This new developed approach integrates quantum chemistry and pathway-like methods.

  18. Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury: role of RISK and SAFE pathways interaction.

    PubMed

    Yu, Liming; Li, Buying; Zhang, Meng; Jin, Zhenxiao; Duan, Weixun; Zhao, Guolong; Yang, Yang; Liu, Zhenhua; Chen, Wensheng; Wang, Siwang; Yang, Jian; Yi, Dinghua; Liu, Jincheng; Yu, Shiqiang

    2016-07-01

    Recently, we demonstrated that melatonin reduced protein kinase RNA (PKR)-like ER kinase (PERK)-eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor-4 (ATF4)-mediated myocardial endoplasmic reticulum (ER) stress and apoptosis during myocardial ischemia-reperfusion (MI/R) injury. However, the underlying mechanisms are still not clear. Myocardial reperfusion injury salvage kinase (RISK) pathway as well as survivor activating factor enhancement (SAFE) pathway are two pivotal intrinsic pro-survival signaling cascades. In this study, we performed in vivo and in vitro experiment to investigate the ameliorative effect of melatonin on ER stress with a focus on RISK and SAFE pathways interaction. Male C57Bl/6 mice received melatonin (300 μg/25 g/day, 3 days before MI/R surgery; 300 μg/25 g, 25 min before the onset of ischemia) pre-treatment with or without the administration of LY294002 (a PI3K/Akt inhibitor), U0126 (an ERK1/2 inhibitor) or AG490 (a STAT3 pathway inhibitor). H9c2 cells were pre-treated with melatonin (100 μM, 8 h) in the presence or absence of LY294002, U0126 or AG490. Compared with the I/R-injured group, melatonin effectively reduced myocardial apoptosis, oxidative stress and improved cardiac function. In addition, melatonin pre-treatment also increased the phosphorylation of Akt, GSK-3β, ERK1/2 and STAT3 and reduced PERK-eIF2α-ATF4-mediated ER stress. However, these effects were blocked by LY294002, U0126 or AG490. Additionally, either LY294002 or U0126 treatment could inhibit STAT3 phosphorylation, whereas AG490 administration also reduced both Akt and ERK1/2 phosphorylation, indicating an interplay exists between RISK and SAFE pathways in melatonin's cardioprotective effect. In summary, our study demonstrates that RISK and SAFE pathways mediate the cardioprotective effect of melatonin against MI/R injury. Melatonin pre-treatment attenuates PERK-eIF2α-ATF4-mediated ER stress and apoptosis during MI/R injury via RISK

  19. Estimating Interaction Effects With Incomplete Predictor Variables

    PubMed Central

    Enders, Craig K.; Baraldi, Amanda N.; Cham, Heining

    2014-01-01

    The existing missing data literature does not provide a clear prescription for estimating interaction effects with missing data, particularly when the interaction involves a pair of continuous variables. In this article, we describe maximum likelihood and multiple imputation procedures for this common analysis problem. We outline 3 latent variable model specifications for interaction analyses with missing data. These models apply procedures from the latent variable interaction literature to analyses with a single indicator per construct (e.g., a regression analysis with scale scores). We also discuss multiple imputation for interaction effects, emphasizing an approach that applies standard imputation procedures to the product of 2 raw score predictors. We thoroughly describe the process of probing interaction effects with maximum likelihood and multiple imputation. For both missing data handling techniques, we outline centering and transformation strategies that researchers can implement in popular software packages, and we use a series of real data analyses to illustrate these methods. Finally, we use computer simulations to evaluate the performance of the proposed techniques. PMID:24707955

  20. Interacting parallel pathways associate sounds with visual identity in auditory cortices.

    PubMed

    Ahveninen, Jyrki; Huang, Samantha; Ahlfors, Seppo P; Hämäläinen, Matti; Rossi, Stephanie; Sams, Mikko; Jääskeläinen, Iiro P

    2016-01-01

    Spatial and non-spatial information of sound events is presumably processed in parallel auditory cortex (AC) "what" and "where" streams, which are modulated by inputs from the respective visual-cortex subsystems. How these parallel processes are integrated to perceptual objects that remain stable across time and the source agent's movements is unknown. We recorded magneto- and electroencephalography (MEG/EEG) data while subjects viewed animated video clips featuring two audiovisual objects, a black cat and a gray cat. Adaptor-probe events were either linked to the same object (the black cat meowed twice in a row in the same location) or included a visually conveyed identity change (the black and then the gray cat meowed with identical voices in the same location). In addition to effects in visual (including fusiform, middle temporal or MT areas) and frontoparietal association areas, the visually conveyed object-identity change was associated with a release from adaptation of early (50-150ms) activity in posterior ACs, spreading to left anterior ACs at 250-450ms in our combined MEG/EEG source estimates. Repetition of events belonging to the same object resulted in increased theta-band (4-8Hz) synchronization within the "what" and "where" pathways (e.g., between anterior AC and fusiform areas). In contrast, the visually conveyed identity changes resulted in distributed synchronization at higher frequencies (alpha and beta bands, 8-32Hz) across different auditory, visual, and association areas. The results suggest that sound events become initially linked to perceptual objects in posterior AC, followed by modulations of representations in anterior AC. Hierarchical what and where pathways seem to operate in parallel after repeating audiovisual associations, whereas the resetting of such associations engages a distributed network across auditory, visual, and multisensory areas. PMID:26419388

  1. Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention.

    PubMed

    Bultman, Scott J

    2014-02-15

    Gene-environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low-moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression. PMID:24270685

  2. Ranibizumab interacts with the VEGF-A/VEGFR-2 signaling pathway in human RPE cells at different levels.

    PubMed

    Ranjbar, Mahdy; Brinkmann, Max Philipp; Tura, Aysegül; Rudolf, Martin; Miura, Yoko; Grisanti, Salvatore

    2016-07-01

    Vascular endothelial growth factor (VEGF) secreted by the retinal pigment epithelium (RPE) plays an important role in ocular homeostasis, but also in diseases, most notably age-related macular degeneration (AMD). To date, anti-VEGF drugs like ranibizumab have been shown to be most effective in treating these pathologic conditions. However, clinical trials suggest that the RPE could degenerate and perish through anti-VEGF treatment. Herein, we evaluated possible pathways and outcomes of the interaction between ranibizumab and human RPE cells (ARPE-19). Results indicate that ranibizumab affects the VEGF-A metabolism in RPE cells from an extra- as well as intracellular site. The drug is taken up into the cells, with the VEGF receptor 2 (VEGFR-2) being involved, and decreases VEGF-A protein levels within the cells as well as extracellularly. Oxidative stress plays a key role in various inflammatory disorders of the eye. Our results suggest that oxidative stress inhibits RPE cell proliferation. This anti-proliferative effect on RPE cells is significantly enhanced through ranibizumab, which does not inhibit RPE cell proliferation substantially in absence of relevant oxidative stress. Therefore, we emphasize that anti-VEGF treatment should be selected carefully in AMD patients with preexistent extensive RPE atrophy. PMID:27163716

  3. Impact of organic-mineral matter interactions on thermal reaction pathways for coal model compounds

    SciTech Connect

    Buchanan, A.C. III; Britt, P.F.; Struss, J.A.

    1995-07-01

    Coal is a complex, heterogeneous solid that includes interdispersed mineral matter. However, knowledge of organic-mineral matter interactions is embryonic, and the impact of these interactions on coal pyrolysis and liquefaction is incomplete. Clay minerals, for example, are known to be effective catalysts for organic reactions. Furthermore, clays such as montmorillonite have been proposed to be key catalysts in the thermal alteration of lignin into vitrinite during the coalification process. Recent studies by Hatcher and coworkers on the evolution of coalified woods using microscopy and NMR have led them to propose selective, acid-catalyzed, solid state reaction chemistry to account for retained structural integrity in the wood. However, the chemical feasibility of such reactions in relevant solids is difficult to demonstrate. The authors have begun a model compound study to gain a better molecular level understanding of the effects in the solid state of organic-mineral matter interactions relevant to both coal formation and processing. To satisfy the need for model compounds that remain nonvolatile solids at temperatures ranging to 450 C, model compounds are employed that are chemically bound to the surface of a fumed silica (Si-O-C{sub aryl}linkage). The organic structures currently under investigation are phenethyl phenyl ether (C{sub 6}H{sub 5}CH{sub 2}CH{sub 2}OC{sub 6}H{sub 5}) derivatives, which serve as models for {beta}-alkyl aryl ether units that are present in lignin and lignitic coals. The solid-state chemistry of these materials at 200--450 C in the presence of interdispersed acid catalysts such as small particle size silica-aluminas and montmorillonite clay will be reported. Initial focus will be on defining the potential impact of these interactions on coal pyrolysis and liquefaction.

  4. Investigation of cyclooxygenase and signaling pathways involved in human platelet aggregation mediated by synergistic interaction of various agonists

    PubMed Central

    Khan, Nadia; Farooq, Ahsana Dar; Sadek, Bassem

    2015-01-01

    In the present study, the mechanism(s) of synergistic interaction of various platelet mediators such as arachidonic acid (AA) when combined with 5-hydroxytryptamine (5-HT) or adenosine diphosphate (ADP) on human platelet aggregation were examined. The results demonstrated that 5-HT had no or negligible effect on aggregation but it did potentiate the aggregation response of AA. Similarly, the combination of subeffective concentrations of ADP and AA exhibited noticeable rise in platelet aggregation. Moreover, the observed synergistic effect of AA with 5-HT on platelets was inhibited by different cyclooxygenase (COX) inhibitors, namely ibuprofen and celecoxib, with half maximal inhibitory effect (IC50) values of 18.0±1.8 and 15.6±3.4 μmol/L, respectively. Interestingly, the synergistic effect observed for AA with 5-HT was, also, blocked by the 5-HT receptor blockers cyproheptadine (IC50=22.0±7 μmol/L), ketanserin (IC50=152±23 μmol/L), phospholipase C (PLC) inhibitor (U73122; IC50=6.1±0.8 μmol/L), and mitogen activated protein kinase (MAPK) inhibitor (PD98059; IC50=3.8±0.5 μmol/L). Likewise, the synergism of AA and ADP was, also, attenuated by COX inhibitors (ibuprofen; IC50=20±4 μmol/L and celecoxib; IC50=24±7 μmol/L), PLC inhibitor (U73122; IC50=3.7±0.3 μmol/L), and MAPK inhibitor (PD98059; IC50=2.8±1.1 μmol/L). Our observed data demonstrate that the combination of subthreshold concentrations of agonists amplifies platelet aggregation and that these synergistic effects largely depend on activation of COX/thromboxane A2, receptor-operated Ca2+ channels, Gq/PLC, and MAPK signaling pathways. Moreover, our data revealed that inhibition of COX pathways by using both selective and/or non-selective COX inhibitors blocks not only AA metabolism and thromboxane A2 formation, but also its binding to Gq receptors and activation of receptor-operated Ca2+ channels in platelets. Overall, our results show that PLC and MAPK inhibitors proved to inhibit the

  5. Investigation of cyclooxygenase and signaling pathways involved in human platelet aggregation mediated by synergistic interaction of various agonists.

    PubMed

    Khan, Nadia; Farooq, Ahsana Dar; Sadek, Bassem

    2015-01-01

    In the present study, the mechanism(s) of synergistic interaction of various platelet mediators such as arachidonic acid (AA) when combined with 5-hydroxytryptamine (5-HT) or adenosine diphosphate (ADP) on human platelet aggregation were examined. The results demonstrated that 5-HT had no or negligible effect on aggregation but it did potentiate the aggregation response of AA. Similarly, the combination of subeffective concentrations of ADP and AA exhibited noticeable rise in platelet aggregation. Moreover, the observed synergistic effect of AA with 5-HT on platelets was inhibited by different cyclooxygenase (COX) inhibitors, namely ibuprofen and celecoxib, with half maximal inhibitory effect (IC50) values of 18.0 ± 1.8 and 15.6 ± 3.4 μmol/L, respectively. Interestingly, the synergistic effect observed for AA with 5-HT was, also, blocked by the 5-HT receptor blockers cyproheptadine (IC50=22.0 ± 7 μmol/L), ketanserin (IC50=152 ± 23 μmol/L), phospholipase C (PLC) inhibitor (U73122; IC50=6.1 ± 0.8 μmol/L), and mitogen activated protein kinase (MAPK) inhibitor (PD98059; IC50=3.8 ± 0.5 μmol/L). Likewise, the synergism of AA and ADP was, also, attenuated by COX inhibitors (ibuprofen; IC50=20 ± 4 μmol/L and celecoxib; IC50=24 ± 7 μmol/L), PLC inhibitor (U73122; IC50=3.7 ± 0.3 μmol/L), and MAPK inhibitor (PD98059; IC50=2.8 ± 1.1 μmol/L). Our observed data demonstrate that the combination of subthreshold concentrations of agonists amplifies platelet aggregation and that these synergistic effects largely depend on activation of COX/thromboxane A2, receptor-operated Ca(2+) channels, Gq/PLC, and MAPK signaling pathways. Moreover, our data revealed that inhibition of COX pathways by using both selective and/or non-selective COX inhibitors blocks not only AA metabolism and thromboxane A2 formation, but also its binding to Gq receptors and activation of receptor-operated Ca(2+) channels in platelets. Overall, our results show that PLC and MAPK inhibitors proved

  6. Intergenerational Continuity in Parenting Behavior: Mediating Pathways and Child Effects

    PubMed Central

    Neppl, Tricia K.; Conger, Rand D.; Scaramella, Laura V.; Ontai, Lenna L.

    2009-01-01

    This prospective, longitudinal investigation examined mechanisms proposed to explain continuities in parenting behavior across two generations (G1, G2). Data came from 187 G2 adults, their mothers (G1), and their children (G3). Prospective information regarding G2 was collected both during adolescence and early adulthood. G1 data were collected during G2’s adolescence and G3 data were generated during the preschool years. Assessments included both observational and self-report measures. The results indicated a direct relationship between G1 and G2 harsh parenting and between G1 and G2 positive parenting. As predicted, specific mediators accounted for intergenerational continuity in particular types of parenting behavior. G2 externalizing behavior mediated the relationship between G1 and G2 harsh parenting, while G2 academic attainment mediated the relationship between G1 and G2 positive parenting. In addition, the hypothesized mediating pathways remained statistically significant after taking into account possible G2 effects on G1 parenting and G3 effects on G2 parenting. PMID:19702389

  7. Pathway Design Effects on Synthetic Vision Head-Up Displays

    NASA Technical Reports Server (NTRS)

    Kramer, Lynda J.; Prinzel, Lawrence J., III; Arthur, Jarvis J., III; Bailey, Randall E.

    2004-01-01

    NASA s Synthetic Vision Systems (SVS) project is developing technologies with practical applications that will eliminate low visibility conditions as a causal factor to civil aircraft accidents while replicating the operational benefits of clear day flight operations, regardless of the actual outside visibility condition. A major thrust of the SVS project involves the development/demonstration of affordable, certifiable display configurations that provide intuitive out-the-window terrain and obstacle information with advanced pathway guidance for transport aircraft. This experiment evaluated the influence of different tunnel and guidance concepts upon pilot situation awareness (SA), mental workload, and flight path tracking performance for Synthetic Vision display concepts using a Head-Up Display (HUD). Two tunnel formats (dynamic, minimal) were evaluated against a baseline condition (no tunnel) during simulated IMC approaches to Reno-Tahoe International airport. Two guidance cues (tadpole, follow-me aircraft) were also evaluated to assess their influence on the tunnel formats. Results indicated that the presence of a tunnel on an SVS HUD had no effect on flight path performance but that it did have significant effects on pilot SA and mental workload. The dynamic tunnel concept with the follow-me aircraft guidance symbol produced the lowest workload and provided the highest SA among the tunnel concepts evaluated.

  8. Controlling a spillover pathway with the molecular cork effect

    NASA Astrophysics Data System (ADS)

    Marcinkowski, Matthew D.; Jewell, April D.; Stamatakis, Michail; Boucher, Matthew B.; Lewis, Emily A.; Murphy, Colin J.; Kyriakou, Georgios; Sykes, E. Charles H.

    2013-06-01

    Spillover of reactants from one active site to another is important in heterogeneous catalysis and has recently been shown to enhance hydrogen storage in a variety of materials. The spillover of hydrogen is notoriously hard to detect or control. We report herein that the hydrogen spillover pathway on a Pd/Cu alloy can be controlled by reversible adsorption of a spectator molecule. Pd atoms in the Cu surface serve as hydrogen dissociation sites from which H atoms can spillover onto surrounding Cu regions. Selective adsorption of CO at these atomic Pd sites is shown to either prevent the uptake of hydrogen on, or inhibit its desorption from, the surface. In this way, the hydrogen coverage on the whole surface can be controlled by molecular adsorption at a minority site, which we term a ‘molecular cork’ effect. We show that the molecular cork effect is present during a surface catalysed hydrogenation reaction and illustrate how it can be used as a method for controlling uptake and release of hydrogen in a model storage system.

  9. Deduction and Analysis of the Interacting Stress Response Pathways of Metal/Radionuclide-reducing Bacteria

    SciTech Connect

    Zhou, Jizhong; He, Zhili

    2010-02-28

    Project Title: Deduction and Analysis of the Interacting Stress Response Pathways of Metal/Radionuclide-reducing Bacteria DOE Grant Number: DE-FG02-06ER64205 Principal Investigator: Jizhong (Joe) Zhou (University of Oklahoma) Key members: Zhili He, Aifen Zhou, Christopher Hemme, Joy Van Nostrand, Ye Deng, and Qichao Tu Collaborators: Terry Hazen, Judy Wall, Adam Arkin, Matthew Fields, Aindrila Mukhopadhyay, and David Stahl Summary Three major objectives have been conducted in the Zhou group at the University of Oklahoma (OU): (i) understanding of gene function, regulation, network and evolution of Desulfovibrio vugaris Hildenborough in response to environmental stresses, (ii) development of metagenomics technologies for microbial community analysis, and (iii) functional characterization of microbial communities with metagenomic approaches. In the past a few years, we characterized four CRP/FNR regulators, sequenced ancestor and evolved D. vulgaris strains, and functionally analyzed those mutated genes identified in salt-adapted strains. Also, a new version of GeoChip 4.0 has been developed, which also includes stress response genes (StressChip), and a random matrix theory-based conceptual framework for identifying functional molecular ecological networks has been developed with the high throughput functional gene array hybridization data as well as pyrosequencing data from 16S rRNA genes. In addition, GeoChip and sequencing technologies as well as network analysis approaches have been used to analyze microbial communities from different habitats. Those studies provide a comprehensive understanding of gene function, regulation, network, and evolution in D. vulgaris, and microbial community diversity, composition and structure as well as their linkages with environmental factors and ecosystem functioning, which has resulted in more than 60 publications.

  10. Signal Propagation in the Human Visual Pathways: An Effective Connectivity Analysis.

    PubMed

    Youssofzadeh, Vahab; Prasad, Girijesh; Fagan, Andrew J; Reilly, Richard B; Martens, Sven; Meaney, James F; Wong-Lin, KongFatt

    2015-09-30

    Although the visual system has been extensively investigated, an integrated account of the spatiotemporal dynamics of long-range signal propagation along the human visual pathways is not completely known or validated. In this work, we used dynamic causal modeling approach to provide insights into the underlying neural circuit dynamics of pattern reversal visual-evoked potentials extracted from concurrent EEG-fMRI data. A recurrent forward-backward connectivity model, consisting of multiple interacting brain regions identified by EEG source localization aided by fMRI spatial priors, best accounted for the data dynamics. Sources were first identified in the thalamic area, primary visual cortex, as well as higher cortical areas along the ventral and dorsal visual processing streams. Consistent with hierarchical early visual processing, the model disclosed and quantified the neural temporal dynamics across the identified activity sources. This signal propagation is dominated by a feedforward process, but we also found weaker effective feedback connectivity. Using effective connectivity analysis, the optimal dynamic causal modeling revealed enhanced connectivity along the dorsal pathway but slightly suppressed connectivity along the ventral pathway. A bias was also found in favor of the right hemisphere consistent with functional attentional asymmetry. This study validates, for the first time, the long-range signal propagation timing in the human visual pathways. A similar modeling approach can potentially be used to understand other cognitive processes and dysfunctions in signal propagation in neurological and neuropsychiatric disorders. Significance statement: An integrated account of long-range visual signal propagation in the human brain is currently incomplete. Using computational neural modeling on our acquired concurrent EEG-fMRI data under a visual evoked task, we found not only a substantial forward propagation toward "higher-order" brain regions but also a

  11. Aldosterone and thyroid hormone interaction on the sodium and potassium transport pathways of rat colonic epithelium.

    PubMed

    Edmonds, C J; Willis, C L

    1990-01-01

    The effect of hypothyroidism on potassium adaptation (shown by increased potassium secretion in response to potassium loading) and on the action of aldosterone on potassium secretion and sodium fluxes was examined in the rat distal colon. Potassium adaptation, particularly the response to an acute potassium load, was impaired by hypothyroidism which also considerably reduced the rise of transepithelial electrical potential difference (p.d.) of total and transcellular (active) lumen-to-plasma sodium fluxes and of potassium secretion normally produced by aldosterone. These changes were, in part, corrected by a short period (3 days) of tri-iodothyronine replacement. Moreover in aldosterone-treated hypothyroid rats, amiloride in the lumen was considerably less effective in reducing the p.d. and sodium fluxes than in aldosterone-treated normal rats. The intracellular sodium transport pool was greater in the hypothyroid than in the normal rats (5.0 +/- 1.1 (S.E.M.) nmol/mg dry weight compared with 2.9 +/- 0.2 nmol/mg dry weight; P less than 0.02). Aldosterone increased the pool in the normal but not in the hypothyroid rats while amiloride had little effect on the pool in the aldosterone-treated hypothyroid rats but almost abolished it in aldosterone-treated normal rats. Aldosterone plays a major part in the adaptation of colonic sodium and potassium transport to sodium depletion or potassium excess; these adaptations were much impaired in hypothyroid animals. The present results are consistent with a deficiency in aldosterone induction of potassium- and amiloride-sensitive sodium pathways in the apical membrane of colonic epithelial cells in hypothyroid rats, a deficiency which limits the stimulant effect of aldosterone on sodium and potassium transport. PMID:2299278

  12. Interactions between auditory 'what' and 'where' pathways revealed by enhanced near-threshold discrimination of frequency and position.

    PubMed

    Tardif, Eric; Spierer, Lucas; Clarke, Stephanie; Murray, Micah M

    2008-03-01

    Partially segregated neuronal pathways ("what" and "where" pathways, respectively) are thought to mediate sound recognition and localization. Less studied are interactions between these pathways. In two experiments, we investigated whether near-threshold pitch discrimination sensitivity (d') is altered by supra-threshold task-irrelevant position differences and likewise whether near-threshold position discrimination sensitivity is altered by supra-threshold task-irrelevant pitch differences. Each experiment followed a 2 x 2 within-subjects design regarding changes/no change in the task-relevant and task-irrelevant stimulus dimensions. In Experiment 1, subjects discriminated between 750 Hz and 752 Hz pure tones, and d' for this near-threshold pitch change significantly increased by a factor of 1.09 when accompanied by a task-irrelevant position change of 65 micros interaural time difference (ITD). No response bias was induced by the task-irrelevant position change. In Experiment 2, subjects discriminated between 385 micros and 431 micros ITDs, and d' for this near-threshold position change significantly increased by a factor of 0.73 when accompanied by task-irrelevant pitch changes (6 Hz). In contrast to Experiment 1, task-irrelevant pitch changes induced a response criterion bias toward responding that the two stimuli differed. The collective results are indicative of facilitative interactions between "what" and "where" pathways. By demonstrating how these pathways may cooperate under impoverished listening conditions, our results bear implications for possible neuro-rehabilitation strategies. We discuss our results in terms of the dual-pathway model of auditory processing. PMID:18191423

  13. Effectiveness and pathways of electrochemical degradation of pretilachlor herbicides.

    PubMed

    Wei, Jinzhi; Feng, Yujie; Sun, Xiaojun; Liu, Junfeng; Zhu, Limin

    2011-05-15

    Pretilachlor used as one kind of acetanilide herbicides is potentially dangerous and biorefractory. In this work, electrochemical degradation of lab-synthetic pretilachlor wastewater was carried out with Sb doped Ti/SnO(2) electrode as anode and stainless steel as cathode. The effect of current density on pretilachlor degradation was investigated, and the degradation pathway of pretilachlor was inferred by analyzing its main degradation intermediates. The results showed that the removal of pretilachlor and TOC in treatment time of 60 min were 98.8% and 43.1% under the conditions of current density of 20 mA cm(-2), initial concentration of pretilachlor of 60 mg L(-1), Na(2)SO(4) dosage of 0.1 mol L(-1), pH of 7.2, respectively, while the energy consumption was 15.8 kWhm(-3). The main reactions for electrochemical degradation of pretilachlor included hydroxylation, oxidation, dechlorination, C-O bond and C-N bond cleavage, resulting in the formation of nine main intermediates. PMID:21382661

  14. Bone Biomarkers on the Pathway to Effective Spaceflight Countermeasures

    NASA Technical Reports Server (NTRS)

    Spatz, Jordan

    2009-01-01

    Osteocyte cells are the most abundant yet least understood bone cell type in the human body. However, recent discovers in osteocyte cell biology have shed light on their importance as key mechanosensing cells regulating the bone remodeling process. Thus, we propose the first ever in vitro gene expression evaluation of osteocytes exposed to simulated microgravity to determine mechanistic pathways of their gravity sensing ability. Improved understanding of the fundamental mechanisms at the osteocyte cellular level may lead to improved treatment options to mitigate the effects of bone loss encountered by astronauts on long duration space missions and provide tailored treatment options for maintaining bone strength of immobilized/partially paralyzed patients here on Earth. Aim 1: Characterize the gene expression patterns and protein levels following exposure of murine osteocytelike cell line (MLO-Y4) to simulated microgravity using the NASA Rotating Wall Vessel (RWV) Bioreactor. Osteocytes are theorized to be the mechanosensors and transducers of mechanical load for bones, yet the biological mechanism of this action remains elusive. We propose to investigate the genetic regulation of the mechanism of the MLO-Y4 cell in the NASA Bioreactor as it is the accepted ground-based analog for simulating vector averaged microgravity.

  15. Conservation and expression of PIWI-interacting RNA pathway genes in male and female adult gonad of amniotes.

    PubMed

    Lim, Shu Ly; Tsend-Ayush, Enkhjargal; Kortschak, R Daniel; Jacob, Reuben; Ricciardelli, Carmela; Oehler, Martin K; Grützner, Frank

    2013-12-01

    The PIWI-interacting RNA (piRNA) pathway is essential for germline development and transposable element repression. Key elements of this pathway are members of the piRNA-binding PIWI/Argonaute protein family and associated factors (e.g., VASA, MAELSTROM, and TUDOR domain proteins). PIWI-interacting RNAs have been identified in mouse testis and oocytes, but information about the expression of the different piRNA pathway genes, in particular in the mammalian ovary, remains incomplete. We investigated the evolution and expression of piRNA pathway genes in gonads of amniote species (chicken, platypus, and mouse). Database searches confirm a high level of conservation and revealed lineage-specific gain and loss of Piwi genes in vertebrates. Expression analysis in mammals shows that orthologs of Piwi-like (Piwil) genes, Mael (Maelstrom), Mvh (mouse vasa homolog), and Tdrd1 (Tudor domain-containing protein 1) are expressed in platypus adult testis. In contrast to mouse, Piwil4 is expressed in platypus and human adult testis. We found evidence for Mael and Piwil2 expression in mouse Sertoli cells. Importantly, we show mRNA expression of Piwil2, Piwil4, and Mael in oocytes and supporting cells of human, mouse, and platypus ovary. We found no Piwil1 expression in mouse and chicken ovary. The conservation of gene expression in somatic parts of the gonad and germ cells of species that diverged over 800 million yr ago indicates an important role in adult male and female gonad. PMID:24108303

  16. Quercetin, a Natural Flavonoid Interacts with DNA, Arrests Cell Cycle and Causes Tumor Regression by Activating Mitochondrial Pathway of Apoptosis

    PubMed Central

    Srivastava, Shikha; Somasagara, Ranganatha R.; Hegde, Mahesh; Nishana, Mayilaadumveettil; Tadi, Satish Kumar; Srivastava, Mrinal; Choudhary, Bibha; Raghavan, Sathees C.

    2016-01-01

    Naturally occurring compounds are considered as attractive candidates for cancer treatment and prevention. Quercetin and ellagic acid are naturally occurring flavonoids abundantly seen in several fruits and vegetables. In the present study, we evaluate and compare antitumor efficacies of quercetin and ellagic acid in animal models and cancer cell lines in a comprehensive manner. We found that quercetin induced cytotoxicity in leukemic cells in a dose-dependent manner, while ellagic acid showed only limited toxicity. Besides leukemic cells, quercetin also induced cytotoxicity in breast cancer cells, however, its effect on normal cells was limited or none. Further, quercetin caused S phase arrest during cell cycle progression in tested cancer cells. Quercetin induced tumor regression in mice at a concentration 3-fold lower than ellagic acid. Importantly, administration of quercetin lead to ~5 fold increase in the life span in tumor bearing mice compared to that of untreated controls. Further, we found that quercetin interacts with DNA directly, and could be one of the mechanisms for inducing apoptosis in both, cancer cell lines and tumor tissues by activating the intrinsic pathway. Thus, our data suggests that quercetin can be further explored for its potential to be used in cancer therapeutics and combination therapy. PMID:27068577

  17. Influence of gold(I) complexes involving adenine derivatives on major drug-drug interaction pathway.

    PubMed

    Dvořák, Zdeněk; Novotná, Aneta; Vančo, Ján; Trávníček, Zdeněk

    2013-12-01

    A series of considerably anti-inflammatory active gold(I) mixed-ligand complexes, involving the benzyl-substituted derivatives of N6-benzyladenine (HLn) and triphenylphosphine (PPh3) as ligands and having the general formula [Au(Ln)(PPh3)]·xH2O (1-4; n=1-4 and x=0-1), was evaluated for the ability to influence the expression of CYP1A1/2 and CYP3A4 and transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon (AhR) receptors in primary human hepatocytes and HepG2 cells. In both tests, evaluating the ability of the complexes to modulate the expression of CYP1A1, CYP1A2 and CYP3A4 in primary human hepatocytes and influence the transcriptional activity of AhR and GR in the reporter cell lines, no negative influence on the major drug-metabolizing cytochrome P450 isoenzymes and their signaling pathway (through GR and AhR receptors) was observed. These positive findings revealed another substantial evidence that could lead to utilization of the complexes as effective and relatively safe drugs for the treatment of hard-to-treat inflammation-related diseases, such as rheumatoid arthritis, comparable or even better than clinically used gold-containing drug Auranofin. PMID:24157406

  18. Interaction between NMDA glutamatergic and nitrergic enteric pathways during in vitro ischemia and reperfusion.

    PubMed

    Filpa, Viviana; Carpanese, Elisa; Marchet, Silvia; Prandoni, Valeria; Moro, Elisabetta; Lecchini, Sergio; Frigo, Gianmario; Giaroni, Cristina; Crema, Francesca

    2015-03-01

    Nitric oxide (NO) and glutamate, via N-methyl-d-aspartate (NMDA) receptors, participate to changes in neuromuscular responses after ischemic/reperfusion (I/R) injury in the gut. In the present study we investigated the existence of a possible interplay between nitrergic and NMDA receptor pathways in the guinea pig ileum after in vitro I/R injury, resorting to functional and biomolecular approaches. In normal metabolic conditions NMDA concentration-dependently enhanced both glutamate (analyzed by high performance liquid chromatography with fluorimetric detection) and NO (spectrophotometrically quantified as NO2(-) and NO3(-)) spontaneous overflow from isolated ileal segments. Both effects were reduced by the NMDA antagonists, (-)-AP5 (10µM) and 5,7-diCl-kynurenic acid (10µM, 5,7-diCl-KYN). N(ω)-propyl-l-arginine (1µM, NPLA) and 1400W (10µM), respectively, nNOS and iNOS inhibitors, reduced NMDA-stimulated glutamate overflow. After in vitro I/R, glutamate overflow increased, and returned to control values in the presence of NPLA and 1400W. NO2(-) and NO3(-) levels transiently increased during I/R and were reduced by both (-)-AP5 and 5,7-diCl-KYN. In longitudinal muscle myenteric plexus preparations, iNOS mRNA and protein levels increased after in vitro I/R; both parameters were reduced to control values by (-)-AP5 and 5,7-diCl-KYN. Both antagonists were also able to reduce ischemia-induced enhancement of nNOS mRNA levels. Protein levels of GluN1, the ubiquitary subunit of NMDA receptors, increased after I/R and were reduced by both NPLA and 1400W. On the whole, this data suggests the existence of a cross-talk between NMDA receptor and nitrergic pathways in guinea pig ileum myenteric plexus, which may participate to neuronal rearrangements occurring during I/R. PMID:25641749

  19. Differential interaction with endocytic and exocytic pathways distinguish parasitophorous vacuoles of Coxiella burnetii and Chlamydia trachomatis.

    PubMed Central

    Heinzen, R A; Scidmore, M A; Rockey, D D; Hackstadt, T

    1996-01-01

    Coxiella burnetii and Chlamydia trachomatis are bacterial obligate intracellular parasites that occupy distinct vacuolar niches within eucaryotic host cells. We have employed immunofluorescence, cytochemistry, fluorescent vital stains, and fluid-phase markers in conjunction with electron, confocal, and conventional microscopy to characterize the vacuolar environments of these pathogens. The acidic nature of the C. burnetii-containing vacuole was confirmed by its acquisition of the acidotropic base acridine orange (AO). The presence of the vacuolar-type (H+) ATPase (V-ATPase) within the Coxiella vacuolar membrane was demonstrated by indirect immunofluorescence, and growth of C. burnetii was inhibited by bafilomycin A1 (Baf A), a specific inhibitor of the V-ATPase. In contrast, AO did not accumulate in C. trachomatis inclusions nor was the V-ATPase found in the inclusion membrane. Moreover, chlamydial growth was not inhibited by Baf A or the lysosomotropic amines methylamine, ammonium chloride, and chloroquine. Vacuoles harboring C. burnetii incorporated the fluorescent fluid- phase markers, fluorescein isothiocyanate-dextran (FITC-dex) and Lucifer yellow (LY), indicating trafficking between that vacuole and the endocytic pathway. Neither FITC-dex nor LY was sequestered by chlamydial inclusions. The late endosomal-prelysosomal marker cation-independent mannose 6-phosphate receptor was not detectable in the vacuolar membranes encompassing either parasite. However, the lysosomal enzymes acid phosphatase and cathepsin D and the lysosomal glycoproteins LAMP-1 and LAMP-2 localized to the C. burnetii vacuole but not the chlamydial vacuole. Interaction of C. trachomatis inclusions with the Golgi-derived vesicles was demonstrated by the transport of sphingomyelin, endogenously synthesized from C6-NBD-ceramide, to the chlamydial inclusion and incorporation into the bacterial cell wall. Similar trafficking of C-NBD-ceramide was not evident in C. burnetii-infected cells

  20. Cascading life-history interactions: alternative density-dependent pathways drive recruitment dynamics in a freshwater fish.

    PubMed

    Vandenbos, Rena E; Tonn, William M; Boss, Shelly M

    2006-07-01

    Although density-dependent mechanisms in early life-history are important regulators of recruitment in many taxa, consequences of such mechanisms on other life-history stages are poorly understood. To examine interacting and cascading effects of mechanisms acting on different life-history stages, we stocked experimental ponds with fathead minnow (Pimephales promelas) at two different densities. We quantified growth and survival of the stocked fish, the eggs they produced, and the resulting offspring during their first season of life. Per-capita production and survival of eggs were inversely related to density of stocked fish; significant egg cannibalism by stocked minnows resulted in initial young-of-the-year (YOY) densities that were inversely related to adult densities. Subsequent growth and survival of YOY were then inversely related to these initial YOY densities, and survival of YOY was selective for larger fish. Because of these compensatory processes in the egg and YOY stages, treatments did not differ in YOY abundance and mean size at the end of the growing season. Because of differences in the intensity of size-selective mortality, however, variation in end-of season sizes of YOY was strongly (and inversely) related to densities of stocked fish. When mortality was severe in the egg stage (high densities of stocked fish), final YOY size distributions were more variable than when the dominant mortality was size-selective in the YOY stage (low stocked fish densities). These differences in size variation could have subsequent recruitment consequences, as overwinter survival is typically selective for YOY fish larger than a critical threshold size. Density-dependent effects on a given life stage are not independent, but will be influenced by earlier stages; alternative recruitment pathways can result when processes at earlier stages differ in magnitude or selectivity. Appreciation of these cascading effects should enhance our overall understanding of the

  1. Effective Interactions from No Core Shell Model

    SciTech Connect

    Dikmen, E.; Lisetskiy, A. F.; Barrett, B. R.; Navratil, P.; Vary, J. P.

    2008-11-11

    We construct the many-body effective Hamiltonian for pf-shell by carrying out 2({Dirac_h}/2{pi}){omega}. NCSM calculations at the 2-body cluster level. We demonstrate how the effective Hamiltonian derived from realistic nucleon-nucleon (NN) potentials for the 2({Dirac_h}/2{pi}){omega} NCSM space should be modified to properly account for the many-body correlations produced by truncating to the major pf-shell. We obtain two-body effective interactions for the pf-shell by using direct projection and use them to reproduce the results of large scale NCSM for other light Ca isotopes.

  2. Antitumor effect and biological pathways of a recombinant adeno-associated virus as a human renal cell carcinoma suppressor.

    PubMed

    Chen, Jie; Ruan, Xiyun; Wang, Shaomei; Zhang, Bin; Liu, Bo; Sun, Zeqiang; Liu, Qingyong

    2014-11-01

    The aims of this work are to study the antitumor effect of the adeno-associated virus on the xenografted tumors of chick embryo chorioallantoic membrane and predict potential genes and biological pathways which are associated with renal cell carcinoma. The adeno-associated virus NT4-TAT-6 × His-VHLbeta was constructed and identified. Then, chick embryos with xenografted tumor were divided into three groups and respectively inoculated with rAAV/NT4-TAT-6 × His-VHLbeta (group A), empty virus (group B), and phosphate-buffered saline (group C, the control subject). Antitumor effect in each group was investigated by means of immunofluorescence observation. Genes interacted with von Hippel-Lindau were screened by Search Tool for the Retrieval of Interacting Genes/Proteins database, while pathway analysis were performed based on Kyoto Encyclopedia of Genes and Genomes. The growth of xenografted tumors inoculated with recombinant adeno-associated virus was slower than the control subjects. The tumor volumes of group A showed significant difference compared with group B and group C (P < 0.05). Growth of xenografted tumors which administered with the recombinant adeno-associated virus was inhibited. Among the protein-protein interaction network, TCEB2, HIF1A, TCEB1, CUL2, RBX1, and PHF17 were hub genes which might be involved in the development of renal cell carcinoma. The most significant signaling pathway was renal cell carcinoma. In this paper, we constructed and identified the recombinant adeno-associated virus NT4-TAT-6 × His-VHLbeta and studied the antitumor effect of the adeno-associated virus on xenografted tumors of chicken embryo chorioallantoic membrane. In addition, genes in the protein-protein interaction network which are associated with renal cell carcinoma were revealed and the biological pathway of renal cell carcinoma was identified. Our results provide a gene-therapeutic agent for the treatment of human renal cell carcinoma. PMID:25091575

  3. Apoptosis-linked gene-2 (ALG-2)/Sec31 interactions regulate endoplasmic reticulum (ER)-to-Golgi transport: a potential effector pathway for luminal calcium.

    PubMed

    Helm, Jared R; Bentley, Marvin; Thorsen, Kevin D; Wang, Ting; Foltz, Lauren; Oorschot, Viola; Klumperman, Judith; Hay, Jesse C

    2014-08-22

    Luminal calcium released from secretory organelles has been suggested to play a regulatory role in vesicle transport at several steps in the secretory pathway; however, its functional roles and effector pathways have not been elucidated. Here we demonstrate for the first time that specific luminal calcium depletion leads to a significant decrease in endoplasmic reticulum (ER)-to-Golgi transport rates in intact cells. Ultrastructural analysis revealed that luminal calcium depletion is accompanied by increased accumulation of intermediate compartment proteins in COPII buds and clusters of unfused COPII vesicles at ER exit sites. Furthermore, we present several lines of evidence suggesting that luminal calcium affected transport at least in part through calcium-dependent interactions between apoptosis-linked gene-2 (ALG-2) and the Sec31A proline-rich region: 1) targeted disruption of ALG-2/Sec31A interactions caused severe defects in ER-to-Golgi transport in intact cells; 2) effects of luminal calcium and ALG-2/Sec31A interactions on transport mutually required each other; and 3) Sec31A function in transport required luminal calcium. Morphological phenotypes of disrupted ALG-2/Sec31A interactions were characterized. We found that ALG-2/Sec31A interactions were not required for the localization of Sec31A to ER exit sites per se but appeared to acutely regulate the stability and trafficking of the cargo receptor p24 and the distribution of the vesicle tether protein p115. These results represent the first outline of a mechanism that connects luminal calcium to specific protein interactions regulating vesicle trafficking machinery. PMID:25006245

  4. AtVPS41-mediated endocytic pathway is essential for pollen tube–stigma interaction in Arabidopsis

    PubMed Central

    Hao, Lihong; Liu, Jingjing; Zhong, Sheng; Gu, Hongya; Qu, Li-Jia

    2016-01-01

    In flowering plants, extensive male–female interactions are required for successful fertilization in which various signaling cascades are involved. Prevacuolar compartments (PVC) and vacuoles are two types of subcellular compartments that terminate signal transduction by sequestrating signaling molecules in yeast and mammalian cells; however, the manner in which they might be involved in male–female interactions in plants is unknown. In this study, we identified Arabidopsis thaliana vacuolar protein sorting 41 (AtVPS41), encoded by a single-copy gene with sequence similarity to yeast Vps41p, as a new factor controlling pollen tube–stigma interaction. Loss of AtVPS41 function disrupted penetration of pollen tubes into the transmitting tissue and thus led to failed male transmission. In the pollen tubes, AtVPS41 protein is associated with PVCs and the tonoplast. We demonstrate that AtVPS41 is required for the late stage of the endocytic pathway (i.e., endomembrane trafficking from PVCs to vacuoles) because internalization of cell-surface molecules was normal in the vps41-deficient pollen tubes, whereas PVC-to-vacuole trafficking was impaired. We further show that the CHCR domain is required for subcellular localization and biological functioning of AtVPS41. These results indicate that the AtVPS41-mediated late stage of the endocytic pathway is essential for pollen tube–stigma interaction in Arabidopsis. PMID:27185920

  5. AtVPS41-mediated endocytic pathway is essential for pollen tube-stigma interaction in Arabidopsis.

    PubMed

    Hao, Lihong; Liu, Jingjing; Zhong, Sheng; Gu, Hongya; Qu, Li-Jia

    2016-05-31

    In flowering plants, extensive male-female interactions are required for successful fertilization in which various signaling cascades are involved. Prevacuolar compartments (PVC) and vacuoles are two types of subcellular compartments that terminate signal transduction by sequestrating signaling molecules in yeast and mammalian cells; however, the manner in which they might be involved in male-female interactions in plants is unknown. In this study, we identified Arabidopsis thaliana vacuolar protein sorting 41 (AtVPS41), encoded by a single-copy gene with sequence similarity to yeast Vps41p, as a new factor controlling pollen tube-stigma interaction. Loss of AtVPS41 function disrupted penetration of pollen tubes into the transmitting tissue and thus led to failed male transmission. In the pollen tubes, AtVPS41 protein is associated with PVCs and the tonoplast. We demonstrate that AtVPS41 is required for the late stage of the endocytic pathway (i.e., endomembrane trafficking from PVCs to vacuoles) because internalization of cell-surface molecules was normal in the vps41-deficient pollen tubes, whereas PVC-to-vacuole trafficking was impaired. We further show that the CHCR domain is required for subcellular localization and biological functioning of AtVPS41. These results indicate that the AtVPS41-mediated late stage of the endocytic pathway is essential for pollen tube-stigma interaction in Arabidopsis. PMID:27185920

  6. Rab28 function in trypanosomes: interactions with retromer and ESCRT pathways

    PubMed Central

    Lumb, Jennifer H.; Leung, Ka Fai; DuBois, Kelly N.; Field, Mark C.

    2011-01-01

    Early endosomal cargo is typically targeted to either a degradative or recycling pathway. Despite established functions for the retromer and ESCRT complexes at late endosomes/multivesicular bodies, the mechanisms integrating and coordinating these functions remain largely unknown. Rab family GTPases are key membrane trafficking organizers and could contribute. Here, in the unicellular organism Trypanosoma brucei, we demonstrate that Rab28 locates to the endosomal pathway and partially colocalizes with Vps23, an ESCRT I component. Rab28 is required for turnover of endocytosed proteins and for lysosomal delivery of protein cargo. Using RNA interference we find that in Rab28-depleted cells, protein levels of ESCRT I (Vps23/28) and retromer (Vps26) are also decreased, suggesting that Rab28 is an important regulator of these factors. We suggest that Rab28 coordinates the activity of retromer-dependent trafficking and ESCRT-mediated degradative pathways. PMID:22100919

  7. Effects of modulation of pentose-phosphate pathway on biosynthesis of ansamitocins in Actinosynnema pretiosum.

    PubMed

    Fan, Yuxiang; Hu, Fengxian; Wei, Liujing; Bai, Linquan; Hua, Qiang

    2016-07-20

    Ansamitocins, produced by Actinosynnema pretiosum, are a group of maytansinoid antibiotics that block the assembly of tubulin into functional microtubules. The precursors of ansamitocin biosynthesis are generally derived from the Embden-Meyerhof-Parnas (EMP) pathway and the tricarboxylic acid cycle. In this study, central carbon flux distributions were analyzed by (13)C-based flux analysis to reveal the contribution of individual central carbon metabolism pathways. To direct more carbon flux into ansamitocin biosynthesis, pentose phosphate (PP) pathway only and the combination of PP pathway and Entner-Doudoroff (ED) pathway were weakened, respectively. Ansamitocin P-3 (AP-3) productions by both kinds of pathways weakened mutant strains were significantly enhanced in chemically defined medium. In order to draw metabolic flux to the biosynthesis of ansamitocins more efficiently, heterologous phosphoglucomutase was subsequently overexpressed based on a mutant strain with combinational regulation of PP pathway and ED pathway. More fluxes were successfully directed into the UDP-glucose synthetic pathway and the AP-3 production was further improved in this case, reaching approximately 185mg/L in fermentation medium. It was demonstrated that eliminating the bypass pathways and favoring the precursor synthetic pathway could effectively improve ansamitocin production by A. pretiosum, suggesting a promising role of metabolic strategy in improving secondary metabolite production. PMID:27173582

  8. Nature of the effective interaction between dendrimers

    SciTech Connect

    Mandal, Taraknath Dasgupta, Chandan Maiti, Prabal K.

    2014-10-14

    We have performed fully atomistic classical molecular dynamics simulations to calculate the effective interaction between two polyamidoamine dendrimers. Using the umbrella sampling technique, we have obtained the potential of mean force (PMF) between the dendrimers and investigated the effects of protonation level and dendrimer size on the PMF. Our results show that the interaction between the dendrimers can be tuned from purely repulsive to partly attractive by changing the protonation level. The PMF profiles are well-fitted by the sum of an exponential and a Gaussian function with the weight of the exponential function dominating over that of the Gaussian function. This observation is in disagreement with the results obtained in previous analytic [C. Likos, M. Schmidt, H. Löwen, M. Ballauff, D. Pötschke, and P. Lindner, Macromolecules 34, 2914 (2001)] and coarse-grained simulation [I. Götze, H. Harreis, and C. Likos, J. Chem. Phys. 120, 7761 (2004)] studies which predicted the effective interaction to be Gaussian.

  9. A role for Drosophila Cyclin J in oogenesis revealed by genetic interactions with the piRNA pathway.

    PubMed

    Atikukke, Govindaraja; Albosta, Paul; Zhang, Huamei; Finley, Russell L

    2014-08-01

    Cyclin J (CycJ) is a poorly characterized member of the Cyclin superfamily of cyclin-dependent kinase regulators, many of which regulate the cell cycle or transcription. Although CycJ is conserved in metazoans its cellular function has not been identified and no mutant defects have been described. In Drosophila, CycJ transcript is present primarily in ovaries and very early embryos, suggesting a role in one or both of these tissues. The CycJ gene (CycJ) lies immediately downstream of armitage (armi), a gene involved in the Piwi-associated RNA (piRNA) pathways that are required for silencing transposons in the germline and adjacent somatic cells. Mutations in armi result in oogenesis defects but a role for CycJ in oogenesis has not been defined. Here we assessed oogenesis in CycJ mutants in the presence or absence of mutations in armi or other piRNA pathway genes. CycJ null ovaries appeared normal, indicating that CycJ is not essential for oogenesis under normal conditions. In contrast, armi null ovaries produced only two egg chambers per ovariole and the eggs had severe axis specification defects, as observed previously for armi and other piRNA pathway mutants. Surprisingly, the CycJ armi double mutant failed to produce any mature eggs. The double null ovaries generally had only one egg chamber per ovariole and the egg chambers frequently contained an overabundance of differentiated germline cells. Production of these compound egg chambers could be suppressed with CycJ transgenes but not with mutations in the checkpoint gene mnk, which suppress oogenesis defects in armi mutants. The CycJ null showed similar genetic interactions with the germline and somatic piRNA pathway gene piwi, and to a lesser extent with aubergine (aub), a member of the germline-specific piRNA pathway. The strong genetic interactions between CycJ and piRNA pathway genes reveal a role for CycJ in early oogenesis. Our results suggest that CycJ is required to regulate egg chamber production or

  10. A role for Drosophila Cyclin J in oogenesis revealed by genetic interactions with the piRNA pathway

    PubMed Central

    Atikukke, Govindaraja; Albosta, Paul; Zhang, Huamei; Finley, Russell L.

    2014-01-01

    Cyclin J (CycJ) is a poorly characterized member of the Cyclin superfamily of cyclin-dependent kinase regulators, many of which regulate the cell cycle or transcription. Although CycJ is conserved in metazoans its cellular function has not been identified and no mutant defects have been described. In Drosophila, CycJ transcript is present primarily in ovaries and very early embryos, suggesting a role in one or both of these tissues. The CycJ gene (CycJ) lies immediately downstream of armitage (armi), a gene involved in the Piwi-associated RNA (piRNA) pathways that are required for silencing transposons in the germline and adjacent somatic cells. Mutations in armi result in oogenesis defects but a role for CycJ in oogenesis has not been defined. Here we assessed oogenesis in CycJ mutants in the presence or absence of mutations in armi or other piRNA pathway genes. CycJ null ovaries appeared normal, indicating that CycJ is not essential for oogenesis under normal conditions. In contrast, armi null ovaries produced only two egg chambers per ovariole and the eggs had severe axis specification defects, as observed previously for armi and other piRNA pathway mutants. Surprisingly, the CycJ armi double mutant failed to produce any mature eggs. The double null ovaries generally had only one egg chamber per ovariole and the egg chambers frequently contained an overabundance of differentiated germline cells. Production of these compound egg chambers could be suppressed with CycJ transgenes but not with mutations in the checkpoint gene mnk, which suppress oogenesis defects in armi mutants. The CycJ null showed similar genetic interactions with the germline and somatic piRNA pathway gene piwi, and to a lesser extent with aubergine (aub), a member of the germline-specific piRNA pathway. The strong genetic interactions between CycJ and piRNA pathway genes reveal a role for CycJ in early oogenesis. Our results suggest that CycJ is required to regulate egg chamber production or

  11. Effective connectivity of neural pathways underlying disgust by multivariate Granger causality analysis

    NASA Astrophysics Data System (ADS)

    Yan, Hao; Wang, Yonghui; Tian, Jie; Liu, Yijun

    2011-03-01

    The disgust system arises phylogenetically in response to dangers to the internal milieu from pathogens and their toxic products. Functional imaging studies have demonstrated that a much wider range of neural structures was involved in triggering disgust reactions. However, less is known regarding how and what neural pathways these neural structures interact. To address this issue, we adopted an effective connectivity based analysis, namely the multivariate Granger causality approach, to explore the causal interactions within these brain networks. Results presented that disgust can induce a wide range of brain activities, such as the insula, the anterior cingulate cortex, the parahippocampus lobe, the dorsal lateral prefrontal cortex, the superior occipital gyrus, and the supplementary motor cortex. These brain areas constitute as a whole, with much denser connectivity following disgust stimuli, in comparison with that of the neutral condition. Moreover, the anterior insula, showing multiple casual interactions with limbic and subcortical areas, was implicated as a central hub in organizing multiple information processing in the disgust system.

  12. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unu...

  13. Effects of photorespiration, the cytochrome pathway, and the alternative pathway on the triple isotopic composition of atmospheric O2

    NASA Astrophysics Data System (ADS)

    Angert, Alon; Rachmilevitch, Shimon; Barkan, Eugeni; Luz, Boaz

    2003-03-01

    The triple isotopic composition of atmospheric O2 is a new tracer used to estimate changes in global productivity. To estimate such changes, knowledge of the relationship between the discrimination against 17O and the discrimination against 18O is needed. This relationship is presented as θ = ln(17α)/ln(18α). Here, the value of theta was evaluated for the most important processes that affect the isotopic composition of oxygen. Similar values were found for dark respiration through the cytochrome pathway (0.516 ± 0.001) and the alternative pathway (0.514 ± 0.001), and slightly higher value was found for diffusion in air (0.521 ± 0.001). The combined effect of diffusion and respiration on the atmosphere was shown to be close to that of dark respiration. The value we found for photorespiration (0.506 ± 0.005) is considerably lower than that of dark respiration. Our results clearly show that the triple isotopic composition of the atmosphere is affected by the relative rates of photorespiration and dark respiration. Also, we show that closing the current global isotopic balance will enable the estimation of the current global rate of photorespiration. Using the Last Glacial Maximum as a case study, we show that variations in global rate of photorespiration affected the triple isotopic composition in the past. Strong fractionations measured in illuminated plants indicated that the alternative pathway is activated in the same conditions that favor high rate of photorespiration. This activation suggests that the global rate of the alternative pathway is higher than believed thus far, and may help to close the gap between the calculated and measured Dole Effect.

  14. Stress Effects on Multiple Memory System Interactions

    PubMed Central

    Ness, Deborah; Calabrese, Pasquale

    2016-01-01

    Extensive behavioural, pharmacological, and neurological research reports stress effects on mammalian memory processes. While stress effects on memory quantity have been known for decades, the influence of stress on multiple memory systems and their distinct contributions to the learning process have only recently been described. In this paper, after summarizing the fundamental biological aspects of stress/emotional arousal and recapitulating functionally and anatomically distinct memory systems, we review recent animal and human studies exploring the effects of stress on multiple memory systems. Apart from discussing the interaction between distinct memory systems in stressful situations, we will also outline the fundamental role of the amygdala in mediating such stress effects. Additionally, based on the methods applied in the herein discussed studies, we will discuss how memory translates into behaviour. PMID:27034845

  15. Contamination Effects Due to Space Environmental Interactions

    NASA Technical Reports Server (NTRS)

    Chen, Philip T.; Paquin, Krista C. (Technical Monitor)

    2001-01-01

    Molecular and particulate contaminants are commonly generated from the orbital spacecraft operations that are under the influence of the space environment. Once generated, these contaminants may attach to the surfaces of the spacecraft or may remain in the vicinity of the spacecraft. In the event these contaminants come to rest on the surfaces of the spacecraft or situated in the line-of-sight of the observation path, they will create various degrees of contamination effect which may cause undesirable effects for normal spacecraft operations, There will be circumstances in which the spacecraft may be subjected to special space environment due to operational conditions. Interactions between contaminants and special space environment may alter or greatly increase the contamination effect due to the synergistic effect. This paper will address the various types of contamination generation on orbit, the general effects of the contamination on spacecraft systems, and the typical impacts on the spacecraft operations due to the contamination effect. In addition, this paper will explain the contamination effect induced by the space environment and will discuss the intensified contamination effect resulting from the synergistic effect with the special space environment.

  16. The Kto-Skd complex can regulate ptc expression by interacting with Cubitus interruptus (Ci) in the Hedgehog signaling pathway.

    PubMed

    Mao, Feifei; Yang, Xiaofeng; Fu, Lin; Lv, Xiangdong; Zhang, Zhao; Wu, Wenqing; Yang, Siqi; Zhou, Zhaocai; Zhang, Lei; Zhao, Yun

    2014-08-01

    The hedgehog (Hh) signaling pathway plays a very important role in metazoan development by controlling pattern formation. Drosophila imaginal discs are subdivided into anterior and posterior compartments that derive from adjacent cell populations. The anterior/posterior (A/P) boundaries, which are critical to maintaining the position of organizers, are established by a complex mechanism involving Hh signaling. Here, we uncover the regulation of ptc in the Hh signaling pathway by two subunits of mediator complex, Kto and Skd, which can also regulate boundary location. Collectively, we provide further evidence that Kto-Skd affects the A/P-axial development of the whole wing disc. Kto can interact with Cubitus interruptus (Ci), bind to the Ci-binding region on ptc promoter, which are both regulated by Hh signals to down-regulate ptc expression. PMID:24962581

  17. The Kto-Skd Complex Can Regulate ptc Expression by Interacting with Cubitus interruptus (Ci) in the Hedgehog Signaling Pathway*

    PubMed Central

    Mao, Feifei; Yang, Xiaofeng; Fu, Lin; Lv, Xiangdong; Zhang, Zhao; Wu, Wenqing; Yang, Siqi; Zhou, Zhaocai; Zhang, Lei; Zhao, Yun

    2014-01-01

    The hedgehog (Hh) signaling pathway plays a very important role in metazoan development by controlling pattern formation. Drosophila imaginal discs are subdivided into anterior and posterior compartments that derive from adjacent cell populations. The anterior/posterior (A/P) boundaries, which are critical to maintaining the position of organizers, are established by a complex mechanism involving Hh signaling. Here, we uncover the regulation of ptc in the Hh signaling pathway by two subunits of mediator complex, Kto and Skd, which can also regulate boundary location. Collectively, we provide further evidence that Kto-Skd affects the A/P-axial development of the whole wing disc. Kto can interact with Cubitus interruptus (Ci), bind to the Ci-binding region on ptc promoter, which are both regulated by Hh signals to down-regulate ptc expression. PMID:24962581

  18. Interactions Between Estrogen- and Ah-Receptor Signalling Pathways in Primary Culture of Salmon Hepatocytes Exposed to Nonylphenol and 3,3',4,4'-Tetrachlorobiphenyl (Congener 77)

    PubMed Central

    Mortensen, Anne S; Arukwe, Augustine

    2007-01-01

    Background The estrogenic and xenobiotic biotransformation gene expressions are receptor-mediated processes that are ligand structure-dependent interactions with estrogen-receptor (ER) and aryl hydrocarbon receptor (AhR), probably involving all subtypes and other co-factors. The anti-estrogenic activities of AhR agonists have been reported. In teleost fish, exposure to AhR agonists has been associated with reduced Vtg synthesis or impaired gonadal development in both in vivo- and in vitro studies. Inhibitory AhR and ER cross-talk have also been demonstrated in breast cancer cells, rodent uterus and mammary tumors. Previous studies have shown that AhR-agonists potentiate xenoestrogen-induced responses in fish in vivo system. Recently, several studies have shown that AhR-agonists directly activate ERα and induce estrogenic responses in mammalian in vitro systems. In this study, two separate experiments were performed to study the molecular interactions between ER and AhR signalling pathways using different concentration of PCB-77 (an AhR-agonist) and time factor, respectively. Firstly, primary Atlantic salmon hepatocytes were exposed to nonylphenol (NP: 5 μM – an ER agonist) singly or in combination with 0.001, 0.01 and 1 μM PCB-77 and sampled at 48 h post-exposure. Secondly, hepatocytes were exposed to NP (5 μM) or PCB-77 (1 μM) singly or in combination for 12, 24, 48 and 72 h. Samples were analyzed using a validated real-time PCR for genes in the ER pathway or known to be NP-responsive and AhR pathway or known to be PCB-77 responsive. Results Our data showed a reciprocal inhibitory interaction between NP and PCB-77. PCB-77 produced anti-NP-mediated effect by decreasing the mRNA expression of ER-responsive genes. NP produced anti-AhR mediated effect or as inhibitor of AhRα, AhRR, ARNT, CYP1A1 and UDPGT expression. A novel aspect of the present study is that low (0.001 μM) and medium (0.01 μM) PCB-77 concentrations increased ERα mRNA expression above

  19. Ecosystem services capacity across heterogeneous forest types: understanding the interactions and suggesting pathways for sustaining multiple ecosystem services.

    PubMed

    Alamgir, Mohammed; Turton, Stephen M; Macgregor, Colin J; Pert, Petina L

    2016-10-01

    As ecosystem services supply from tropical forests is declining due to deforestation and forest degradation, much effort is essential to sustain ecosystem services supply from tropical forested landscapes, because tropical forests provide the largest flow of multiple ecosystem services among the terrestrial ecosystems. In order to sustain multiple ecosystem services, understanding ecosystem services capacity across heterogeneous forest types and identifying certain ecosystem services that could be managed to leverage positive effects across the wider bundle of ecosystem services are required. We sampled three forest types, tropical rainforests, sclerophyll forests, and rehabilitated plantation forests, over an area of 32,000m(2) from Wet Tropics bioregion, Australia, aiming to compare supply and evaluate interactions and patterns of eight ecosystem services (global climate regulation, air quality regulation, erosion regulation, nutrient regulation, cyclone protection, habitat provision, energy provision, and timber provision). On average, multiple ecosystem services were highest in the rainforests, lowest in sclerophyll forests, and intermediate in rehabilitated plantation forests. However, a wide variation was apparent among the plots across the three forest types. Global climate regulation service had a synergistic impact on the supply of multiple ecosystem services, while nutrient regulation service was found to have a trade-off impact. Considering multiple ecosystem services, most of the rehabilitated plantation forest plots shared the same ordination space with rainforest plots in the ordination analysis, indicating that rehabilitated plantation forests may supply certain ecosystem services nearly equivalent to rainforests. Two synergy groups and one trade-off group were identified. Apart from conserving rainforests and sclerophyll forests, our findings suggest two additional integrated pathways to sustain the supply of multiple ecosystem services from a

  20. The Many Faces of Fear: Comparing the Pathways and Impacts of Nonconsumptive Predator Effects on Prey Populations

    PubMed Central

    Preisser, Evan L.; Bolnick, Daniel I.

    2008-01-01

    Background Most ecological models assume that predator and prey populations interact solely through consumption: predators reduce prey densities by killing and consuming individual prey. However, predators can also reduce prey densities by forcing prey to adopt costly defensive strategies. Methodology/Principal Findings We build on a simple Lotka-Volterra predator-prey model to provide a heuristic tool for distinguishing between the demographic effects of consumption (consumptive effects) and of anti-predator defenses (nonconsumptive effects), and for distinguishing among the multiple mechanisms by which anti-predator defenses might reduce prey population growth rates. We illustrate these alternative pathways for nonconsumptive effects with selected empirical examples, and use a meta-analysis of published literature to estimate the mean effect size of each pathway. Overall, predation risk tends to have a much larger impact on prey foraging behavior than measures of growth, survivorship, or fecundity. Conclusions/Significance While our model provides a concise framework for understanding the many potential NCE pathways and their relationships to each other, our results confirm empirical research showing that prey are able to partially compensate for changes in energy income, mitigating the fitness effects of defensive changes in time budgets. Distinguishing the many facets of nonconsumptive effects raises some novel questions, and will help guide both empirical and theoretical studies of how predation risk affects prey dynamics. PMID:18560575

  1. Local and distal effects of arbuscular mycorrhizal colonization on direct pathway Pi uptake and root growth in Medicago truncatula.

    PubMed

    Watts-Williams, Stephanie J; Jakobsen, Iver; Cavagnaro, Timothy R; Grønlund, Mette

    2015-07-01

    Two pathways exist for plant Pi uptake from soil: via root epidermal cells (direct pathway) or via associations with arbuscular mycorrhizal (AM) fungi, and the two pathways interact in a complex manner. This study investigated distal and local effects of AM colonization on direct root Pi uptake and root growth, at different soil P levels. Medicago truncatula was grown at three soil P levels in split-pots with or without AM fungal inoculation and where one root half grew into soil labelled with (33)P. Plant genotypes included the A17 wild type and the mtpt4 mutant. The mtpt4 mutant, colonized by AM fungi, but with no functional mycorrhizal pathway for Pi uptake, was included to better understand effects of AM colonization per se. Colonization by AM fungi decreased expression of direct Pi transporter genes locally, but not distally in the wild type. In mtpt4 mutant plants, direct Pi transporter genes and the Pi starvation-induced gene Mt4 were more highly expressed than in wild-type roots. In wild-type plants, less Pi was taken up via the direct pathway by non-colonized roots when the other root half was colonized by AM fungi, compared with non-mycorrhizal plants. Colonization by AM fungi strongly influenced root growth locally and distally, and direct root Pi uptake activity locally, but had only a weak influence on distal direct pathway activity. The responses to AM colonization in the mtpt4 mutant suggested that in the wild type, the increased P concentration of colonized roots was a major factor driving the effects of AM colonization on direct root Pi uptake. PMID:25944927

  2. Bem1p contributes to secretory pathway polarization through a direct interaction with Exo70p

    PubMed Central

    Liu, Dongmei

    2014-01-01

    The exocyst serves to tether secretory vesicles to cortical sites specified by polarity determinants, in preparation for fusion with the plasma membrane. Although most exocyst components are brought to these sites by riding on secretory vesicles as they are actively transported along actin cables, Exo70p displays actin-independent localization to these sites, implying an interaction with a polarity determinant. Here we show that Exo70p directly and specifically binds to the polarity determinant scaffold protein Bem1p. The interaction involves multiple domains of both Exo70p and Bem1p. Mutations in Exo70p that disrupt its interaction with Bem1, without impairing its interactions with other known binding partners, lead to the loss of actin-independent localization. Synthetic genetic interactions confirm the importance of the Exo70p–Bem1p interaction, although there is some possible redundancy with Sec3p and Sec15p, other exocyst components that also interact with polarity determinants. Similar to Sec3p, the actin-independent localization of Exo70p requires a synergistic interaction with the phosphoinositide PI(4,5)P2. PMID:25313406

  3. Effects of bursty protein production on the noisy oscillatory properties of downstream pathways

    NASA Astrophysics Data System (ADS)

    Toner, D. L. K.; Grima, R.

    2013-08-01

    Experiments show that proteins are translated in sharp bursts; similar bursty phenomena have been observed for protein import into compartments. Here we investigate the effect of burstiness in protein expression and import on the stochastic properties of downstream pathways. We consider two identical pathways with equal mean input rates, except in one pathway proteins are input one at a time and in the other proteins are input in bursts. Deterministically the dynamics of these two pathways are indistinguishable. However the stochastic behavior falls in three categories: (i) both pathways display or do not display noise-induced oscillations; (ii) the non-bursty input pathway displays noise-induced oscillations whereas the bursty one does not; (iii) the reverse of (ii). We derive necessary conditions for these three cases to classify systems involving autocatalysis, trimerization and genetic feedback loops. Our results suggest that single cell rhythms can be controlled by regulation of burstiness in protein production.

  4. A cellular genetics approach identifies gene-drug interactions and pinpoints drug toxicity pathway nodes

    PubMed Central

    Suzuki, Oscar T.; Frick, Amber; Parks, Bethany B.; Trask, O. Joseph; Butz, Natasha; Steffy, Brian; Chan, Emmanuel; Scoville, David K.; Healy, Eric; Benton, Cristina; McQuaid, Patricia E.; Thomas, Russell S.; Wiltshire, Tim

    2014-01-01

    New approaches to toxicity testing have incorporated high-throughput screening across a broad-range of in vitro assays to identify potential key events in response to chemical or drug treatment. To date, these approaches have primarily utilized repurposed drug discovery assays. In this study, we describe an approach that combines in vitro screening with genetic approaches for the experimental identification of genes and pathways involved in chemical or drug toxicity. Primary embryonic fibroblasts isolated from 32 genetically-characterized inbred mouse strains were treated in concentration-response format with 65 compounds, including pharmaceutical drugs, environmental chemicals, and compounds with known modes-of-action. Integrated cellular responses were measured at 24 and 72 h using high-content imaging and included cell loss, membrane permeability, mitochondrial function, and apoptosis. Genetic association analysis of cross-strain differences in the cellular responses resulted in a collection of candidate loci potentially underlying the variable strain response to each chemical. As a demonstration of the approach, one candidate gene involved in rotenone sensitivity, Cybb, was experimentally validated in vitro and in vivo. Pathway analysis on the combined list of candidate loci across all chemicals identified a number of over-connected nodes that may serve as core regulatory points in toxicity pathways. PMID:25221565

  5. Does a Common Pathway Transduce Symbiotic Signals in Plant-Microbe Interactions?

    PubMed

    Genre, Andrea; Russo, Giulia

    2016-01-01

    Recent years have witnessed major advances in our knowledge of plant mutualistic symbioses such as the rhizobium-legume symbiosis (RLS) and arbuscular mycorrhizas (AM). Some of these findings caused the revision of longstanding hypotheses, but one of the most solid theories is that a conserved set of plant proteins rules the transduction of symbiotic signals from beneficial glomeromycetes and rhizobia in a so-called common symbiotic pathway (CSP). Nevertheless, the picture still misses several elements, and a few crucial points remain unclear. How does one common pathway discriminate between - at least - two symbionts? Can we exclude that microbes other than AM fungi and rhizobia also use this pathway to communicate with their host plants? We here discuss the possibility that our current view is biased by a long-lasting focus on legumes, whose ability to develop both AM and RLS is an exception among plants and a recent innovation in their evolution; investigations in non-legumes are starting to place legume symbiotic signaling in a broader perspective. Furthermore, recent studies suggest that CSP proteins act in a wider scenario of symbiotic and non-symbiotic signaling. Overall, evidence is accumulating in favor of distinct activities for CSP proteins in AM and RLS, depending on the molecular and cellular context where they act. PMID:26909085

  6. Does a Common Pathway Transduce Symbiotic Signals in Plant–Microbe Interactions?

    PubMed Central

    Genre, Andrea; Russo, Giulia

    2016-01-01

    Recent years have witnessed major advances in our knowledge of plant mutualistic symbioses such as the rhizobium-legume symbiosis (RLS) and arbuscular mycorrhizas (AM). Some of these findings caused the revision of longstanding hypotheses, but one of the most solid theories is that a conserved set of plant proteins rules the transduction of symbiotic signals from beneficial glomeromycetes and rhizobia in a so-called common symbiotic pathway (CSP). Nevertheless, the picture still misses several elements, and a few crucial points remain unclear. How does one common pathway discriminate between – at least – two symbionts? Can we exclude that microbes other than AM fungi and rhizobia also use this pathway to communicate with their host plants? We here discuss the possibility that our current view is biased by a long-lasting focus on legumes, whose ability to develop both AM and RLS is an exception among plants and a recent innovation in their evolution; investigations in non-legumes are starting to place legume symbiotic signaling in a broader perspective. Furthermore, recent studies suggest that CSP proteins act in a wider scenario of symbiotic and non-symbiotic signaling. Overall, evidence is accumulating in favor of distinct activities for CSP proteins in AM and RLS, depending on the molecular and cellular context where they act. PMID:26909085

  7. Psychophysiological effects of human-animal interaction: theoretical issues and long-term interaction effects.

    PubMed

    Virués-Ortega, Javier; Buela-Casal, Gualberto

    2006-01-01

    This paper reviews literature published on the psychophysiological effects of long-term human-animal interaction (i.e., pet ownership, pet adoption). A literature search was conducted using PsycInfo and Medline databases. Although the available evidence is far from being consistent, it can be concluded that, in some cases, long-term relationships with animals may moderate baseline physiological variables, particularly blood pressure. Results proved more coherent in studies where animals were adopted by owners as part of the procedure. This paper examines existing hypotheses seeking to account for these effects and the supporting evidence. Two major hypotheses have been suggested to explain the psychophysiological effects of long-term interaction, namely (1) stress-buffering effects of noncritical social support provided by pets; and (2) classical conditioning of relaxation. These mechanisms may partially account for the long-term health outcomes observed in a number of human-animal interaction studies. PMID:16462556

  8. Interactions between nutritional and opioidergic pathways in the control of LH secretion in male sheep.

    PubMed

    Celi, Pietro; Miller, David W; Blache, Dominique; Martin, Graeme B

    2010-01-01

    naloxone, suggesting that an opioidergic mechanism is not involved in the suppressive effect of restricted nutrition on the gonadotrophic axis. Rather, because testosterone secretion was increased on the high plane of nutrition, the LH responses to naloxone are better explained by the effects of testosterone on opioidergic mechanisms. Finally, we failed to observe any interaction between opioids and calcium in the control of LH secretion. PMID:19394769

  9. Convergence of multi-channel effective interactions

    NASA Astrophysics Data System (ADS)

    Wagner, M.; Schaefer, B.-J.; Wambach, J.; Kuo, T. T. S.; Brown, G. E.

    2006-11-01

    A detailed analysis of the convergence properties of the Andreozzi-Lee-Suzuki iteration method, which is used for the calculation of low-momentum effective potentials Vlowk, is presented. After summarizing different modifications of the iteration method for one-flavor channels we introduce a simple model to study the generalization of the iteration method to multi-flavor channels. The failure of a straightforward generalization is discussed. The introduction of a channel-dependent cutoff cures the conceptual and technical problems. This novel method has already been applied successfully for realistic hyperon-nucleon interactions.

  10. Simple effective interaction for dimensional crossover

    NASA Astrophysics Data System (ADS)

    Constantin, Lucian A.

    2016-03-01

    We show that the effective electron-electron interaction veff[n ] (r ,r') =erf [|r - r'|b (n ) ]/|r -r'| , with n being the electronic density and b (n ) fixed from the compressibility sum rule, is remarkably accurate in both three and two dimensions, competing with the actual state-of-the-art exchange-correlation static kernels. Using this result, we propose a simple isotropic approximation for the quasi-two-dimensional regime, which gives a realistic wave vector analysis of the correlation energy, in the context of the linear response time-dependent density functional theory.

  11. MANORAA (Mapping Analogous Nuclei Onto Residue And Affinity) for identifying protein–ligand fragment interaction, pathways and SNPs

    PubMed Central

    Tanramluk, Duangrudee; Narupiyakul, Lalita; Akavipat, Ruj; Gong, Sungsam; Charoensawan, Varodom

    2016-01-01

    Protein–ligand interaction analysis is an important step of drug design and protein engineering in order to predict the binding affinity and selectivity between ligands to the target proteins. To date, there are more than 100 000 structures available in the Protein Data Bank (PDB), of which ∼30% are protein–ligand (MW below 1000 Da) complexes. We have developed the integrative web server MANORAA (Mapping Analogous Nuclei Onto Residue And Affinity) with the aim of providing a user-friendly web interface to assist structural study and design of protein–ligand interactions. In brief, the server allows the users to input the chemical fragments and present all the unique molecular interactions to the target proteins with available three-dimensional structures in the PDB. The users can also link the ligands of interest to assess possible off-target proteins, human variants and pathway information using our all-in-one integrated tools. Taken together, we envisage that the server will facilitate and improve the study of protein–ligand interactions by allowing observation and comparison of ligand interactions with multiple proteins at the same time. (http://manoraa.org). PMID:27131358

  12. MANORAA (Mapping Analogous Nuclei Onto Residue And Affinity) for identifying protein-ligand fragment interaction, pathways and SNPs.

    PubMed

    Tanramluk, Duangrudee; Narupiyakul, Lalita; Akavipat, Ruj; Gong, Sungsam; Charoensawan, Varodom

    2016-07-01

    Protein-ligand interaction analysis is an important step of drug design and protein engineering in order to predict the binding affinity and selectivity between ligands to the target proteins. To date, there are more than 100 000 structures available in the Protein Data Bank (PDB), of which ∼30% are protein-ligand (MW below 1000 Da) complexes. We have developed the integrative web server MANORAA (Mapping Analogous Nuclei Onto Residue And Affinity) with the aim of providing a user-friendly web interface to assist structural study and design of protein-ligand interactions. In brief, the server allows the users to input the chemical fragments and present all the unique molecular interactions to the target proteins with available three-dimensional structures in the PDB. The users can also link the ligands of interest to assess possible off-target proteins, human variants and pathway information using our all-in-one integrated tools. Taken together, we envisage that the server will facilitate and improve the study of protein-ligand interactions by allowing observation and comparison of ligand interactions with multiple proteins at the same time. (http://manoraa.org). PMID:27131358

  13. Effects of nonequilibrium atmospheric pressure plasmas on the heterotrophic pathways of bacteria and on their cell morphology

    NASA Astrophysics Data System (ADS)

    Laroussi, Mounir; Richardson, J. Paul; Dobbs, Fred C.

    2002-07-01

    To date, most research on the interaction of nonequilibrium, atmospheric pressure plasma discharges with bacteria has concentrated on the germicidal effects. Therefore, published results deal mainly with killing efficacy and little attention is given to physical mechanisms and biochemical pathways and their potential alterations when cells of microorganisms are exposed to the plasma. In this letter, an attempt to investigate the effects of plasma exposure on the biochemical pathways of bacteria is presented. In addition, using electron microscopy, we investigate if any gross morphological changes take place when cells are exposed to a lethal dose of plasma. We are testing the hypothesis that disruption of the cell membrane, sometimes to the point of cell lysis, is the mechanism whereby plasma kills cells.

  14. Assessing Spurious Interaction Effects in Structural Equation Modeling

    ERIC Educational Resources Information Center

    Harring, Jeffrey R.; Weiss, Brandi A.; Li, Ming

    2015-01-01

    Several studies have stressed the importance of simultaneously estimating interaction and quadratic effects in multiple regression analyses, even if theory only suggests an interaction effect should be present. Specifically, past studies suggested that failing to simultaneously include quadratic effects when testing for interaction effects could…

  15. GAIP Interacting Protein C-Terminus Regulates Autophagy and Exosome Biogenesis of Pancreatic Cancer through Metabolic Pathways

    PubMed Central

    Bhattacharya, Santanu; Pal, Krishnendu; Sharma, Anil K.; Dutta, Shamit K.; Lau, Julie S.; Yan, Irene K.; Wang, Enfeng; Elkhanany, Ahmed; Alkharfy, Khalid M.; Sanyal, Arunik; Patel, Tushar C.; Chari, Suresh T.; Spaller, Mark R.; Mukhopadhyay, Debabrata

    2014-01-01

    GAIP interacting protein C terminus (GIPC) is known to play an important role in a variety of physiological and disease states. In the present study, we have identified a novel role for GIPC as a master regulator of autophagy and the exocytotic pathways in cancer. We show that depletion of GIPC-induced autophagy in pancreatic cancer cells, as evident from the upregulation of the autophagy marker LC3II. We further report that GIPC regulates cellular trafficking pathways by modulating the secretion, biogenesis, and molecular composition of exosomes. We also identified the involvement of GIPC on metabolic stress pathways regulating autophagy and microvesicular shedding, and observed that GIPC status determines the loading of cellular cargo in the exosome. Furthermore, we have shown the overexpression of the drug resistance gene ABCG2 in exosomes from GIPC-depleted pancreatic cancer cells. We also demonstrated that depletion of GIPC from cancer cells sensitized them to gemcitabine treatment, an avenue that can be explored as a potential therapeutic strategy to overcome drug resistance in cancer. PMID:25469510

  16. Quantifying Solvophobic Effects in Nonpolar Cohesive Interactions.

    PubMed

    Yang, Lixu; Adam, Catherine; Cockroft, Scott L

    2015-08-19

    The hydrophobic effect plays a central role in determining the structure, activity, and properties of biomolecules and materials. In contrast, the general manifestation of this phenomenon in other solvents—the solvophobic effect—although widely invoked, is currently poorly defined because of the lack of a universally accepted descriptor. Here we have used synthetic molecular balances to measure solvent effects on aromatic, aliphatic, and fluorous nonpolar interactions. Our solvent screening data combined with independent experimental measurements of supramolecular association, single-molecule folding, and bulk phase transfer energies were all found to correlate well with the cohesive energy density (ced) of the solvent. Meanwhile, other measures of solvent cohesion, such as surface tension and internal pressure, gave inferior correlations. Thus, we establish ced as a readily accessible, quantitative descriptor of solvophobic association in a range of chemical contexts. PMID:26159869

  17. Transverse effects of microbunch radiative interaction

    SciTech Connect

    Derbenev, Ya.S.; Shiltsev, V.D.

    1996-06-03

    In this article the authors study effects of microbunch cooperative electromagnetic radiation in a bend on transverse beam dynamics. An overtaking radiative interaction between different parts of the bunch results in three major forces variable along the bunch. Longitudinal force leads to energy loss and causes the bunch emittance growth in the bend due to the dispersion effect. Radial force consists of logarithmically large ``Talman`` centrifugal force and smaller centripetal force. Due to general radius-energy dependence in the bend, the ``Talman`` force does not affect beam dynamics while the centripetal force leads to projected emittance growth. Finally, radial and vertical focusing forces lead to trajectory distortions which vary along the bunch. These cooperative forces significantly affect the dynamics of short high-populated bunch in bends.

  18. Defining Adverse Outcome Pathways for Effects of the Fungicide Propiconazole of Fish Reproduction

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are used to describe the linkage of chemical interactions in terms of molecular initiating events to whole organism responses suitable for risk assessment. This study was conducted to develop AOPs for the model fungicide propiconazole relative to r...

  19. Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway.

    PubMed

    Huang, Chunling; Zhang, Yuan; Kelly, Darren J; Tan, Christina Y R; Gill, Anthony; Cheng, Delfine; Braet, Filip; Park, Jin-Sung; Sue, Carolyn M; Pollock, Carol A; Chen, Xin-Ming

    2016-01-01

    Hyperglycemia upregulates thioredoxin interacting protein (TXNIP) expression, which in turn induces ROS production, inflammatory and fibrotic responses in the diabetic kidney. Dysregulation of autophagy contributes to the development of diabetic nephropathy. However, the interaction of TXNIP with autophagy/mitophagy in diabetic nephropathy is unknown. In this study, streptozotocin-induced diabetic rats were given TXNIP DNAzyme or scrambled DNAzyme for 12 weeks respectively. Fibrotic markers, mitochondrial function and mitochondrial reactive oxygen species (mtROS) were assessed in kidneys. Tubular autophagy and mitophagy were determined in kidneys from both human and rats with diabetic nephropathy. TXNIP and autophagic signaling molecules were examined. TXNIP DNAzyme dramatically attenuated extracellular matrix deposition in the diabetic kidneys compared to the control DNAzyme. Accumulation of autophagosomes and reduced autophagic clearance were shown in tubular cells of human diabetic compared to non-diabetic kidneys, which was reversed by TXNIP DNAzyme. High glucose induced mitochondrial dysfunction and mtROS production, and inhibited mitophagy in proximal tubular cells, which was reversed by TXNIP siRNA. TXNIP inhibition suppressed diabetes-induced BNIP3 expression and activation of the mTOR signaling pathway. Collectively, hyperglycemia-induced TXNIP contributes to the dysregulation of tubular autophagy and mitophagy in diabetic nephropathy through activation of the mTOR signaling pathway. PMID:27381856

  20. The Sestrins interact with GATOR2 to negatively regulate the amino acid sensing pathway upstream of mTORC1

    PubMed Central

    Chantranupong, Lynne; Wolfson, Rachel L.; Orozco, Jose M.; Saxton, Robert A.; Scaria, Sonia M.; Bar-Peled, Liron; Spooner, Eric; Isasa, Marta; Gygi, Steven P.; Sabatini, David M.

    2014-01-01

    The mTORC1 kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA/B bound to RagC/D) to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase activating protein (GAP) for RagA/B and an inhibitor of the amino acid sensing pathway. Here, we find that the Sestrins, a family of poorly understood growth regulators (Sestrin1-3), interact with GATOR2 in an amino acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 signaling requires GATOR1 and the Rag GTPases, and the Sestrins regulate the localization of mTORC1 in response to amino acids. Thus, we identify the Sestrins as GATOR2-interacting proteins that regulate the amino acid sensing branch of the mTORC1 pathway. PMID:25263562

  1. Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway

    PubMed Central

    Huang, Chunling; Zhang, Yuan; Kelly, Darren J.; Tan, Christina Y. R.; Gill, Anthony; Cheng, Delfine; Braet, Filip; Park, Jin-Sung; Sue, Carolyn M.; Pollock, Carol A.; Chen, Xin-Ming

    2016-01-01

    Hyperglycemia upregulates thioredoxin interacting protein (TXNIP) expression, which in turn induces ROS production, inflammatory and fibrotic responses in the diabetic kidney. Dysregulation of autophagy contributes to the development of diabetic nephropathy. However, the interaction of TXNIP with autophagy/mitophagy in diabetic nephropathy is unknown. In this study, streptozotocin-induced diabetic rats were given TXNIP DNAzyme or scrambled DNAzyme for 12 weeks respectively. Fibrotic markers, mitochondrial function and mitochondrial reactive oxygen species (mtROS) were assessed in kidneys. Tubular autophagy and mitophagy were determined in kidneys from both human and rats with diabetic nephropathy. TXNIP and autophagic signaling molecules were examined. TXNIP DNAzyme dramatically attenuated extracellular matrix deposition in the diabetic kidneys compared to the control DNAzyme. Accumulation of autophagosomes and reduced autophagic clearance were shown in tubular cells of human diabetic compared to non-diabetic kidneys, which was reversed by TXNIP DNAzyme. High glucose induced mitochondrial dysfunction and mtROS production, and inhibited mitophagy in proximal tubular cells, which was reversed by TXNIP siRNA. TXNIP inhibition suppressed diabetes-induced BNIP3 expression and activation of the mTOR signaling pathway. Collectively, hyperglycemia-induced TXNIP contributes to the dysregulation of tubular autophagy and mitophagy in diabetic nephropathy through activation of the mTOR signaling pathway. PMID:27381856

  2. Functional anatomy and interaction of fast and slow visual pathways in macaque monkeys.

    PubMed

    Chen, Chi-Ming; Lakatos, Peter; Shah, Ankoor S; Mehta, Ashesh D; Givre, Syndee J; Javitt, Daniel C; Schroeder, Charles E

    2007-07-01

    We measured the timing, areal distribution, and laminar profile of fast, wavelength-insensitive and slower, wavelength-sensitive responses in V1 and extrastriate areas, using laminar current-source density analysis in awake macaque monkeys. There were 3 main findings. 1) We confirmed previously reported significant ventral-dorsal stream latency lags at the level of V4 (V4 mean = 38.7 ms vs. middle temporal mean = 26.9 ms) and inferotemporal cortex (IT mean = 43.4 ms vs. dorsal bank of the superior temporal sulcus mean = 33.9 ms). 2) We found that wavelength-sensitive inputs in areas V1, V4, and IT lagged the wavelength-insensitive responses by significant margins; this lag increased over successive levels of the system. 3) We found that laminar activation profiles in V4 and IT were inconsistent with "feedforward" input through the ascending ventral cortical pathway; the likely alternative input routes include both lateral inputs from the dorsal stream and direct inputs from nonspecific thalamic neurons. These findings support a "Framing" Model of ventral stream visual processing in which rapidly conducted inputs, mediated by one or more accessory pathways, modulate the processing of more slowly conducted feedforward inputs. PMID:16950866

  3. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer.

    PubMed

    Zhu, Haiyan; Wu, Jun; Zhang, Wenwen; Luo, Hui; Shen, Zhaojun; Cheng, Huihui; Zhu, Xueqiong

    2016-01-01

    Pyruvate kinase M2 (PKM2) is a key driver of aerobic glycolysis in cancer cells and has been shown to be up-regulated by mTOR in vitro. Our previous proteomic profiling studies showed that PKM2 was significantly upregulated in cervical cancer tissues after treatment with neoadjuvant chemotherapy (NACT). Whether PKM2 expression predicts cisplatin-based NACT sensitivity and is mTOR dependent in cervical cancer patients remains unclear. Using paired tumor samples (pre- and post-chemotherapy) from 36 cervical cancer patients, we examined mTOR, HIF-1α, c-Myc, and PKM2 expression in cervical cancer samples and investigated the response to cisplatin-based NACT. In addition, we established PKM2 suppressed cervical cancer cell lines and evaluated their sensitivity to cisplatin in vitro. We found that the mTOR/HIF-1α/c-Myc/PKM2 signaling pathway was significantly downregulated in post-chemotherapy cervical cancer tissues. High levels of mTOR, HIF-1α, c-Myc, and PKM2 were associated with a positive chemotherapy response in cervical cancer patients treated with cisplatin-based NACT. In vitro, PKM2 knockdown desensitized cervical cancer cells to cisplatin. Moreover, PKM2 had complex interactions with mTOR pathways. mTOR, HIF1α, c-Myc, and PKM2 expression in cervical cancer may serve as predictive biomarkers to cisplatin-based chemotherapy. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. PMID:27492148

  4. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer

    PubMed Central

    Zhu, Haiyan; Wu, Jun; Zhang, Wenwen; Luo, Hui; Shen, Zhaojun; Cheng, Huihui; Zhu, Xueqiong

    2016-01-01

    Pyruvate kinase M2 (PKM2) is a key driver of aerobic glycolysis in cancer cells and has been shown to be up-regulated by mTOR in vitro. Our previous proteomic profiling studies showed that PKM2 was significantly upregulated in cervical cancer tissues after treatment with neoadjuvant chemotherapy (NACT). Whether PKM2 expression predicts cisplatin-based NACT sensitivity and is mTOR dependent in cervical cancer patients remains unclear. Using paired tumor samples (pre- and post-chemotherapy) from 36 cervical cancer patients, we examined mTOR, HIF-1α, c-Myc, and PKM2 expression in cervical cancer samples and investigated the response to cisplatin-based NACT. In addition, we established PKM2 suppressed cervical cancer cell lines and evaluated their sensitivity to cisplatin in vitro. We found that the mTOR/HIF-1α/c-Myc/PKM2 signaling pathway was significantly downregulated in post-chemotherapy cervical cancer tissues. High levels of mTOR, HIF-1α, c-Myc, and PKM2 were associated with a positive chemotherapy response in cervical cancer patients treated with cisplatin-based NACT. In vitro, PKM2 knockdown desensitized cervical cancer cells to cisplatin. Moreover, PKM2 had complex interactions with mTOR pathways. mTOR, HIF1α, c-Myc, and PKM2 expression in cervical cancer may serve as predictive biomarkers to cisplatin-based chemotherapy. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. PMID:27492148

  5. Modeling Effects of RNA on Capsid Assembly Pathways via Coarse-Grained Stochastic Simulation

    PubMed Central

    Smith, Gregory R.; Xie, Lu; Schwartz, Russell

    2016-01-01

    The environment of a living cell is vastly different from that of an in vitro reaction system, an issue that presents great challenges to the use of in vitro models, or computer simulations based on them, for understanding biochemistry in vivo. Virus capsids make an excellent model system for such questions because they typically have few distinct components, making them amenable to in vitro and modeling studies, yet their assembly can involve complex networks of possible reactions that cannot be resolved in detail by any current experimental technology. We previously fit kinetic simulation parameters to bulk in vitro assembly data to yield a close match between simulated and real data, and then used the simulations to study features of assembly that cannot be monitored experimentally. The present work seeks to project how assembly in these simulations fit to in vitro data would be altered by computationally adding features of the cellular environment to the system, specifically the presence of nucleic acid about which many capsids assemble. The major challenge of such work is computational: simulating fine-scale assembly pathways on the scale and in the parameter domains of real viruses is far too computationally costly to allow for explicit models of nucleic acid interaction. We bypass that limitation by applying analytical models of nucleic acid effects to adjust kinetic rate parameters learned from in vitro data to see how these adjustments, singly or in combination, might affect fine-scale assembly progress. The resulting simulations exhibit surprising behavioral complexity, with distinct effects often acting synergistically to drive efficient assembly and alter pathways relative to the in vitro model. The work demonstrates how computer simulations can help us understand how assembly might differ between the in vitro and in vivo environments and what features of the cellular environment account for these differences. PMID:27244559

  6. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells

    SciTech Connect

    Cai, Liquan; Wang, Dan; Fisher, Alfred L.; Wang, Zhou

    2014-05-02

    Highlights: • RNAi screen identified genetic enhancers for the C. elegans homolog of EAF2. • EAF2 and RBBP4 proteins physically bind to each other and alter transcription. • Overexpression of EAF2 and RBBP4 induces the cell death in prostate cancer cells. - Abstract: The tumor suppressor EAF2 is regulated by androgen signaling and associated with prostate cancer. While EAF2 and its partner ELL have been shown to be members of protein complexes involved in RNA polymerase II transcriptional elongation, the biologic roles for EAF2 especially with regards to the development of cancer remains poorly understood. We have previously identified the eaf-1 gene in Caenorhabditiselegans as the ortholog of EAF2, and shown that eaf-1 interacts with the ELL ortholog ell-1 to control development and fertility in worms. To identify genetic pathways that interact with eaf-1, we screened RNAi libraries consisting of transcription factors, phosphatases, and chromatin-modifying factors to identify genes which enhance the effects of eaf-1(tm3976) on fertility. From this screen, we identified lin-53, hmg-1.2, pha-4, ruvb-2 and set-6 as hits. LIN-53 is the C. elegans ortholog of human retinoblastoma binding protein 4/7 (RBBP 4/7), which binds to the retinoblastoma protein and inhibits the Ras signaling pathway. We find that lin-53 showed a synthetic interaction with eaf-1(tm3976) where knockdown of lin-53 in an eaf-1(tm3976) mutant resulted in sterile worms. This phenotype may be due to cell death as the treated worms contain degenerated embryos with increased expression of the ced-1:GFP cell death marker. Further we find that the interaction between eaf-1 and lin-53/RBBP4/7 also exists in vertebrates, which is reflected by the formation of a protein complex between EAF2 and RBBP4/7. Finally, overexpression of either human EAF2 or RBBP4 in LNCaP cells induced the cell death while knockdown of EAF2 in LNCaP enhanced cell proliferation, indicating an important role of EAF2 in

  7. Temperature Induced Syllable Breaking Unveils Nonlinearly Interacting Timescales in Birdsong Motor Pathway

    PubMed Central

    Goldin, Matías A.; Alonso, Leandro M.; Alliende, Jorge A.; Goller, Franz; Mindlin, Gabriel B.

    2013-01-01

    The nature of telencephalic control over premotor and motor circuits is debated. Hypotheses range from complete usurping of downstream circuitry to highly interactive mechanisms of control. We show theoretically and experimentally, that telencephalic song motor control in canaries is consistent with a highly interactive strategy. As predicted from a theoretical model of respiratory control, mild cooling of a forebrain nucleus (HVC) led to song stretching, but further cooling caused progressive restructuring of song, consistent with the hypothesis that respiratory gestures are subharmonic responses to a timescale present in the output of HVC. This interaction between a life-sustaining motor function (respiration) and telencephalic song motor control suggests a more general mechanism of how nonlinear integration of evolutionarily new brain structures into existing circuitry gives rise to diverse, new behavior. PMID:23818988

  8. The Stability of Ribosome Biogenesis Factor WBSCR22 Is Regulated by Interaction with TRMT112 via Ubiquitin-Proteasome Pathway

    PubMed Central

    Õunap, Kadri; Leetsi, Lilian; Matsoo, Maarja; Kurg, Reet

    2015-01-01

    The human WBSCR22 protein is a 18S rRNA methyltransferase involved in pre-rRNA processing and ribosome 40S subunit biogenesis. Recent studies have shown that the protein function in ribosome synthesis is independent of its enzymatic activity. In this work, we have studied the WBSCR22 protein interaction partners by SILAC-coupled co-immunoprecipitation assay and identified TRMT112 as the interaction partner of WBSCR22. Knock-down of TRMT112 expression decreased the WBSCR22 protein level in mammalian cells, suggesting that the stability of WBSCR22 is regulated through the interaction with TRMT112. The localization of the TRMT112 protein is determined by WBSCR22, and the WBSCR22-TRMT112 complex is localized in the cell nucleus. We provide evidence that the interaction between WBSCR22/Bud23 and TRMT112/Trm112 is conserved between mammals and yeast, suggesting that the function of TRMT112 as a co-activator of methyltransferases is evolutionarily conserved. Finally, we show that the transiently expressed WBSCR22 protein is ubiquitinated and degraded through the proteasome pathway, revealing the tight control of the WBSCR22 protein level in the cells. PMID:26214185

  9. Human male sex determination and sexual differentiation: pathways, molecular interactions and genetic disorders.

    PubMed

    Kucinskas, Laimutis; Just, Walter

    2005-01-01

    The complex mechanisms are responsible for male sex determination and differentiation. The steps of formation of the testes are dependent on a series of Y-linked, X-linked and autosomal genes actions and interactions. After formation of testes the gonads secrete hormones, which are essential for the formation of the male genitalia. Hormones are transcription regulators, which function by specific receptors. Ambiguous genitalia are result of disruption of genetic interaction. This review describes the mechanisms, which lead to differentiation of male sex and ways by which the determination and differentiation may be interrupted by naturally occurring mutations, causing different syndromes and diseases. PMID:16160410

  10. Sirt1 decreased adipose inflammation by interacting with Akt2 and inhibiting mTOR/S6K1 pathway in mice.

    PubMed

    Liu, Zhenjiang; Gan, Lu; Liu, Guannv; Chen, Yizhe; Wu, Tianjiao; Feng, Fei; Sun, Chao

    2016-08-01

    Sirtuin type 1 (Sirt1) and protein kinase B (Akt2) are associated with development of obesity and inflammation, but the molecular mechanisms of Sirt1 and Akt2 interaction on adipose inflammation remain unclear. To explore these mechanisms, a mouse model was used. Mice were fed with a high-fat diet (HFD) for 8 weeks, with interventions of resveratrol (RES) or nicotinamide (NAM) during the last 15 days. The HFD reduced Sirt1 mRNA in adipose tissue and elevated interleukin-6 (IL-6) expression. RES reduced the adipose tissue weight, increased the Sirt1 mRNA level, and reduced both mRNA and protein levels of IL-6, MCP-1, inducible nitric oxide synthase, and TNF-α by inhibiting phosphorylation of Akt2 in adipose tissue. Additionally, macrophage type I marker genes were reduced while macrophage type II marker genes were elevated by RES addition. Moreover, activation of Akt2 signal by using insulin significantly blunted the inhibitory effect of RES on adipose inflammation. Immunoprecipitation assay demonstrated that RES enhances the protein-protein interaction between Sirt1 and Akt2, but NAM inhibits this interaction. Furthermore, Sirt1 significantly reduced the levels of raptor and inactivated mammalian target of rapamycin (mTOR)C1 signal by interacting with Akt2, and confirmed that RES attenuated adipose inflammation by inhibiting the mTOR/S6K1 pathway via rapamycin. PMID:27317762

  11. Regeneration of Sensory Hair Cells Requires Localized Interactions between the Notch and Wnt Pathways.

    PubMed

    Romero-Carvajal, Andrés; Navajas Acedo, Joaquín; Jiang, Linjia; Kozlovskaja-Gumbrienė, Agnė; Alexander, Richard; Li, Hua; Piotrowski, Tatjana

    2015-08-10

    In vertebrates, mechano-electrical transduction of sound is accomplished by sensory hair cells. Whereas mammalian hair cells are not replaced when lost, in fish they constantly renew and regenerate after injury. In vivo tracking and cell fate analyses of all dividing cells during lateral line hair cell regeneration revealed that support and hair cell progenitors localize to distinct tissue compartments. Importantly, we find that the balance between self-renewal and differentiation in these compartments is controlled by spatially restricted Notch signaling and its inhibition of Wnt-induced proliferation. The ability to simultaneously study and manipulate individual cell behaviors and multiple pathways in vivo transforms the lateral line into a powerful paradigm to mechanistically dissect sensory organ regeneration. The striking similarities to other vertebrate stem cell compartments uniquely place zebrafish to help elucidate why mammals possess such low capacity to regenerate hair cells. PMID:26190147

  12. Mast Cell-Nerve Cell Interaction at Acupoint: Modeling Mechanotransduction Pathway Induced by Acupuncture

    PubMed Central

    Yao, Wei; Yang, Hongwei; Yin, Na; Ding, Guanghong

    2014-01-01

    Mast cells are found abundant at sites of acupoints. Nerve cells share perivascular localization with mast cells. Acupuncture (mechanical stimuli) can activate mast cells to release adenosine triphosphate (ATP) which can activate nerve cells and modulates pain-processing pathways in response to acupuncture. In this paper, a mathematical model was constructed for describing intracellular Ca2+ signal and ATP release in a coupled mast cell and nerve cell system induced by mechanical stimuli. The results showed mechanical stimuli lead to a intracellular Ca2+ rise in the mast cell and ATP release, ATP diffuses in the extracellular space (ECS) and activates the nearby nerve cells, then induces electrical current in the nerve cell which spreads in the neural network. This study may facilitate our understanding of the mechanotransduction process induced by acupuncture and provide a methodology for quantitatively analyzing acupuncture treatment. PMID:24910530

  13. Unfavorable electrostatic and steric interactions in DNA polymerase β E295K mutant interfere with the enzyme’s pathway

    PubMed Central

    Li, Yunlang; Gridley, Chelsea L.; Jaeger, Joachim; Sweasy, Joann B.; Schlick, Tamar

    2012-01-01

    Mutations in DNA polymerase β (pol β) have been associated with approximately 30% of human tumors. The E295K mutation of pol β has been linked to gastric carcinoma via interference with base excision repair. To interpret the different behavior of E295K compared to wild-type pol β in atomic and energetic detail, we resolve a binary crystal complex of E295K at 2.5 Å and apply transition path sampling (TPS) to delineate the closing pathway of the E295K pol β mutant. Conformational changes are important components in the enzymatic pathway that lead to and ready the enzyme for the chemical reaction. Our analyses show that the closing pathway of E295K mutant differs from the wild-type pol β in terms of the individual transition states along the pathway, associated energies, and the active site conformation in the final closed form of the mutant. In particular, the closed state of E295K has a more distorted active site than the active site in the wild-type pol β. In addition, the total energy barrier in the conformational closing pathway is 65 ± 11 kJ/mol, much higher than that estimated for both correct (e.g., G:C) and incorrect (e.g., G:A) wild-type pol β systems (42 ± 8 kJ/mol and 45 ± 7 kJ/mol, respectively). In particular, the rotation of Arg258 is the rate-limiting step in the conformational pathway of E295K due to unfavorable electrostatic and steric interactions. The distorted active site in the closed relative to open state and the high energy barrier in the conformational pathway may explain in part why the E295K mutant is observed to be inactive. Interestingly, however, following the closing of the thumb but prior to the rotation of Arg258, the E295K mutant complex has a similar energy level compared to the wild-type pol β. This suggests that the E295K mutant may associate with DNA with similar affinity, but it may be hampered in continuing the process of chemistry. Supporting experimental data come from the observation that the catalytic activity

  14. The Pathway Active Learning Environment: An interactive web-based tool for physics education

    NASA Astrophysics Data System (ADS)

    Nakamura, Christopher Matthew

    The work described here represents an effort to design, construct, and test an interactive online multimedia learning environment that can provide physics instruction to students in their homes. The system was designed with one-on-one human tutoring in mind as the mode of instruction. The system uses an original combination of a video-based tutor that incorporates natural language processing video-centered lessons and additional illustrative multimedia. Our Synthetic Interview (SI) tutor provides pre-recorded video answers from expert physics instructors in response to students' typed natural language questions. Our lessons cover Newton's laws and provide a context for the tutoring interaction to occur, connect physics ideas to real-world behavior of mechanical systems, and allow for quantitative testing of physics. Additional multimedia can be used to supplement the SI tutors' explanations and illustrate the physics of interest. The system is targeted at students of algebra-based and concept-based physics at the college and high school level. The system logs queries to the SI tutor, responses to lesson questions and several other interactions with the system, tagging those interactions with a username and timestamp. We have provided several groups of students with access to our system under several different conditions ranging from the controlled conditions of our interview facility to the naturalistic conditions of use at home. In total nearly two-hundred students have accessed the system. To gain insight into the ways students might use the system and understand the utility of its various components we analyzed qualitative interview data collected with 22 algebra-based physics students who worked with our system in our interview facility. We also performed a descriptive analysis of data from the system's log of user interactions. Finally we explored the use of machine learning to explore the possibility of using automated assessment to augment the interactive

  15. Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

    SciTech Connect

    Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana; Mennecozzi, Milena; Accordi, Benedetta; Basso, Giuseppe; Gaspar, John Antonydas; Zagoura, Dimitra; Barilari, Manuela; Palosaari, Taina; Sachinidis, Agapios; Bremer-Hoffmann, Susanne

    2014-10-15

    According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2{sup +} neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. - Highlights: • HESCs derived neuronal cells serve as benchmark for iPSC based neuronal toxicity test development. • Comparisons between hESCs and hiPSCs demonstrated variability of the epigenetic state • CREB pathway modulation have been explored in relation to the neurotoxicant exposure KG-501 • hiPSC might be promising tools to translate theoretical AoPs into toxicological in vitro tests.

  16. Effective Social Interaction Strategies for Inclusive Settings

    ERIC Educational Resources Information Center

    Terpstra, Judith E.; Tamura, Ronald

    2008-01-01

    Many strategies and interventions exist in the education of young children with disabilities. One area of intervention is that of social interaction, including social skills instruction, peer interaction strategies, and play skills. Interaction and social skill strategies for use with children with and without disabilities for the purpose of…

  17. Effectiveness of Artistic Interaction through Video Conferencing

    ERIC Educational Resources Information Center

    Eristi, Suzan Duygu

    2011-01-01

    This study investigated Turkish and Canadian primary school students' ways of expressing their perception of interactive art education through video conferencing and that of cultural interaction through pictorial representations. The qualitative research data were collected in the form of pictures and interviews on interactive art education along…

  18. Interaction of MDM33 with mitochondrial inner membrane homeostasis pathways in yeast

    PubMed Central

    Klecker, Till; Wemmer, Megan; Haag, Mathias; Weig, Alfons; Böckler, Stefan; Langer, Thomas; Nunnari, Jodi; Westermann, Benedikt

    2015-01-01

    Membrane homeostasis affects mitochondrial dynamics, morphology, and function. Here we report genetic and proteomic data that reveal multiple interactions of Mdm33, a protein essential for normal mitochondrial structure, with components of phospholipid metabolism and mitochondrial inner membrane homeostasis. We screened for suppressors of MDM33 overexpression-induced growth arrest and isolated binding partners by immunoprecipitation of cross-linked cell extracts. These approaches revealed genetic and proteomic interactions of Mdm33 with prohibitins, Phb1 and Phb2, which are key components of mitochondrial inner membrane homeostasis. Lipid profiling by mass spectrometry of mitochondria isolated from Mdm33-overexpressing cells revealed that high levels of Mdm33 affect the levels of phosphatidylethanolamine and cardiolipin, the two key inner membrane phospholipids. Furthermore, we show that cells lacking Mdm33 show strongly decreased mitochondrial fission activity indicating that Mdm33 is critical for mitochondrial membrane dynamics. Our data suggest that MDM33 functionally interacts with components important for inner membrane homeostasis and thereby supports mitochondrial division. PMID:26669658

  19. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts.

    PubMed

    Zhu, Yingting; Zhu, Min; Lance, Peter

    2012-10-01

    COX-2 and iNOS are two major inflammatory mediators implicated in colorectal inflammation and cancer. Previously, the role of colorectal fibroblasts involved in regulation of COX-2 and iNOS expression was largely ignored. In addition, the combined interaction of COX-2 and iNOS signalings and their significance in the progression of colorectal inflammation and cancer within the fibroblasts have received little investigation. To address those issues, we investigated the role of colonic fibroblasts in the regulation of COX-2 and iNOS gene expression, and explored possible mechanisms of interaction between COX-2 and iNOS signalings using a colonic CCD-18Co fibroblast line and LPS, a potential stimulator of COX-2 and iNOS. Our results clearly demonstrated that LPS activated COX-2 gene expression and enhanced PGE(2) production, stimulated iNOS gene expression and promoted NO production in the fibroblasts. Interestingly, activation of COX-2 signaling by LPS was not involved in activation of iNOS signaling, while activation of iNOS signaling by LPS contributed in part to activation of COX-2 signaling. Further analysis indicated that PKC plays a major role in the activation and interaction of COX-2 and iNOS signalings induced by LPS in the fibroblasts. PMID:22683859

  20. Pathways of Understanding: the Interactions of Humanity and Global Environmental Change

    NASA Technical Reports Server (NTRS)

    Jacobson, Harold K.; Katzenberger, John; Lousma, Jack; Mooney, Harold A.; Moss, Richard H.; Kuhn, William; Luterbacher, Urs; Wiegandt, Ellen

    1992-01-01

    How humans, interacting within social systems, affect and are affected by global change is explored. Recognizing the impact human activities have on the environment and responding to the need to document the interactions among human activities, the Consortium for International Earth Science Information Network (CIESIN) commissioned a group of 12 scientists to develop a framework illustrating the key human systems that contribute to global change. This framework, called the Social Process Diagram, will help natural and social scientists, educators, resource managers and policy makers envision and analyze how human systems interact among themselves and with the natural system. The Social Process Diagram consists of the following blocks that constitute the Diagram's structural framework: (1) fund of knowledge and experience; (2) preferences and expectations; (3) factors of production and technology; (4) population and social structure; (5) economic systems; (6) political systems and institutions; and (7) global scale environmental processes. To demonstrate potential ways the Diagram can be used, this document includes 3 hypothetical scenarios of global change issues: global warming and sea level rise; the environmental impact of human population migration; and energy and the environment. These scenarios demonstrate the Diagram's usefulness for visualizing specific processes that might be studied to evaluate a particular global change issues. The scenario also shows that interesting and unanticipated questions may emerge as links are explored between categories on the Diagram.

  1. Adverse Outcome Pathways and Ecological Risk Assessment: Bridging to Population-Level Effects

    SciTech Connect

    Kramer, Vincent J.; Etterson, Matthew A.; Hecker, Markus; Murphy, Cheryl A.; Roesijadi, Guritno; Spade, Daniel J.; Spromberg, Julann A.; Wang, Magnus; Ankley, Gerald T.

    2010-11-24

    The viability of populations of plants and animals is a key focus for environmental regulation. Population-level responses integrate the cumulative effects of chemical stressors on individuals as those individuals interact with and are affected by their con-specifics, competitors, predators, prey, habitat and other biotic and abiotic factors. Models of population-level effects of contaminants can integrate information from lower levels of biological organization and feed that information into higher-level community and ecosystem models. As individual-level endpoints are utilized to predict population responses, this requires that biological responses at lower levels of organization be translated into a form that is useable by the population modeler. In this paper we describe how mechanistic data, as captured in adverse outcome pathways, can be translated into modeling focused on population-level risk assessments. First, we present a succinct overview of different approaches to population modeling, and discuss the types of data needed for these models. Then we discuss how toxicity data are used currently for population modeling, and provide recommendations as to how testing might be modified to better generate information to support modeling. From this we describe how different key processes measured at the level of the individual serve as the bridge between mechanistic toxicology data and predictions of population status, and provide case examples of how this linkage has been/can be achieved.

  2. Destruction complex function in the Wnt signaling pathway of Drosophila requires multiple interactions between Adenomatous polyposis coli 2 and Armadillo.

    PubMed

    Kunttas-Tatli, Ezgi; Zhou, Meng-Ning; Zimmerman, Sandra; Molinar, Olivia; Zhouzheng, Fangyuan; Carter, Krista; Kapur, Megha; Cheatle, Alys; Decal, Richard; McCartney, Brooke M

    2012-03-01

    The tumor suppressor Adenomatous polyposis coli (APC) negatively regulates Wnt signaling through its activity in the destruction complex. APC binds directly to the main effector of the pathway, β-catenin (βcat, Drosophila Armadillo), and helps to target it for degradation. In vitro studies demonstrated that a nonphosphorylated 20-amino-acid repeat (20R) of APC binds to βcat through the N-terminal extended region of a 20R. When phosphorylated, the phospho-region of an APC 20R also binds βcat and the affinity is significantly increased. These distinct APC-βcat interactions suggest different models for the sequential steps of destruction complex activity. However, the in vivo role of 20R phosphorylation and extended region interactions has not been rigorously tested. Here we investigated the functional role of these molecular interactions by making targeted mutations in Drosophila melanogaster APC2 that disrupt phosphorylation and extended region interactions and deletion mutants missing the Armadillo binding repeats. We tested the ability of these mutants to regulate Wnt signaling in APC2 null and in APC2 APC1 double-null embryos. Overall, our in vivo data support the role of phosphorylation and extended region interactions in APC2's destruction complex function, but suggest that the extended region plays a more significant functional role. Furthermore, we show that the Drosophila 20Rs with homology to the vertebrate APC repeats that have the highest affinity for βcat are functionally dispensable, contrary to biochemical predictions. Finally, for some mutants, destruction complex function was dependent on APC1, suggesting that APC2 and APC1 may act cooperatively in the destruction complex. PMID:22174073

  3. Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways.

    PubMed

    Dyall, S C; Mandhair, H K; Fincham, R E A; Kerr, D M; Roche, M; Molina-Holgado, F

    2016-08-01

    Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects. EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists. Furthermore, in NSCs derived from IL-1β deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1β signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1β deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair. PMID:27044662

  4. Traf2 interacts with Smad4 and regulates BMP signaling pathway in MC3T3-E1 osteoblasts

    SciTech Connect

    Shimada, Koichi; Ikeda, Kyoko; Ito, Koichi

    2009-12-18

    Bone morphogenetic proteins (BMPs) play important roles in osteoblast differentiation and maturation. In mammals, the BMP-induced receptor-regulated Smads form complexes with Smad4. These complexes translocate and accumulate in the nucleus, where they regulate the transcription of various target genes. However, the function of Smad4 remains unclear. We performed a yeast two-hybrid screen using Smad4 as bait and a cDNA library derived from bone marrow, to indentify the proteins interacting with Smad4. cDNA clones for Tumor necrosis factor (TNF) receptor-associated factor 2 (Traf2) were identified, and the interaction between the endogenous proteins was confirmed in the mouse osteoblast cell line MC3T3-E1. To investigate the function of Traf2, we silenced it with siRNA. The level of BMP-2 protein in the medium, the expression levels of the Bmp2 gene and BMP-induced transcription factor genes, including Runx2, Dlx5, Msx2, and Sp7, and the phosphorylated-Smad1 protein level were increased in cells transfected with Traf2 siRNA. The nuclear accumulation of Smad1 increased with TNF-{alpha} stimulation for 30 min at Traf2 silencing. These results suggest that the TNF-{alpha}-stimulated nuclear accumulation of Smad1 may be dependent on Traf2. Thus, the interaction between Traf2 and Smad4 may play a role in the cross-talk between TNF-{alpha} and BMP signaling pathways.

  5. Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway.

    PubMed

    Cho, Ching Chang; Chou, Ruey Hwang; Yu, Chin

    2016-08-19

    The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models-the S100A5-RAGE V domain and S100A5-Pentamidine complex-and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. PMID:27297108

  6. Conformational selection in a protein-protein interaction revealed by dynamic pathway analysis

    SciTech Connect

    Chakrabarti, Kalyan S.; Agafonov, Roman V.; Pontiggia, Francesco; Otten, Renee; Higgins, Matthew K.; Schertler, Gebhard F. X.; Oprian, Daniel D.; Kern, Dorothee

    2015-12-24

    Molecular recognition plays a central role in biology, and protein dynamics has been acknowledged to be important in this process. However, it is highly debated whether conformational changes happen before ligand binding to produce a binding-competent state (conformational selection) or are caused in response to ligand binding (induced fit). Proposals for both mechanisms in protein/protein recognition have been primarily based on structural arguments. However, the distinction between them is a question of the probabilities of going via these two opposing pathways. Here we present a direct demonstration of exclusive conformational selection in protein/protein recognition by measuring the flux for rhodopsin kinase binding to its regulator recoverin, an important molecular recognition in the vision system. Using NMR spectroscopy, stopped-flow kinetics and isothermal titration calorimetry we show that recoverin populates a minor conformation in solution that exposes a hydrophobic binding pocket responsible for binding rhodopsin kinase. Lastly, protein dynamics in free recoverin limits the overall rate of binding.

  7. Conformational selection in a protein-protein interaction revealed by dynamic pathway analysis

    DOE PAGESBeta

    Chakrabarti, Kalyan S.; Agafonov, Roman V.; Pontiggia, Francesco; Otten, Renee; Higgins, Matthew K.; Schertler, Gebhard F. X.; Oprian, Daniel D.; Kern, Dorothee

    2015-12-24

    Molecular recognition plays a central role in biology, and protein dynamics has been acknowledged to be important in this process. However, it is highly debated whether conformational changes happen before ligand binding to produce a binding-competent state (conformational selection) or are caused in response to ligand binding (induced fit). Proposals for both mechanisms in protein/protein recognition have been primarily based on structural arguments. However, the distinction between them is a question of the probabilities of going via these two opposing pathways. Here we present a direct demonstration of exclusive conformational selection in protein/protein recognition by measuring the flux for rhodopsinmore » kinase binding to its regulator recoverin, an important molecular recognition in the vision system. Using NMR spectroscopy, stopped-flow kinetics and isothermal titration calorimetry we show that recoverin populates a minor conformation in solution that exposes a hydrophobic binding pocket responsible for binding rhodopsin kinase. Lastly, protein dynamics in free recoverin limits the overall rate of binding.« less

  8. TROL-FNR interaction reveals alternative pathways of electron partitioning in photosynthesis

    PubMed Central

    Vojta, Lea; Carić, Dejana; Cesar, Vera; Antunović Dunić, Jasenka; Lepeduš, Hrvoje; Kveder, Marina; Fulgosi, Hrvoje

    2015-01-01

    In photosynthesis, final electron transfer from ferredoxin to NADP+ is accomplished by the flavo enzyme ferredoxin:NADP+ oxidoreductase (FNR). FNR is recruited to thylakoid membranes via integral membrane thylakoid rhodanase-like protein TROL. We address the fate of electrons downstream of photosystem I when TROL is absent. We have employed electron paramagnetic resonance (EPR) spectroscopy to study free radical formation and electron partitioning in TROL-depleted chloroplasts. DMPO was used to detect superoxide anion (O2.−) formation, while the generation of other free radicals was monitored by Tiron. Chloroplasts from trol plants pre-acclimated to different light conditions consistently exhibited diminished O2.− accumulation. Generation of other radical forms was elevated in trol chloroplasts in all tested conditions, except for the plants pre-acclimated to high-light. Remarkably, dark- and growth light-acclimated trol chloroplasts were resilient to O2.− generation induced by methyl-viologen. We propose that the dynamic binding and release of FNR from TROL can control the flow of photosynthetic electrons prior to activation of the pseudo-cyclic electron transfer pathway. PMID:26041075

  9. TROL-FNR interaction reveals alternative pathways of electron partitioning in photosynthesis.

    PubMed

    Vojta, Lea; Carić, Dejana; Cesar, Vera; Antunović Dunić, Jasenka; Lepeduš, Hrvoje; Kveder, Marina; Fulgosi, Hrvoje

    2015-01-01

    In photosynthesis, final electron transfer from ferredoxin to NADP(+) is accomplished by the flavo enzyme ferredoxin:NADP(+) oxidoreductase (FNR). FNR is recruited to thylakoid membranes via integral membrane thylakoid rhodanase-like protein TROL. We address the fate of electrons downstream of photosystem I when TROL is absent. We have employed electron paramagnetic resonance (EPR) spectroscopy to study free radical formation and electron partitioning in TROL-depleted chloroplasts. DMPO was used to detect superoxide anion (O2(.-)) formation, while the generation of other free radicals was monitored by Tiron. Chloroplasts from trol plants pre-acclimated to different light conditions consistently exhibited diminished O2(.-) accumulation. Generation of other radical forms was elevated in trol chloroplasts in all tested conditions, except for the plants pre-acclimated to high-light. Remarkably, dark- and growth light-acclimated trol chloroplasts were resilient to O2(.-) generation induced by methyl-viologen. We propose that the dynamic binding and release of FNR from TROL can control the flow of photosynthetic electrons prior to activation of the pseudo-cyclic electron transfer pathway. PMID:26041075

  10. Conformational Selection in a Protein-Protein Interaction revealed by Dynamic Pathway Analysis

    PubMed Central

    Chakrabarti, Kalyan S.; Agafonov, Roman V.; Pontiggia, Francesco; Otten, Renee; Higgins, Matthew K.; Schertler, Gebhard F. X.; Oprian, Daniel D.; Kern, Dorothee

    2015-01-01

    SUMMARY Molecular recognition plays a central role in biology, and protein dynamics has been acknowledged to be important in this process. However, it is highly debated whether conformational changes happen before ligand binding to produce a binding-competent state (conformational selection) or are caused in response to ligand binding (induced fit). Proposals for both mechanisms in protein/protein recognition have been primarily based on structural arguments. However, the distinction between them is a question of the probabilities of going via these two opposing pathways. Here we present a direct demonstration of exclusive conformational selection in protein/protein recognition by measuring the flux for rhodopsin kinase binding to its regulator recoverin, an important molecular recognition in the vision system. Using NMR spectroscopy, stopped-flow kinetics and isothermal titration calorimetry we show that recoverin populates a minor conformation in solution that exposes a hydrophobic binding pocket responsible for binding rhodopsin kinase. Protein dynamics in free recoverin limits the overall rate of binding. PMID:26725117

  11. Prioritizing disease-linked variants, genes, and pathways with an interactive whole-genome analysis pipeline.

    PubMed

    Lee, In-Hee; Lee, Kyungjoon; Hsing, Michael; Choe, Yongjoon; Park, Jin-Ho; Kim, Shu Hee; Bohn, Justin M; Neu, Matthew B; Hwang, Kyu-Baek; Green, Robert C; Kohane, Isaac S; Kong, Sek Won

    2014-05-01

    Whole-genome sequencing (WGS) studies are uncovering disease-associated variants in both rare and nonrare diseases. Utilizing the next-generation sequencing for WGS requires a series of computational methods for alignment, variant detection, and annotation, and the accuracy and reproducibility of annotation results are essential for clinical implementation. However, annotating WGS with up to date genomic information is still challenging for biomedical researchers. Here, we present one of the fastest and highly scalable annotation, filtering, and analysis pipeline-gNOME-to prioritize phenotype-associated variants while minimizing false-positive findings. Intuitive graphical user interface of gNOME facilitates the selection of phenotype-associated variants, and the result summaries are provided at variant, gene, and genome levels. Moreover, the enrichment results of specific variants, genes, and gene sets between two groups or compared with population scale WGS datasets that is already integrated in the pipeline can help the interpretation. We found a small number of discordant results between annotation software tools in part due to different reporting strategies for the variants with complex impacts. Using two published whole-exome datasets of uveal melanoma and bladder cancer, we demonstrated gNOME's accuracy of variant annotation and the enrichment of loss-of-function variants in known cancer pathways. gNOME Web server and source codes are freely available to the academic community (http://gnome.tchlab.org). PMID:24478219

  12. Respiratory responses to cold water immersion: neural pathways, interactions, and clinical consequences awake and asleep.

    PubMed

    Datta, Avijit; Tipton, Michael

    2006-06-01

    The ventilatory responses to immersion and changes in temperature are reviewed. A fall in skin temperature elicits a powerful cardiorespiratory response, termed "cold shock," comprising an initial gasp, hypertension, and hyperventilation despite a profound hypocapnia. The physiology and neural pathways of this are examined with data from original studies. The respiratory responses to skin cooling override both conscious and other autonomic respiratory controls and may act as a precursor to drowning. There is emerging evidence that the combination of the reestablishment of respiratory rhythm following apnea, hypoxemia, and coincident sympathetic nervous and cyclic vagal stimulation appears to be an arrhythmogenic trigger. The potential clinical implications of this during wakefulness and sleep are discussed in relation to sudden death during immersion, underwater birth, and sleep apnea. A drop in deep body temperature leads to a slowing of respiration, which is more profound than the reduced metabolic demand seen with hypothermia, leading to hypercapnia and hypoxia. The control of respiration is abnormal during hypothermia, and correction of the hypoxia by inhalation of oxygen may lead to a further depression of ventilation and even respiratory arrest. The immediate care of patients with hypothermia needs to take these factors into account to maximize the chances of a favorable outcome for the rescued casualty. PMID:16714416

  13. Prioritizing disease-linked variants, genes, and pathways with an interactive whole genome analysis pipeline

    PubMed Central

    Lee, In-Hee; Lee, Kyungjoon; Hsing, Michael; Choe, Yongjoon; Park, Jin-Ho; Kim, Shu Hee; Bohn, Justin M.; Neu, Matthew B.; Hwang, Kyu-Baek; Green, Robert C.; Kohane, Isaac S.; Kong, Sek Won

    2014-01-01

    Whole genome sequencing (WGS) studies are uncovering disease-associated variants in both rare and non-rare diseases. Utilizing the next-generation sequencing for WGS requires a series of computational methods for alignment, variant detection, and annotation, and the accuracy and reproducibility of annotation results are essential for clinical implementation. However, annotating WGS with up to date genomic information is still challenging for biomedical researchers. Here we present one of the fastest and highly scalable annotation, filtering, and analysis pipeline –gNOME – to prioritize phenotype-associated variants while minimizing false positive findings. Intuitive graphical user interface of gNOME facilitates the selection of phenotype associated variants, and the result summaries are provided at variant-, gene-, and genome-levels. Moreover, the enrichment results of specific variants, genes, and gene sets between two groups or compared to population scale WGS datasets that is already integrated in the pipeline can help the interpretation. We found a small number of discordant results between annotation software tools in part due to different reporting strategies for the variants with complex impacts. Using two published whole exome datasets of uveal melanoma and bladder cancer, we demonstrated gNOME's accuracy of variant annotation and the enrichment of loss of function variants in known cancer pathways. gNOME web-server and source codes are freely available to the academic community. PMID:24478219

  14. Interactive effects of pests increase seed yield.

    PubMed

    Gagic, Vesna; Riggi, Laura Ga; Ekbom, Barbara; Malsher, Gerard; Rusch, Adrien; Bommarco, Riccardo

    2016-04-01

    Loss in seed yield and therefore decrease in plant fitness due to simultaneous attacks by multiple herbivores is not necessarily additive, as demonstrated in evolutionary studies on wild plants. However, it is not clear how this transfers to crop plants that grow in very different conditions compared to wild plants. Nevertheless, loss in crop seed yield caused by any single pest is most often studied in isolation although crop plants are attacked by many pests that can cause substantial yield losses. This is especially important for crops able to compensate and even overcompensate for the damage. We investigated the interactive impacts on crop yield of four insect pests attacking different plant parts at different times during the cropping season. In 15 oilseed rape fields in Sweden, we estimated the damage caused by seed and stem weevils, pollen beetles, and pod midges. Pest pressure varied drastically among fields with very low correlation among pests, allowing us to explore interactive impacts on yield from attacks by multiple species. The plant damage caused by each pest species individually had, as expected, either no, or a negative impact on seed yield and the strongest negative effect was caused by pollen beetles. However, seed yield increased when plant damage caused by both seed and stem weevils was high, presumably due to the joint plant compensatory reaction to insect attack leading to overcompensation. Hence, attacks by several pests can change the impact on yield of individual pest species. Economic thresholds based on single species, on which pest management decisions currently rely, may therefore result in economically suboptimal choices being made and unnecessary excessive use of insecticides. PMID:27099712

  15. The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways.

    PubMed

    Shin, Youngah; Klucken, Jochen; Patterson, Cam; Hyman, Bradley T; McLean, Pamela J

    2005-06-24

    Alpha-synuclein is a major component of Lewy bodies, the pathological hallmark of Parkinson disease, dementia with Lewy bodies, and related disorders. Misfolding and aggregation of alpha-synuclein is thought to be a critical cofactor in the pathogenesis of certain neurodegenerative diseases. In the current study, we investigate the role of the carboxyl terminus of Hsp70-interacting protein (CHIP) in alpha-synuclein aggregation. We demonstrate that CHIP is a component of Lewy bodies in the human brain, where it colocalizes with alpha-synuclein and Hsp70. In a cell culture model, endogenous CHIP colocalizes with alpha-synuclein and Hsp70 in intracellular inclusions, and overexpression of CHIP inhibits alpha-synuclein inclusion formation and reduces alpha-synuclein protein levels. We demonstrate that CHIP can mediate alpha-synuclein degradation by two discrete mechanisms that can be dissected using deletion mutants; the tetratricopeptide repeat domain is critical for proteasomal degradation, whereas the U-box domain is sufficient to direct alpha-synuclein toward the lysosomal degradation pathway. Furthermore, alpha-synuclein, synphilin-1, and Hsp70 all coimmunoprecipitate with CHIP, raising the possibility of a direct alpha-synuclein-CHIP interaction. The fact that the tetratricopeptide repeat domain is required for the effects of CHIP on alpha-synuclein inclusion morphology, number of inclusions, and proteasomal degradation as well as the direct interaction of CHIP with Hsp70 implicates a cooperation of CHIP and Hsp70 in these processes. Taken together, these data suggest that CHIP acts a molecular switch between proteasomal and lysosomal degradation pathways. PMID:15845543

  16. Interaction between cAMP and intracellular Ca(2+)-signaling pathways during odor-perception and adaptation in Drosophila.

    PubMed

    Murmu, Meena Sriti; Martin, Jean-René

    2016-09-01

    Binding of an odorant to olfactory receptors triggers cascades of second messenger systems in olfactory receptor neurons (ORNs). Biochemical studies indicate that the transduction mechanism at ORNs is mediated by cyclic adenosine monophosphate (cAMP) and/or inositol,1,4,5-triphosphate (InsP3)-signaling pathways in an odorant-dependent manner. However, the interaction between these two second messenger systems during olfactory perception or adaptation processes is much less understood. Here, we used interfering-RNAi to disrupt the level of cAMP alone or in combination with the InsP3-signaling pathway cellular targets, InsP3 receptor (InsP3R) or ryanodine receptor (RyR) in ORNs, and quantify at ORN axon terminals in the antennal lobe, the odor-induced Ca(2+)-response. In-vivo functional bioluminescence Ca(2+)-imaging indicates that a single 5s application of an odor increased Ca(2+)-transients at ORN axon terminals. However, compared to wild-type controls, the magnitude and duration of ORN Ca(2+)-response was significantly diminished in cAMP-defective flies. In a behavioral assay, perception of odorants was defective in flies with a disrupted cAMP level suggesting that the ability of flies to correctly detect an odor depends on cAMP. Simultaneous disruption of cAMP level and InsP3R or RyR further diminished the magnitude and duration of ORN response to odorants and affected the flies' ability to detect an odor. In conclusion, this study provides functional evidence that cAMP and InsP3-signaling pathways act in synergy to mediate odor processing within the ORN axon terminals, which is encoded in the magnitude and duration of ORN response. PMID:27212269

  17. Receptor-Drug Interaction: Europium Employment for Studying the Biochemical Pathway of G-Protein-Coupled Receptor Activation

    PubMed Central

    Antonio, Colabufo Nicola; Grazia, Perrone Maria; Marialessandra, Contino; Francesco, Berardi; Roberto, Perrone

    2007-01-01

    In medicinal chemistry field, the biochemical pathways, involved in 7-transmembrane domains G-protein coupled receptors (GPCRs) activation, are commonly studied to establish the activity of ligands towards GPCRs. The most studied steps are the measurement of activated GTP-α subunit and stimulated intracellular cAMP. At the present, many researchers defined agonist or antagonist activity of potential GPCRs drugs employing [35S]GTPγS or [3H]cAMP as probes. Recently, the corresponding lanthanide labels Eu-GTP and Eu-cAMP as alternative to radiochemicals have been developed because they are highly sensitive, easy to automate, easily synthesized, they display a much longer shelf-life and they can be used in multilabel experiments. In the present review, the receptor-drug interaction by europium employment for studying the biochemical pathway of GPCR activation has been focused. Moreover, comparative studies between lanthanide label probes and the corresponding radiolabeled compounds have been carried out. PMID:18350113

  18. Targeting the interaction of Aurora kinases and SIRT1 mediated by Wnt signaling pathway in colorectal cancer: A critical review.

    PubMed

    Subramaniyan, Boopathi; Jagadeesan, Kaviya; Ramakrishnan, Sabitha; Mathan, Ganeshan

    2016-08-01

    The Aurora kinases belong to the family of serine/threonine kinase, a central regulator of mitosis and their expression increased during G2/M phase. It is classified into Aurora A, B and C, each has distinct roles in cellular processes, which includes regulation of spindle assembly, function of centrosomes, cytoskeleton and cytokinesis. During cancer growth, their rapid increase makes most attractive marker for cancer treatment at present. However Aurora A kinase is known to be a marker for cancer therapy, the most important serine/threonine kinase of Aurora B kinase involvement in cancer is still inadequate. Subsequently, the recent findings revealed that the class III histone deacetylase of SIRT1 is a key regulator to activate Aurora kinases from S phase damaged DNA through Wnt signaling pathway. Even if both Aurora A kinase and SIRT1 serve as a marker for cancer therapy, the present review reveals it is interaction in Wnt signaling pathway that solely for colorectal cancer. PMID:27470380

  19. Effects of Trophic Status on Mercury Methylation Pathways in Peatlands

    NASA Astrophysics Data System (ADS)

    Hines, M. E.; Zhang, L.; Sampath, S.; Hu, R.; Barkay, T.

    2014-12-01

    Methyl mercury (MeHg) is a bioaccumulative toxicant. It was believed to be produced by sulfate (SO4)- and iron- reducing bacteria (SRB and FeRB), but recent studies suggest that organisms that possess the gene cluster (hgcAB) can methylate Hg, which includes other microbial groups besides SRB and FeRB. Many areas known to accumulate high levels of MeHg are freshwater wetlands that lack sufficient electron acceptors to support the production of MeHg. To test the hypothesis that oligotrophic wetlands are able to methylate Hg by pathways that are not respiratory, peat was collected from three wetland sites in Alaska and three in Massachusetts that represented a trophic gradient. We determined rates of gas (CH4, CO2, H2) and LMW organic acid (formate, acetate, propionate, butyrate) formation, and rates of Hg methylation using the short-lived radioisotope 197Hg (half life 2.67 days). Two temperate sites exhibited strong terminal respiration (methanogenesis) and syntrophy, while the Alaskan sites and an oligotrophic temperate site exhibited low rates of both. Primary fermentation was an important process in the latter sites. Hg methylation was most active at the minerotrophic sites that exhibited active syntrophy and methanogenesis. Methylation decreased greatly in the presence of a methanogenic inhibitor and was stimulated by H2 indicating that methanogens and perhaps syntrophs were primary methylators. In the oligotrophic sites, the addition of SO4 stimulated methylation while a SO4 reduction inhibitor decreased methylation. There was no evidence of SO4 reduction in these samples suggesting that methylation was conducted by SRB that were metabolizing via fermentation and not SO4 reduction. While further studies are required to decipher the role of syntrophs including SRB varieties such as Syntrophobacter sp., these results indicate that fermentative bacteria may be able to significantly methylate Hg in wetlands that do not support anaerobic respiration.

  20. Optimal Scaling of Interaction Effects in Generalized Linear Models

    ERIC Educational Resources Information Center

    van Rosmalen, Joost; Koning, Alex J.; Groenen, Patrick J. F.

    2009-01-01

    Multiplicative interaction models, such as Goodman's (1981) RC(M) association models, can be a useful tool for analyzing the content of interaction effects. However, most models for interaction effects are suitable only for data sets with two or three predictor variables. Here, we discuss an optimal scaling model for analyzing the content of…

  1. SIAH-1 interacts with alpha-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis.

    PubMed

    Germani, A; Bruzzoni-Giovanelli, H; Fellous, A; Gisselbrecht, S; Varin-Blank, N; Calvo, F

    2000-12-01

    SIAH-1, a human homologue of the Drosophila seven in absentia (Sina), has been implicated in ubiquitin-mediated proteolysis of different target proteins through its N-terminal RING finger domain. SIAH-1 is also induced during p53-mediated apoptosis. Furthermore, SIAH-1-transfected breast cancer cell line MCF-7 exhibits an altered mitotic process resulting in multinucleated giant cells. Now, using the two-hybrid system, we identified two new SIAH interacting proteins: Kid (kinesin like DNA binding protein) and alpha-tubulin. We demonstrate that SIAH is involved in the degradation of Kid via the ubiquitin-proteasome pathway. Our results suggest that SIAH-1 but not its N-terminal deletion mutant, affects the mitosis by an enhanced reduction of kinesin levels. Our results imply, for the first time, SIAH-1 in regulating the degradation of proteins directly implicated in the mitotic process. PMID:11146551

  2. Interactions of Xanthomonas type-III effector proteins with the plant ubiquitin and ubiquitin-like pathways

    PubMed Central

    Üstün, Suayib; Börnke, Frederik

    2014-01-01

    In eukaryotes, regulated protein turnover is required during many cellular processes, including defense against pathogens. Ubiquitination and degradation of ubiquitinated proteins via the ubiquitin–proteasome system (UPS) is the main pathway for the turnover of intracellular proteins in eukaryotes. The extensive utilization of the UPS in host cells makes it an ideal pivot for the manipulation of cellular processes by pathogens. Like many other Gram-negative bacteria, Xanthomonas species secrete a suite of type-III effector proteins (T3Es) into their host cells to promote virulence. Some of these T3Es exploit the plant UPS to interfere with immunity. This review summarizes T3E examples from the genus Xanthomonas with a proven or suggested interaction with the host UPS or UPS-like systems and also discusses the apparent paradox that arises from the presence of T3Es that inhibit the UPS in general while others rely on its activity for their function. PMID:25566304

  3. SubtiWiki-a database for the model organism Bacillus subtilis that links pathway, interaction and expression information.

    PubMed

    Michna, Raphael H; Commichau, Fabian M; Tödter, Dominik; Zschiedrich, Christopher P; Stülke, Jörg

    2014-01-01

    Genome annotation and access to information from large-scale experimental approaches at the genome level are essential to improve our understanding of living cells and organisms. This is even more the case for model organisms that are the basis to study pathogens and technologically important species. We have generated SubtiWiki, a database for the Gram-positive model bacterium Bacillus subtilis (http://subtiwiki.uni-goettingen.de/). In addition to the established companion modules of SubtiWiki, SubtiPathways and SubtInteract, we have now created SubtiExpress, a third module, to visualize genome scale transcription data that are of unprecedented quality and density. Today, SubtiWiki is one of the most complete collections of knowledge on a living organism in one single resource. PMID:24178028

  4. SubtiWiki–a database for the model organism Bacillus subtilis that links pathway, interaction and expression information

    PubMed Central

    Michna, Raphael H.; Commichau, Fabian M.; Tödter, Dominik; Zschiedrich, Christopher P.; Stülke, Jörg

    2014-01-01

    Genome annotation and access to information from large-scale experimental approaches at the genome level are essential to improve our understanding of living cells and organisms. This is even more the case for model organisms that are the basis to study pathogens and technologically important species. We have generated SubtiWiki, a database for the Gram-positive model bacterium Bacillus subtilis (http://subtiwiki.uni-goettingen.de/). In addition to the established companion modules of SubtiWiki, SubtiPathways and SubtInteract, we have now created SubtiExpress, a third module, to visualize genome scale transcription data that are of unprecedented quality and density. Today, SubtiWiki is one of the most complete collections of knowledge on a living organism in one single resource. PMID:24178028

  5. Anillin interacts with microtubules and is part of the astral pathway that defines cortical domains.

    PubMed

    van Oostende Triplet, Chloe; Jaramillo Garcia, Melina; Haji Bik, Husni; Beaudet, Daniel; Piekny, Alisa

    2014-09-01

    Cytokinesis occurs by the ingression of an actomyosin ring that separates the cell into two daughter cells. The mitotic spindle, comprising astral and central spindle microtubules, couples contractile ring ingression with DNA segregation. Cues from the central spindle activate RhoA, the upstream regulator of the contractile ring. However, additional cues from the astral microtubules also reinforce the localization of active RhoA. Using human cells, we show that astral and central spindle microtubules independently control the localization of contractile proteins during cytokinesis. Astral microtubules restrict the accumulation and localization of contractile proteins during mitosis, whereas the central spindle forms a discrete ring by directing RhoA activation in the equatorial plane. Anillin stabilizes the contractile ring during cytokinesis. We show that human anillin interacts with astral microtubules and that this interaction is competed by the cortical recruitment of anillin by active RhoA. Anillin restricts the localization of myosin to the equatorial cortex and that of NuMA (part of the microtubule-tethering complex that regulates spindle position) to the polar cortex. The sequestration of anillin by astral microtubules might alter the organization of cortical proteins to polarize cells for cytokinesis. PMID:24994938

  6. A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

    PubMed

    Taipale, Mikko; Tucker, George; Peng, Jian; Krykbaeva, Irina; Lin, Zhen-Yuan; Larsen, Brett; Choi, Hyungwon; Berger, Bonnie; Gingras, Anne-Claude; Lindquist, Susan

    2014-07-17

    Chaperones are abundant cellular proteins that promote the folding and function of their substrate proteins (clients). In vivo, chaperones also associate with a large and diverse set of cofactors (cochaperones) that regulate their specificity and function. However, how these cochaperones regulate protein folding and whether they have chaperone-independent biological functions is largely unknown. We combined mass spectrometry and quantitative high-throughput LUMIER assays to systematically characterize the chaperone-cochaperone-client interaction network in human cells. We uncover hundreds of chaperone clients, delineate their participation in specific cochaperone complexes, and establish a surprisingly distinct network of protein-protein interactions for cochaperones. As a salient example of the power of such analysis, we establish that NUDC family cochaperones specifically associate with structurally related but evolutionarily distinct β-propeller folds. We provide a framework for deciphering the proteostasis network and its regulation in development and disease and expand the use of chaperones as sensors for drug-target engagement. PMID:25036637

  7. Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways.

    PubMed

    Macdonald, James B; Macdonald, Brooke; Golitz, Loren E; LoRusso, Patricia; Sekulic, Aleksandar

    2015-02-01

    The last decade has spawned an exciting new era of oncotherapy in dermatology, including the development of targeted therapies for metastatic melanoma and basal cell carcinoma. Along with skin cancer, deregulation of the PI3K-AKT-mTOR and RAS-RAF-MEK-ERK intracellular signaling pathways contributes to tumorigenesis of a multitude of other cancers, and inhibitors of these pathways are being actively studied. Similar to other classes of targeted therapies, cutaneous adverse effects are among the most frequent toxicities observed with mitogen-activated protein kinase pathway inhibitors, PI3K-AKT-mTOR inhibitors, hedgehog signaling pathway inhibitors, and immunotherapies. Given the rapid expansion of these families of targeted treatments, dermatologists will be essential in offering dermatologic supportive care measures to cancer patients being treated with these agents. Part II of this continuing medical education article reviews skin-related adverse sequelae, including the frequency of occurrence and the implications associated with on- and off-target cutaneous toxicities of inhibitors of the RAS-RAF-MEK-ERK pathway, PI3K-AKT-mTOR pathway, hedgehog signaling pathway, and immunotherapies. PMID:25592339

  8. Molecular interaction of the first 3 enzymes of the de novo pyrimidine biosynthetic pathway of Trypanosoma cruzi

    SciTech Connect

    Nara, Takeshi; Hashimoto, Muneaki; Hirawake, Hiroko; Liao, Chien-Wei; Fukai, Yoshihisa; Suzuki, Shigeo; Tsubouchi, Akiko; Morales, Jorge; Takamiya, Shinzaburo; Fujimura, Tsutomu; Taka, Hikari; Mineki, Reiko; Fan, Chia-Kwung; Inaoka, Daniel Ken; Inoue, Masayuki; Tanaka, Akiko; Harada, Shigeharu; Kita, Kiyoshi; and others

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer An Escherichia coli strain co-expressing CPSII, ATC, and DHO of Trypanosoma cruzi was constructed. Black-Right-Pointing-Pointer Molecular interactions between CPSII, ATC, and DHO of T. cruzi were demonstrated. Black-Right-Pointing-Pointer CPSII bound with both ATC and DHO. Black-Right-Pointing-Pointer ATC bound with both CPSII and DHO. Black-Right-Pointing-Pointer A functional tri-enzyme complex might precede the establishment of the fused enzyme. -- Abstract: The first 3 reaction steps of the de novo pyrimidine biosynthetic pathway are catalyzed by carbamoyl-phosphate synthetase II (CPSII), aspartate transcarbamoylase (ATC), and dihydroorotase (DHO), respectively. In eukaryotes, these enzymes are structurally classified into 2 types: (1) a CPSII-DHO-ATC fusion enzyme (CAD) found in animals, fungi, and amoebozoa, and (2) stand-alone enzymes found in plants and the protist groups. In the present study, we demonstrate direct intermolecular interactions between CPSII, ATC, and DHO of the parasitic protist Trypanosoma cruzi, which is the causative agent of Chagas disease. The 3 enzymes were expressed in a bacterial expression system and their interactions were examined. Immunoprecipitation using an antibody specific for each enzyme coupled with Western blotting-based detection using antibodies for the counterpart enzymes showed co-precipitation of all 3 enzymes. From an evolutionary viewpoint, the formation of a functional tri-enzyme complex may have preceded-and led to-gene fusion to produce the CAD protein. This is the first report to demonstrate the structural basis of these 3 enzymes as a model of CAD. Moreover, in conjunction with the essentiality of de novo pyrimidine biosynthesis in the parasite, our findings provide a rationale for new strategies for developing drugs for Chagas disease, which target the intermolecular interactions of these 3 enzymes.

  9. Interactive effects of fire and large herbivores on web-building spiders.

    PubMed

    Foster, C N; Barton, P S; Wood, J T; Lindenmayer, D B

    2015-09-01

    Altered disturbance regimes are a major driver of biodiversity loss worldwide. Maintaining or re-creating natural disturbance regimes is therefore the focus of many conservation programmes. A key challenge, however, is to understand how co-occurring disturbances interact to affect biodiversity. We experimentally tested for the interactive effects of prescribed fire and large macropod herbivores on the web-building spider assemblage of a eucalypt forest understorey and investigated the role of vegetation in mediating these effects using path analysis. Fire had strong negative effects on the density of web-building spiders, which were partly mediated by effects on vegetation structure, while negative effects of large herbivores on web density were not related to changes in vegetation. Fire amplified the effects of large herbivores on spiders, both via vegetation-mediated pathways and by increasing herbivore activity. The importance of vegetation-mediated pathways and fire-herbivore interactions differed for web density and richness and also differed between web types. Our results demonstrate that for some groups of web-building spiders, the effects of co-occurring disturbance drivers may be mostly additive, whereas for other groups, interactions between drivers can amplify disturbance effects. In our study system, the use of prescribed fire in the presence of high densities of herbivores could lead to reduced densities and altered composition of web-building spiders, with potential cascading effects through the arthropod food web. Our study highlights the importance of considering both the independent and interactive effects of disturbances, as well as the mechanisms driving their effects, in the management of disturbance regimes. PMID:25935217

  10. Electron-phonon interaction effects in tantalum

    SciTech Connect

    Al-Lehaibi, A.; Swihart, J.C.; Butler, W.H.; Pinski, F.J.

    1987-09-15

    The results of calculations for a number of electron-phonon interaction effects for tantalum are presented. The calculations are based on Korringa-Kohn-Rostoker energy bands, Born--von Karman phonons, and the rigid-muffin-tin approximation for the electron-phonon matrix element. The calculated Eliashberg spectral function ..cap alpha../sup 2/F is compared with the earlier tunneling data of Shen and the proximity tunneling data of Wolf et al. The calculated and tunneling transverse-phonon peaks agree well, but the height of the tunneling longitudinal-phonon peak is smaller than the calculated results. The calculated electron-phonon coupling parameter lambda is 0.88, which is larger than the lambda determined from superconducting tunneling and superconducting T/sub c/ measurements, but is slightly smaller than the lambda determined from electronic specific-heat measurements. Calculated phonon linewidths along various symmetry directions are presented. The temperature dependence of the electrical resistivity due to phonon scattering is calculated in the lowest-order variational approximation and it agrees with experiment. The point-contact spectral function of Kulik, G(..omega..), is determined and compared with ..cap alpha../sup 2/F(..omega..). The agreement between calculated and measured electronic specific heat and high-temperature electrical resistivity gives strong support to the validity of the rigid-muffin-tin approximation for electron-phonon matrix elements.

  11. Pairing interaction effects in exciton level densities

    SciTech Connect

    Fu, C.Y.

    1989-01-01

    Recent progress in pairing corrections for exciton state-density formulas used in pre-compound nuclear reaction theories is reviewed. These correction factors are, strictly speaking, dependent on the nuclear excitation energy U and the exciton number n. A simple formula for (U,n)-dependent pairing corrections has been derived, based on the BCS pairing equations for constant single-particle spacing, for the exciton state-density formula for one kind of Fermion. It has been shown that the constant-pairing-energy correction used in standard state-density formulas, such U{sub 0} in Gilbert and Cameron, is a limiting case of the general (U,n)-dependent results. Spin cutoff factors with pairing effects were also obtained using the same theory and parameterized into an explicit (U,n)-dependent function, thereby defining a simple exciton level-density formula for applications in quantum mechanical precompound theories. Preliminary results from extending such simple pairing-interaction representations to level-density formulas for two kinds of Fermions are summarized. The results show that the ratios in the exciton level densities in the one-Fermion and two-Fermion approaches vary with both U and n, thus likely leading to differences in calculated compound to precompound ratios. However, the differences in the spin cutoff factors in the two cases are found to be rather small. 12 refs., 3 figs.

  12. MORN5 Expression during Craniofacial Development and Its Interaction with the BMP and TGFβ Pathways

    PubMed Central

    Cela, Petra; Hampl, Marek; Fu, Katherine K.; Kunova Bosakova, Michaela; Krejci, Pavel; Richman, Joy M.; Buchtova, Marcela

    2016-01-01

    MORN5 (MORN repeat containing 5) is encoded by a locus positioned on chromosome 17 in the chicken genome. The MORN motif is found in multiple copies in several proteins including junctophilins or phosphatidylinositol phosphate kinase family and the MORN proteins themselves are found across the animal and plant kingdoms. MORN5 protein has a characteristic punctate pattern in the cytoplasm in immunofluorescence imaging. Previously, MORN5 was found among differentially expressed genes in a microarray profiling experiment of the chicken embryo head. Here, we provided in situ hybridization to analyse, in detail, the MORN5 expression in chick craniofacial structures. The expression of MORN5 was first observed at stage HH17-18 (E2.5). MORN5 expression gradually appeared on either side of the primitive oral cavity, within the maxillary region. At stage HH20 (E3), prominent expression was localized in the mandibular prominences lateral to the midline. From stage HH20 up to HH29 (E6), there was strong expression in restricted regions of the maxillary and mandibular prominences. The frontonasal mass (in the midline of the face) expressed MORN5, starting at HH27 (E5). The expression was concentrated in the corners or globular processes, which will ultimately fuse with the cranial edges of the maxillary prominences. MORN5 expression was maintained in the fusion zone up to stage HH29. In sections MORN5 expression was localized preferentially in the mesenchyme. Previously, we examined signals that regulate MORN5 expression in the face based on a previous microarray study. Here, we validated the array results with in situ hybridization and QPCR. MORN5 was downregulated 24 h after Noggin and/or RA treatment. We also determined that BMP pathway genes are downstream of MORN5 following siRNA knockdown. Based on these results, we conclude that MORN5 is both regulated by and required for BMP signaling. The restricted expression of MORN5 in the lip fusion zone shown here supports the

  13. The Effect of Water on Crack Interaction

    NASA Astrophysics Data System (ADS)

    Gaede, O.; Regenauer-Lieb, K.

    2009-04-01

    While the mechanical coupling between pore fluid and solid phase is relatively well understood, quantitative studies dealing with chemical-mechanical weakening in geological materials are rare. Many classical poroelastic problems can be addressed with the simple law of effective stress. Experimental studies show that the presence of a chemically active fluid can have effects that exceed the predictions of the law of effective stress. These chemical fluid-rock interactions alter the mechanical properties of the solid phase. Especially chemical-mechanical weakening has important ramifications for many areas of applied geosciences ranging from nuclear waste disposal over reservoir enhancement to fault stability. In this study, we model chemically induced changes of the size of the process zone around a crack tip. The knowledge of the process zone size is used to extend existing effective medium approximations of cracked solids. The stress distribution around a crack leads to a chemical potential gradient. This gradient will be a driver for mass diffusion through the solid phase. As an example, mass diffusion is towards the crack tip for a mode I crack. In this case a chemical reaction, that weakens the solid phase, will increase the size of the process zone around the crack tip. We apply our model to the prominent hydrolytic weakening effect observed in the quartz-water system (Griggs and Blacic, 1965). Hydrolytic weakening is generally attributed to water hydrolyzing the strong Si-O bonds of the quartz crystal. The hydrolysis replaces a Si-O-Si bridge with a relatively weak hydrogen bridge between two silanol groups. This enhances dislocation mobility and hence the yield stress is reduced. The plastic process zone around a crack tip is therefore larger in a wet crystal than in a dry crystal. We calculate the size of the process zone by solving this coupled mechanical-chemical problem with the Finite Element code ABAQUS. We consider single crack, collinear crack and

  14. Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues.

    PubMed

    Madak-Erdogan, Zeynep; Kim, Sung Hoon; Gong, Ping; Zhao, Yiru C; Zhang, Hui; Chambliss, Ken L; Carlson, Kathryn E; Mayne, Christopher G; Shaul, Philip W; Korach, Kenneth S; Katzenellenbogen, John A; Katzenellenbogen, Benita S

    2016-01-01

    There is great medical need for estrogens with favorable pharmacological profiles that support desirable activities for menopausal women, such as metabolic and vascular protection, but that lack stimulatory activities on the breast and uterus. We report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue-selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained "pathway preferential estrogens" (PaPEs), which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear PaPEs, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily. PMID:27221711

  15. Molecular pathways: tumor-derived microvesicles and their interactions with immune cells in vivo.

    PubMed

    Pucci, Ferdinando; Pittet, Mikael J

    2013-05-15

    Cancer is not merely a cell-intrinsic genetic disease but also the result of complex cell-extrinsic interactions with host components, including immune cells. For example, effector T lymphocytes and natural killer cells are thought to participate in an immunosurveillance process, which eliminates neoplastic cells, whereas regulatory T lymphocytes and some myeloid cells, including macrophages, can create a milieu that prevents antitumor activity, supports tumor growth, and reduces survival of the host. Increasing evidence supports the notion that carcinoma cells communicate with immune cells directly, both within and away from the tumor stroma, and that this process fosters suppression of immunosurveillance and promotes tumor outgrowth. An important mode of communication between carcinoma cells and immune cells may involve tumor-derived microvesicles (tMV), also known as exosomes, ectosomes, or microparticles. These microvesicles carry lipids, proteins, mRNAs and microRNAs and travel short or long distances to deliver undegraded and undiluted material to other cells. Here, we consider the capacity of tMVs to control tumor-associated immune responses and highlight the known and unknown actions of tMVs in vivo. We also discuss why microvesicles may play a role in cancer diagnostics and prognostics and how they could be harnessed for anticancer therapy. PMID:23426276

  16. Neighborhood Disadvantage: Pathways of Effects for Young Children

    ERIC Educational Resources Information Center

    Kohen, Dafna E.; Leventhal, Tama; Dahinten, V. Susan; McIntosh, Cameron N.

    2008-01-01

    The present study used Canadian National Longitudinal data to examine a model of the mechanisms through which the effects of neighborhood socioeconomic conditions impact young children's verbal and behavioral outcomes (N = 3,528; M age = 5.05 years, SD= 0.86). Integrating elements of social disorganization theory and family stress models, and…

  17. Cardiovascular effects of Juniperus excelsa are mediated through multiple pathways.

    PubMed

    Khan, Munasib; Khan, Arif-Ullah; Najeeb-ur-Rehman; Zafar, Muhammad Abdullah; Hazrat, Ali; Gilani, Anwarul-Hassan

    2012-01-01

    Juniperus excelsa Bieb. is used in folk medicine for lowering blood pressure (BP). Its BP-lowering effect, endothelium-dependent and endothelium-independent vasodilator effects, and cardio-modulatory effect are reported here. The crude extract of J. excelsa (Je.Cr) which tested positive for the presence of anthraquinone, flavonoids, saponins, sterols, terpenes, and tannins induced a dose-dependent (10-300 mg/kg) fall in the arterial BP of anesthetized rats. In isolated rabbit aorta, Je.Cr (0.01-5.0 mg/mL) inhibited high K(+) (80 mM)- and phenylephrine (1 μM)-induced contractions, like that caused by verapamil and papaverine. In endothelium-intact rat aortic preparations, N(ω)-nitro-l-arginine methyl ester hydrochloride-sensitive vasodilator activity was noted from Je.Cr, which also relaxed the endothelium-denuded aorta tissues. In guinea pig atria, Je.Cr initially caused mild cardiac stimulation, followed by inhibition, like that exhibited by papaverine. Je.Cr prolonged the R-R interval in electrocardiogram of rats under anesthesia. These results reveal that cardiovascular effects of J. excelsa are mediated possibly through a combination of Ca(++) antagonism, nitric oxide-modulating mechanism, and phosphodiesterase inhibitory mechanism, which explain its medicinal use in hypertension. PMID:22468685

  18. Mapping a Pathway to Schoolwide Highly Effective Teaching

    ERIC Educational Resources Information Center

    Routman, Regie

    2012-01-01

    The best way to raise achievement levels is to improve teaching; and that goal is most easily reached through a school-wide system that starts with strong, effective leadership and raises expectations for teachers and their students. Collaboration, shared goals, and the adoption of Professional Learning Communities is crucial, the author says; so…

  19. The PTK7 and ROR2 Protein Receptors Interact in the Vertebrate WNT/Planar Cell Polarity (PCP) Pathway*

    PubMed Central

    Martinez, Sébastien; Scerbo, Pierluigi; Giordano, Marilyn; Daulat, Avais M.; Lhoumeau, Anne-Catherine; Thomé, Virginie; Kodjabachian, Laurent; Borg, Jean-Paul

    2015-01-01

    The non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine kinase receptor with poorly defined functions lacking catalytic activity. Here we show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells. We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, Ptk7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that Ptk7 is required for papc activation induced by Wnt5a. Interestingly, we find that Wnt5a stimulates the release of the tagged Ptk7 intracellular domain, which can translocate into the nucleus and activate papc expression. This study reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements. PMID:26499793

  20. Optimization of photosynthesis by multiple metabolic pathways involving interorganelle interactions: resource sharing and ROS maintenance as the bases.

    PubMed

    Sunil, Bobba; Talla, Sai K; Aswani, Vetcha; Raghavendra, Agepati S

    2013-11-01

    The bioenergetic processes of photosynthesis and respiration are mutually beneficial. Their interaction extends to photorespiration, which is linked to optimize photosynthesis. The interplay of these three pathways is facilitated by two major phenomena: sharing of energy/metabolite resources and maintenance of optimal levels of reactive oxygen species (ROS). The resource sharing among different compartments of plant cells is based on the production/utilization of reducing equivalents (NADPH, NADH) and ATP as well as on the metabolite exchange. The responsibility of generating the cellular requirements of ATP and NAD(P)H is mostly by the chloroplasts and mitochondria. In turn, besides the chloroplasts, the mitochondria, cytosol and peroxisomes are common sinks for reduced equivalents. Transporters located in membranes ensure the coordinated movement of metabolites across the cellular compartments. The present review emphasizes the beneficial interactions among photosynthesis, dark respiration and photorespiration, in relation to metabolism of C, N and S. Since the bioenergetic reactions tend to generate ROS, the cells modulate chloroplast and mitochondrial reactions, so as to ensure that the ROS levels do not rise to toxic levels. The patterns of minimization of ROS production and scavenging of excess ROS in intracellular compartments are highlighted. Some of the emerging developments are pointed out, such as model plants, orientation/movement of organelles and metabolomics. PMID:23881384

  1. Proapoptotic RYBP interacts with FANK1 and induces tumor cell apoptosis through the AP-1 signaling pathway.

    PubMed

    Ma, Wen; Zhang, Xuan; Li, Meng; Ma, Xiaoli; Huang, Bingren; Chen, Hong; Chen, Deng

    2016-08-01

    Ring1 and YY1 Binding Protein (RYBP) induces tumor-specific cell apoptosis, but the underlying molecular mechanism has not been fully understood. Here we conducted a yeast two hybrid screen and identified FANK1 (Fibronectin type III and ankyrin repeat domains 1) as a novel RYBP-interacting protein. This interaction was confirmed by coimmunoprecipitation, GST pulldown and immunofluorescence assays. We mapped that the FNIII domain at the N-terminal of FANK1 binds to the Serine/Threonine-rich region at the C-terminal of RYBP. Further studies showed that overexpression of RYBP stabilized, whereas knockdown of RYBP by its specific shRNAs reduced, the expression of FANK1. Mechanistic studies revealed that RYBP inhibited the proteasome degradation of polyubiquitinated FANK1, thus prolonging the half-life of FANK1 protein. Functional studies indicated that RYBP activates FANK1-mediated activator protein 1 (AP-1) signaling pathway which contributes to tumor cell apoptosis. Taken together, our current study uncovered a new mechanism which RYBP utilizes to exert its pro-apoptotic activity in human tumor cells. PMID:27060496

  2. Infant Pathways to Externalizing Behavior: Evidence of Genotype x Environment Interaction

    ERIC Educational Resources Information Center

    Leve, Leslie D.; Kerr, David C. R.; Shaw, Daniel; Ge, Xiaojia; Neiderhiser, Jenae M.; Scaramella, Laura V.; Reid, John B.; Conger, Rand; Reiss, David

    2010-01-01

    To further the understanding of the effects of early experiences, 9-month-old infants were observed during a frustration task. The analytical sample was composed of 348 linked triads of participants (adoptive parents, adopted child, and birth parent[s]) from a prospective adoption study. It was hypothesized that genetic risk for externalizing…

  3. Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.

    PubMed

    Naushad, Shaik Mohammad; Ramaiah, M Janaki; Pavithrakumari, Manickam; Jayapriya, Jaganathan; Hussain, Tajamul; Alrokayan, Salman A; Gottumukkala, Suryanarayana Raju; Digumarti, Raghunadharao; Kutala, Vijay Kumar

    2016-04-15

    In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400 μg/day) and B12 (6 μg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A × MTHFR C677T (primary), COMT H108L × CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A × cSHMT C1420T and CYP1A1 m2 × CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1. PMID:26784656

  4. Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics.

    PubMed

    Lion, Mattia; Bisio, Alessandra; Tebaldi, Toma; De Sanctis, Veronica; Menendez, Daniel; Resnick, Michael A; Ciribilli, Yari; Inga, Alberto

    2013-04-15

    Estrogen receptors (ERs) and p53 can interact via cis-elements to regulate the angiogenesis-related VEGFR-1 (FLT1) gene, as we reported previously. Here, we address cooperation between these transcription factors on a global scale. Human breast adenocarcinoma MCF7 cells were exposed to single or combinatorial treatments with the chemotherapeutic agent doxorubicin and the ER ligand 17β-estradiol (E2). Whole-genome transcriptome changes were measured by expression microarrays. Nearly 200 differentially expressed genes were identified that showed limited responsiveness to either doxorubicin treatment or ER ligand alone but were upregulated in a greater than additive manner following combined treatment. Based on exposure to 5-fuorouracil and nutlin-3a, the combined responses were treatment-specific. Among 16 genes chosen for validation using quantitative real-time PCR, seven (INPP5D, TLR5, KRT15, EPHA2, GDNF, NOTCH1, SOX9) were confirmed to be novel direct targets of p53, based on responses in MCF7 cells silenced for p53 or cooperative targets of p53 and ER. Promoter pattern searches and chromatin IP experiments for the INPP5D, TLR5, KRT15 genes supported direct, cis-mediated p53 and/or ER regulation through canonical and noncanonical p53 and ER response elements. Collectively, we establish that combinatorial activation of p53 and ER can induce novel gene expression programs that have implications for cell-cell communications, adhesion, cell differentiation, development and inflammatory responses as well as cancer treatments. PMID:23518503

  5. Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics

    PubMed Central

    Lion, Mattia; Bisio, Alessandra; Tebaldi, Toma; De Sanctis, Veronica; Menendez, Daniel; Resnick, Michael A.; Ciribilli, Yari; Inga, Alberto

    2013-01-01

    Estrogen receptors (ERs) and p53 can interact via cis-elements to regulate the angiogenesis-related VEGFR-1 (FLT1) gene, as we reported previously. Here, we address cooperation between these transcription factors on a global scale. Human breast adenocarcinoma MCF7 cells were exposed to single or combinatorial treatments with the chemotherapeutic agent doxorubicin and the ER ligand 17β-estradiol (E2). Whole-genome transcriptome changes were measured by expression microarrays. Nearly 200 differentially expressed genes were identified that showed limited responsiveness to either doxorubicin treatment or ER ligand alone but were upregulated in a greater than additive manner following combined treatment. Based on exposure to 5-fuorouracil and nutlin-3a, the combined responses were treatment-specific. Among 16 genes chosen for validation using quantitative real-time PCR, seven (INPP5D, TLR5, KRT15, EPHA2, GDNF, NOTCH1, SOX9) were confirmed to be novel direct targets of p53, based on responses in MCF7 cells silenced for p53 or cooperative targets of p53 and ER. Promoter pattern searches and chromatin IP experiments for the INPP5D, TLR5, KRT15 genes supported direct, cis-mediated p53 and/or ER regulation through canonical and noncanonical p53 and ER response elements. Collectively, we establish that combinatorial activation of p53 and ER can induce novel gene expression programs that have implications for cell-cell communications, adhesion, cell differentiation, development and inflammatory responses as well as cancer treatments. PMID:23518503

  6. HIV-1 Capsid-Cyclophilin Interactions Determine Nuclear Import Pathway, Integration Targeting and Replication Efficiency

    PubMed Central

    Schaller, Torsten; Ocwieja, Karen E.; Rasaiyaah, Jane; Price, Amanda J.; Brady, Troy L.; Roth, Shoshannah L.; Hué, Stéphane; Fletcher, Adam J.; Lee, KyeongEun; KewalRamani, Vineet N.; Noursadeghi, Mahdad; Jenner, Richard G.; James, Leo C.; Bushman, Frederic D.; Towers, Greg J.

    2011-01-01

    Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion of the Nup358/RanBP2 cyclophilin (Cyp) domain to the tripartite motif of TRIM5 created a novel inhibitor of HIV-1 replication, consistent with an interaction in vivo. In contrast to CypA binding to HIV-1 CA, Nup358 binding is insensitive to inhibition with cyclosporine, allowing contributions from CypA and Nup358 to be distinguished. Inhibition of CypA reduced dependence on Nup358 and the nuclear basket protein Nup153, suggesting that CypA regulates the choice of the nuclear import machinery that is engaged by the virus. HIV-1 cyclophilin-binding mutants CA G89V and P90A favored integration in genomic regions with a higher density of transcription units and associated features than wild type virus. Integration preference of wild type virus in the presence of cyclosporine was similarly altered to regions of higher transcription density. In contrast, HIV-1 CA alterations in another patch on the capsid surface that render the virus less sensitive to Nup358 or TRN-SR2 depletion (CA N74D, N57A) resulted in integration in genomic regions sparse in transcription units. Both groups of CA mutants are impaired in replication in HeLa cells and human monocyte derived macrophages. Our findings link HIV-1 engagement of cyclophilins with both integration targeting and replication efficiency and provide insight into the conservation of viral cyclophilin recruitment. PMID:22174692

  7. Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway

    PubMed Central

    Xu, Huanli; Zhao, Xin; Liu, Xiaohui; Xu, Pingxiang; Zhang, Keming; Lin, Xiukun

    2015-01-01

    Defects in apoptosis are common phenomena in many types of cancer and are also a critical step in tumorigenesis. Targeting the apoptotic pathway has been considered an intriguing strategy for cancer therapy. Traditional Chinese medicine (TCM) has been used in the People’s Republic of China for thousands of years, and many of the medicines have been confirmed to be effective in the treatment of a number of tumors. With increasing cancer rates worldwide, the antitumor effects of TCMs have attracted more and more attention globally. Many of the TCMs have been shown to have antitumor activity through multiple targets, and apoptosis pathway-related targets have been extensively studied and defined to be promising. This review focuses on several antitumor TCMs, especially those with clinical efficacy, based on their effects on the apoptotic signaling pathway. The problems with and prospects of development of TCMs as anticancer agents are also presented. PMID:26056434

  8. Effective Theories Of The Strong Interaction

    SciTech Connect

    Dr. Ubirajara van Kolck

    2004-07-31

    This is the final report corresponding to the full funding period (08/01-07/04) in the Department of Energy Outstanding Junior Investigator Grant DE-FG03-01ER41196. The development of an understanding of the interplay between perturbative and non-perturbative effects in strong-interacting systems forms the broad context of this research. The main thrust is the application of effective theories to QCD. Topics included a new power counting in the pionful effective theory, low-energy Compton scattering, charge-symmetry breaking in pion production and in the two-nucleon potential, parity violation, coupled-channel scattering, shallow resonances and halo nuclei, chiral symmetry in the baryon spectrum, existence of a tetraquark state, and molecular meson states. DOE grant DE-FG03-01ER41196 was used to partially support in the period 08/01-07/04 the research activities of the Principal Investigator, Dr. Ubirajara van Kolck, one post-doctoral research associate, Dr. Boris A. Gelman, and one graduate student, Mr. Will Hockings. During the grant period the PI was first Assistant then Associate Professor of Physics at the University of Arizona (UA), and a RHIC Physics Fellow at the RIKEN-BNL Research Center (RBRC). The association with RBRC ended in the Summer of 2004. Since September of 2002 the PI has also been partially supported by a Sloan Research Fellowship. Dr. Boris Gelman was supported by the grant from September 2002 to May 2004. He joined the UA after receiving a Ph.D. from the University of Maryland in the Summer of 2002. He left to take a research associate position in the nuclear theory group of the State University of New York at Stony Brook. The support of a post-doctoral researcher on this grant for two years was only possible by carrying over first- and second-year funds to later years. In addition, Mr. William Hockings started doing research under the PI's guidance. Mr. Hockings took Independent Study courses with the PI, while working as a teaching

  9. Impact of global climate change on ecosystem-level interactions among sympatric plants from all three photosynthetic pathways. Terminal report

    SciTech Connect

    Nobel, P.S.

    1997-12-17

    The proposed research will determine biochemical and physiological responses to variations in environmental factors for plants of all three photosynthetic pathways under competitive situations in the field. These responses will be used to predict the effects of global climatic change on an ecosystem in the northwestern Sonoran Desert where the C{sub 3} subshrub Encelia farinosa, the C{sub 4} bunchgrass Hilaria rigida, and the CAM succulent Agave deserti are co-dominants. These perennials are relatively short with overlapping shallow roots facilitating the experimental measurements as well as leading to competition for soil water. Net CO{sub 2} uptake over 24-h periods measured in the laboratory will be analyzed using an environmental productivity index (EPI) that can incorporate simultaneous effects of soil water, air temperature, and light. Based on EPI, net CO{sub 2} uptake and hence plant productivity will be predicted for the three species in the field under various treatments. Activity of the two CO{sub 2} fixation enzymes, Rubisco and PEPCase, will be determined for these various environmental conditions; also, partitioning of carbon to various organs will be measured based on {sup 14}CO{sub 2} labeling and dry weight analysis. Thus, enzymatic and partitioning controls on competition among sympatric model plants representing all three photosynthetic pathways will be investigated.

  10. Crystal Structure of UBA2[superscript ufd]-Ubc9: Insights into E1-E2 Interactions in Sumo Pathways

    SciTech Connect

    Wang, Jing; Taherbhoy, Asad M.; Hunt, Harold W.; Seyedin, Steven N.; Miller, David W.; Miller, Darcie J.; Huang, Danny T.; Schulman, Brenda A.

    2012-04-30

    Canonical ubiquitin-like proteins (UBLs) such as ubiquitin, Sumo, NEDD8, and ISG15 are ligated to targets by E1-E2-E3 multienzyme cascades. The Sumo cascade, conserved among all eukaryotes, regulates numerous biological processes including protein localization, transcription, DNA replication, and mitosis. Sumo conjugation is initiated by the heterodimeric Aos1-Uba2 E1 enzyme (in humans called Sae1-Uba2), which activates Sumo's C-terminus, binds the dedicated E2 enzyme Ubc9, and promotes Sumo C-terminal transfer between the Uba2 and Ubc9 catalytic cysteines. To gain insights into details of E1-E2 interactions in the Sumo pathway, we determined crystal structures of the C-terminal ubiquitin fold domain (ufd) from yeast Uba2 (Uba2{sup ufd}), alone and in complex with Ubc9. The overall structures of both yeast Uba2{sup ufd} and Ubc9 superimpose well on their individual human counterparts, suggesting conservation of fundamental features of Sumo conjugation. Docking the Uba2{sup ufd}-Ubc9 and prior full-length human Uba2 structures allows generation of models for steps in Sumo transfer from Uba2 to Ubc9, and supports the notion that Uba2 undergoes remarkable conformational changes during the reaction. Comparisons to previous structures from the NEDD8 cascade demonstrate that UBL cascades generally utilize some parallel E1-E2 interaction surfaces. In addition, the structure of the Uba2{sup ufd}-Ubc9 complex reveals interactions unique to Sumo E1 and E2. Comparison with a previous Ubc9-E3 complex structure demonstrates overlap between Uba2 and E3 binding sites on Ubc9, indicating that loading with Sumo and E3-catalyzed transfer to substrates are strictly separate steps. The results suggest mechanisms establishing specificity and order in Sumo conjugation cascades.

  11. Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer.

    PubMed

    Fan, Cong; Wang, Yunshan; Liu, Ziming; Sun, Ying; Wang, Xiuwen; Wei, Guangwei; Wei, Junmin

    2015-07-01

    Metformin, a widely prescribed antidiabetic drug, has previously been shown to lower the risk of certain types of cancer, including that of breast cancer, and to improve prognosis. Its anticancer effects, which are mediated by the activation of AMP-activated protein kinase (AMPK), have become notable. The Sonic hedgehog (Shh) signaling pathway is involved in changes in mammary ducts and malignant transformation. The aim of the present study was to elucidate the role of the Shh pathway in mediating the anticancer effects of metformin and the correlation between AMPK and the Shh pathway. We investigated the effectiveness of metformin in inhibiting the proliferation, migration, invasion and stemness of breast cancer cells in vitro using RNA extraction and reverse transcription‑polymerase chain reaction (RT-PCR), western blot analysis, cell proliferation assay, scratch-wound assay (cell migration assay), cell invasion assay, mammosphere culture and flow cytometry. In in vivo experiments, a tumor xenograft model was used to detect the effects of metformin on cancer cell proliferation. The results revealed that the treatment of breast cancer cells with metformin led to the inhibition of the Shh signaling pathway. Importantly, metformin inhibited recombinant human Shh (rhShh)‑induced cell migration, invasion, and stemness, and impaired cell proliferation both in vitro and in vivo. Furthermore, the small interfering RNA (siRNA)‑mediated downregulation of AMPK reversed the inhibitory effects of metformin on rhShh‑induced Gli-1 expression and stemness. Our findings identified a role of the Shh signaling pathway in the anticancer effects of metformin in breast cancer. Furthermore, we revealed that the metformin-mediated inhibition of the Shh signaling pathway may be dependent on AMPK. PMID:25999130

  12. The Effects of Ecological Variables on Parent-Infant Interaction.

    ERIC Educational Resources Information Center

    Lamb, Michael E.

    This paper summarizes the findings of a series of studies on the effects of "ecological variables" on mother-father-sibling-infant interactions. Under consideration were: (1) the effects of stress on the parental preferences of young infants; (2) the effects of the presence of one parent on the interactions within the other parent-infant dyad; (3)…

  13. 40 CFR 610.23 - Operator interaction effects.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 30 2011-07-01 2011-07-01 false Operator interaction effects. 610.23... Analysis § 610.23 Operator interaction effects. The device will also be evaluated with respect to: (a) The..., operation and maintenance; (c) The extent to which device installation or use, or the effects of...

  14. 40 CFR 610.23 - Operator interaction effects.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 29 2010-07-01 2010-07-01 false Operator interaction effects. 610.23... Analysis § 610.23 Operator interaction effects. The device will also be evaluated with respect to: (a) The..., operation and maintenance; (c) The extent to which device installation or use, or the effects of...

  15. 40 CFR 610.23 - Operator interaction effects.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 30 2014-07-01 2014-07-01 false Operator interaction effects. 610.23... Analysis § 610.23 Operator interaction effects. The device will also be evaluated with respect to: (a) The..., operation and maintenance; (c) The extent to which device installation or use, or the effects of...

  16. 40 CFR 610.23 - Operator interaction effects.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 31 2012-07-01 2012-07-01 false Operator interaction effects. 610.23... Analysis § 610.23 Operator interaction effects. The device will also be evaluated with respect to: (a) The..., operation and maintenance; (c) The extent to which device installation or use, or the effects of...

  17. Effects of support on bifunctional methanol oxidation pathways catalyzed by polyoxometallate keggin clusters

    SciTech Connect

    Liu, Haichao; Iglesia, Enrique

    2003-12-26

    H5PV2Mo10O40 polyoxometallate Keggin clusters supported on ZrO2, TiO2, SiO2, and Al2O3 are effective catalysts for CH3OH oxidation reactions to form HCHO, methyl formate (MF), and dimethoxymethane (DMM). Rates and selectivities and the structure of supported clusters depend on the surface properties of the oxide supports. Raman spectroscopy showed that Keggin structures remained essentially intact on ZrO2, TiO2, and SiO2 after treatment in air at 553 K, but decomposed to MoOx and VOx oligomers on Al2O3. Accessible protons per Keggin unit (KU) were measured during CH3OH oxidation by titration with 2,6-di-tert-butyl pyridine. For similar KU surface densities (0.28 0.37 KU/nm2), the number of accessible protons was larger on SiO2 than on ZrO2 and TiO2 and much smaller on Al2O3 supports, even though residual dimethyl ether (DME) synthesis rates after titrant saturation indicated that the fractional dispersion of KU was similar on the first three supports. These effects of support on structure and on H+ accessibility reflect varying extents of interaction between polyoxometallate clusters and supports. Rates of CH3OH oxidative dehydrogenation per KU were higher on ZrO2 and TiO2 than on SiO2 at similar KU surface densities (0.28 0.37 KU/nm2) and dispersion, indicating that redox properties of Keggin clusters depend on the identity of the support used to disperse them. ZrO2 and TiO2 supports appear to enhance the reducibility of anchored polyoxometallate clusters. Rates were much lower on Al2O3, because structural degradation led to less reactive MoOx and VOx domains. CH3OH reactions involve primary oxidation to form HCHO and subsequent secondary reactions to form DMM and MF. These reactions involve HCHO CH3OH acetalization steps leading to methoxymethanol (CH3OCH2OH) or hemiacetal intermediates, which condense with CH3OH on acid sites to form DMM or dehydrogenate to form MF. COx formation rates are much lower than those of other reactions, and DME forms in parallel

  18. Mercury as a Global Pollutant: Sources, Pathways, and Effects

    PubMed Central

    2013-01-01

    Mercury (Hg) is a global pollutant that affects human and ecosystem health. We synthesize understanding of sources, atmosphere-land-ocean Hg dynamics and health effects, and consider the implications of Hg-control policies. Primary anthropogenic Hg emissions greatly exceed natural geogenic sources, resulting in increases in Hg reservoirs and subsequent secondary Hg emissions that facilitate its global distribution. The ultimate fate of emitted Hg is primarily recalcitrant soil pools and deep ocean waters and sediments. Transfers of Hg emissions to largely unavailable reservoirs occur over the time scale of centuries, and are primarily mediated through atmospheric exchanges of wet/dry deposition and evasion from vegetation, soil organic matter and ocean surfaces. A key link between inorganic Hg inputs and exposure of humans and wildlife is the net production of methylmercury, which occurs mainly in reducing zones in freshwater, terrestrial, and coastal environments, and the subsurface ocean. Elevated human exposure to methylmercury primarily results from consumption of estuarine and marine fish. Developing fetuses are most at risk from this neurotoxin but health effects of highly exposed populations and wildlife are also a concern. Integration of Hg science with national and international policy efforts is needed to target efforts and evaluate efficacy. PMID:23590191

  19. TIMP-2 Interaction with MT1-MMP Activates the AKT Pathway and Protects Tumor Cells from Apoptosis

    PubMed Central

    Valacca, Cristina; Tassone, Evelyne; Mignatti, Paolo

    2015-01-01

    Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with an extracellular catalytic domain and a short cytoplasmic tail, degrades a variety of extracellular matrix (ECM) components. In addition, MT1-MMP activates intracellular signaling through proteolysis-dependent and independent mechanisms. We have previously shown that binding of tissue inhibitor of metalloproteinases-2 (TIMP-2) to MT1-MMP controls cell proliferation and migration, as well as tumor growth in vivo by activating the Ras—extracellular signal regulated kinase-1 and -2 (ERK1/2) pathway through a mechanism that requires the cytoplasmic but not the proteolytic domain of MT1-MMP. Here we show that in MT1-MMP expressing cells TIMP-2 also induces rapid and sustained activation of AKT in a dose- and time-dependent manner and by a mechanism independent of the proteolytic activity of MT1-MMP. Fibroblast growth factor receptor-1 mediates TIMP-2 induction of ERK1/2 but not of AKT activation; however, Ras activation is necessary to transduce the TIMP-2-activated signal to both the ERK1/2 and AKT pathways. ERK1/2 and AKT activation by TIMP-2 binding to MT1-MMP protects tumor cells from apoptosis induced by serum starvation. Conversely, TIMP-2 upregulates apoptosis induced by three-dimensional type I collagen in epithelial cancer cells. Thus, TIMP-2 interaction with MT1-MMP provides tumor cells with either pro- or anti-apoptotic signaling depending on the extracellular environment and apoptotic stimulus. PMID:26331622

  20. rugose (rg), a Drosophila A kinase anchor protein, is required for retinal pattern formation and interacts genetically with multiple signaling pathways.

    PubMed Central

    Shamloula, Hoda K; Mbogho, Mkajuma P; Pimentel, Angel C; Chrzanowska-Lightowlers, Zosia M A; Hyatt, Vanneta; Okano, Hideyuki; Venkatesh, Tadmiri R

    2002-01-01

    In the developing Drosophila eye, cell fate determination and pattern formation are directed by cell-cell interactions mediated by signal transduction cascades. Mutations at the rugose locus (rg) result in a rough eye phenotype due to a disorganized retina and aberrant cone cell differentiation, which leads to reduction or complete loss of cone cells. The cone cell phenotype is sensitive to the level of rugose gene function. Molecular analyses show that rugose encodes a Drosophila A kinase anchor protein (DAKAP 550). Genetic interaction studies show that rugose interacts with the components of the EGFR- and Notch-mediated signaling pathways. Our results suggest that rg is required for correct retinal pattern formation and may function in cell fate determination through its interactions with the EGFR and Notch signaling pathways. PMID:12072466

  1. Climate targets and cost-effective climate stabilization pathways

    NASA Astrophysics Data System (ADS)

    Held, H.

    2015-08-01

    Climate economics has developed two main tools to derive an economically adequate response to the climate problem. Cost benefit analysis weighs in any available information on mitigation costs and benefits and thereby derives an "optimal" global mean temperature. Quite the contrary, cost effectiveness analysis allows deriving costs of potential policy targets and the corresponding cost- minimizing investment paths. The article highlights pros and cons of both approaches and then focusses on the implications of a policy that strives at limiting global warming to 2 °C compared to pre-industrial values. The related mitigation costs and changes in the energy sector are summarized according to the IPCC report of 2014. The article then points to conceptual difficulties when internalizing uncertainty in these types of analyses and suggests pragmatic solutions. Key statements on mitigation economics remain valid under uncertainty when being given the adequate interpretation. Furthermore, the expected economic value of perfect climate information is found to be on the order of hundreds of billions of Euro per year if a 2°-policy were requested. Finally, the prospects of climate policy are sketched.

  2. Curcumin protects against ischemic spinal cord injury: The pathway effect.

    PubMed

    Zhang, Jinhua; Wei, Hao; Lin, Meimei; Chen, Chunmei; Wang, Chunhua; Liu, Maobai

    2013-12-25

    Inducible nitric oxide synthase and N-methyl-D-aspartate receptors have been shown to participate in nerve cell injury during spinal cord ischemia. This study observed a protective effect of curcumin on ischemic spinal cord injury. Models of spinal cord ischemia were established by ligating the lumbar artery from the left renal artery to the bifurcation of the abdominal aorta. At 24 hours after model establishment, the rats were intraperitoneally injected with curcumin. Reverse transcription-polymerase chain reaction and immunohistochemical results demonstrated that after spinal cord ischemia, inducible nitric oxide synthase and N-methyl-D-aspartate receptor mRNA and protein expression significantly increased. However, curcumin significantly decreased inducible nitric oxide synthase and N-methyl-D-aspartate receptor mRNA and protein expression in the ischemic spinal cord. Tarlov scale results showed that curcumin significantly improved motor function of the rat hind limb after spinal cord ischemia. The results demonstrate that curcumin exerts a neuroprotective fect against ischemic spinal cord injury by decreasing inducible nitric oxide synthase and N-methyl-D-aspartate receptor expression. PMID:25206661

  3. Reputation Effects in Public and Private Interactions

    PubMed Central

    Ohtsuki, Hisashi; Iwasa, Yoh; Nowak, Martin A.

    2015-01-01

    We study the evolution of cooperation in a model of indirect reciprocity where people interact in public and private situations. Public interactions have a high chance to be observed by others and always affect reputation. Private interactions have a lower chance to be observed and only occasionally affect reputation. We explore all second order social norms and study conditions for evolutionary stability of action rules. We observe the competition between “honest” and “hypocritical” strategies. The former cooperate both in public and in private. The later cooperate in public, where many others are watching, but try to get away with defection in private situations. The hypocritical idea is that in private situations it does not pay-off to cooperate, because there is a good chance that nobody will notice it. We find simple and intuitive conditions for the evolution of honest strategies. PMID:26606239

  4. A metabolomics strategy to explore urinary biomarkers and metabolic pathways for assessment of interaction between Danhong injection and low-dose aspirin during their synergistic treatment.

    PubMed

    Li, Jianping; Guo, Jianming; Shang, Erxin; Zhu, Zhenhua; Zhu, Kevin Yue; Li, Shujiao; Zhao, Buchang; Jia, Lifu; Zhao, Jing; Tang, Zhishu; Duan, Jinao

    2016-07-15

    The drug combination of Danhong injection (DHI) and low-dose aspirin (ASA) was frequently applied for the treatment of cardiovascular and cerebrovascular diseases. Due to the drug interactions, a lot of potential benefits and risks might exist side by side in the course of combination therapy. However, there had been no studies of interaction between DHI and ASA. Metabolomics was a powerful tool to explore endogenous biomarkers and metabolic pathways. In present study, metabolic profiling with ultra-high-performance liquid chromatography coupled to quadrupole time of flight mass spectrometry (UHPLC-QTOF/MS) coupled with multivariate statistical analysis was performed to provide insight into understanding the interaction between DHI and low-dose ASA. Eleven potential biomarkers of three types were identified and seven metabolic pathways were constructed. The results showed that the interaction between DHI and low-dose ASA during synergistic treatment indeed affected some key endogenous biomarkers and metabolic pathways, which could not happen when DHI or low-dose ASA was used alone. The quality and quantity of endogenous metabolite were both influenced by interaction between DHI and low-dose ASA. In details, the amount of flavin mononucleotide, L-2, 4-diaminobutyric acid (DABA) and 4-aminohippuric acid were significantly increased. On the contrary, the amount of 3-methyluridine, 4, 6-dihydroxyquinoline, cortolone-3-glucuronide, and serotonin were significantly decreased. Furthermore, O-phosphotyrosine, 3-methyl-2-butenal, indoxyl sulfate and dolichyl diphosphate were disappeared in urine. As to metabolic pathways, riboflavin metabolism, pentose and glucuronate interconversions, and tryptophan metabolism were all significantly influenced. The emerging alterations of biomarkers and metabolic pathways were associated with a lot of drugs and diseases based on literature researches, which might influence the co-administration of other drugs or the treatments of relevant

  5. The chemical interaction between adrenochrome, three different classes of antipsychotic drugs and metabolites of the kynurenine pathway.

    PubMed

    Miller, Christine L

    2015-03-01

    Two kynurenine metabolites, 3-hydroxykynurenine and 3-hydroxyanthranilic acid, are known to inhibit melanin polymer formation in in vitro reactions catalyzed by tyrosinase. The present study expands that finding to include inhibition of chlorpromazine-stimulated melanin formation from the endogenous melanin precursor adrenochrome. Several kynurenine pathway metabolites tested had no measurable effect on the reaction: tryptophan, kynurenine, kynurenic acid, quinolinic acid and nicotinic acid. However, at a concentration of 0.5mM in a pH 7.4 reaction mix, 3-hydroxykynurenine exerted~72% inhibition on product formation and the same concentration of 3-hydroxyanthranilic acid caused complete inhibition. Two other classes of antipsychotic drugs were evaluated in this paradigm, represented by olanzapine and minocycline. Although the adrenochrome reaction of both drugs was strongly inhibited by 3-hydroxyanthranilic acid, 3-hydroxykynurenine inhibited product formation from only the minocycline reaction. The results are discussed in terms of the well-studied kynurenine pathway upregulation in psychotic disorders and how such upregulation may either influence the efficacy of antipsychotic drug treatment or relate to the mechanism of action of these drugs. PMID:25554565

  6. Effects of aerosol emission pathways on future warming and human health

    NASA Astrophysics Data System (ADS)

    Partanen, Antti-Ilari; Matthews, Damon

    2016-04-01

    The peak global temperature is largely determined by cumulative emissions of long-lived greenhouse gases. However, anthropogenic emissions include also so-called short-lived climate forcers (SLCFs), which include aerosol particles and methane. Previous studies with simple models indicate that the timing of SLCF emission reductions has only a small effect on the rate of global warming and even less of an effect on global peak temperatures. However, these simple model analyses do not capture the spatial dynamics of aerosol-climate interactions, nor do they consider the additional effects of aerosol emissions on human health. There is therefore merit in assessing how the timing of aerosol emission reductions affects global temperature and premature mortality caused by elevated aerosol concentrations, using more comprehensive climate models. Here, we used an aerosol-climate model ECHAM-HAMMOZ to simulate the direct and indirect radiative forcing resulting from aerosol emissions. We simulated Representative Concentration Pathway (RCP) scenarios, and we also designed idealized low and high aerosol emission pathways based on RCP4.5 scenario (LOW and HIGH, respectively). From these simulations, we calculated the Effective Radiative Forcing (ERF) from aerosol emissions between 1850 and 2100, as well as aerosol concentrations used to estimate the premature mortality caused by particulate pollution. We then use the University of Victoria Earth System Climate Model to simulate the spatial and temporal pattern of climate response to these aerosol-forcing scenarios, in combination with prescribed emissions of both short and long-lived greenhouse gases according to the RCP4.5 scenario. In the RCP scenarios, global mean ERF declined during the 21st century from ‑1.3 W m‑2 to ‑0.4 W m‑2 (RCP8.5) and ‑0.2 W m‑2 (RCP2.6). In the sensitivity scenarios, the forcing at the end of the 21st century was ‑1.6 W m‑2 (HIGH) and practically zero (LOW). The difference in global

  7. Hillslope-swamp interactions and flow pathways in a hypermaritime rainforest, British Columbia

    NASA Astrophysics Data System (ADS)

    Fitzgerald, D. F.; Price, J. S.; Gibson, J. J.

    2003-10-01

    mitigate some of the harmful effects of logging operations by respecting the integrity of headwater wetland systems. The nature and magnitude of such perturbations will require further study. Copyright

  8. Effect of interactions on the conductance of graphene nanoribbons

    SciTech Connect

    Bazzanella, M.; Faccioli, P.; Lipparini, E.

    2010-11-15

    We study the effects of the interaction between electrons and holes on the conductance G of quasi-one-dimensional graphene systems. We first consider as a benchmark the limit in which all interactions are negligible, recovering the predictions of the tight-binding approximation for the spectrum of the system, and the well-known result G=4e{sup 2}/h for the lowest conductance quantum. Then we consider an exactly solvable field theoretical model in which the electromagnetic interactions are effectively local. Finally, we use the effective-field theory formalism to develop an exactly solvable model in which we also include the effect of nonlocal interactions. We find that such interactions turn the nominally metallic armchair graphene nanoribbon into a semiconductor while the short-range interactions lead to a correction to the G=4e{sup 2}/h formula.

  9. ERK and β-arrestin interaction: a converging-point of signaling pathways for multiple types of cell-surface receptors

    PubMed Central

    Eishingdrelo, Haifeng; Sun, Wei; Li, Hua; Wang, Li; Eishingdrelo, Alex; Dai, Sheng; McKew, John C.; Zheng, Wei

    2016-01-01

    β-arrestin, a signal adaptor protein, mediates intracellular signal transductions through protein-protein interactions by bringing two or more proteins in proximity. Extracellular signal-regulated kinase (ERK), a protein kinase in the family of mitogen-activated protein kinases (MAPKs), is involved in various receptor signal pathways. Interaction of ERK with β-arrestin or formation of ERK/β-arrestin signal complex occurs in response to activation of a variety of cell-surface receptors. The ERK/β-arrestin signal complex may be a common transducer to converge a variety of extracellular stimuli to similar downstream intracellular signaling pathways. By using a cell based protein-protein interaction LinkLight assay technology, we demonstrate a direct interaction between ERK and β-arrestin in respond to extracellular stimuli, which can be sensitively and quantitatively monitored. Activations of G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and cytokine receptors promote formation of the ERK/β-arrestin signal complex. Our data indicate that the ERK/β-arrestin signal complex is a common transducer participated in a variety of receptor signaling pathways. Furthermore, we demonstrate that receptor antagonists or kinase inhibitors can block the agonist induced ERK and β-arrestin interaction. Thus, the ERK/β-arrestin interaction assay is useful for screening of new receptor modulators. PMID:25361946

  10. Effects of Intergenerational Interaction on Aging

    ERIC Educational Resources Information Center

    Hernandez, Carmen Requena; Gonzalez, Marta Zubiaur

    2008-01-01

    The world population pyramid has changed shape. However, this does not mean that societies have changed their negative concept of old age. Our study proposes an intergenerational service-learning program with 179 university students and 101 slightly depressed elderly people. The results show that the elderly people who interacted improved in…

  11. The Interactivity Effect in Multimedia Learning

    ERIC Educational Resources Information Center

    Evans, Chris; Gibbons, Nicola J.

    2007-01-01

    The aim of this study was to determine whether the addition of interactivity to a computer-based learning package enhances the learning process. A sample of 33 (22 male and 11 female) undergraduates on a Business and Management degree used a multimedia system to learn about the operation of a bicycle pump. The system consisted of a labelled…

  12. Enhancing Interactive Tutorial Effectiveness through Visual Cueing

    ERIC Educational Resources Information Center

    Jamet, Eric; Fernandez, Jonathan

    2016-01-01

    The present study investigated whether learning how to use a web service with an interactive tutorial can be enhanced by cueing. We expected the attentional guidance provided by visual cues to facilitate the selection of information in static screen displays that corresponded to spoken explanations. Unlike most previous studies in this area, we…

  13. Pathways for Communicating the Effects of Stratospheric Ozone to Northern Hemisphere Stratospheric Climate

    NASA Astrophysics Data System (ADS)

    Albers, John Robert

    The central objective of this thesis is to establish a framework for understanding how zonally asymmetric ozone (ZAO) and zonal-mean ozone combine to communicate changes in stratospheric ozone to the Earth's climate system. Achieving this objective revolves around three major research tasks. Tasks one and two use a mechanistic chemistry-dynamical model, while the third task incorporates the NOGAPS general circulation model. The first task develops a generalized framework for understanding how ZAO affects planetary wave driving and circulation of the middle atmosphere. The second task uses this framework to analyze how ozone loss and recovery "precondition" planetary waves as they propagate upwards through the lower stratosphere, thereby generating large circulation changes in the upper stratosphere and lower mesosphere. The final task utilizes the hypotheses developed in tasks one and two within the context of a general circulation model with interactive stratospheric chemistry. As part of task one, a mechanistic model that couples quasigeostrophic dynamics, radiative transfer, ozone transport, and ozone photochemistry was developed to study the effects of ZAO on the Northern Hemisphere (NH) polar vortex. ZAO affects the vortex via two pathways. The first pathway (P1) hinges on modulation of the propagation and damping of a planetary wave by ZAO; the second pathway (P2) hinges on modulation of the wave-ozone flux convergences by ZAO. In the steady state, both P1 and P2 play important roles in modulating the zonal-mean circulation. The relative importance of wave propagation versus wave damping in P1 is diagnosed using an ozone-modified refractive index and an ozone-modified vertical energy flux. In the lower stratosphere, ZAO causes wave propagation and wave damping to oppose each other. The result is a small change in planetary wave drag but a large reduction in wave amplitude. Thus in the lower stratosphere, ZAO "preconditions'' the wave before it propagates into

  14. Molecular convergence of clock and photosensory pathways through PIF3-TOC1 interaction and co-occupancy of target promoters.

    PubMed

    Soy, Judit; Leivar, Pablo; González-Schain, Nahuel; Martín, Guiomar; Diaz, Céline; Sentandreu, Maria; Al-Sady, Bassem; Quail, Peter H; Monte, Elena

    2016-04-26

    A mechanism for integrating light perception and the endogenous circadian clock is central to a plant's capacity to coordinate its growth and development with the prevailing daily light/dark cycles. Under short-day (SD) photocycles, hypocotyl elongation is maximal at dawn, being promoted by the collective activity of a quartet of transcription factors, called PIF1, PIF3, PIF4, and PIF5 (phytochrome-interacting factors). PIF protein abundance in SDs oscillates as a balance between synthesis and photoactivated-phytochrome-imposed degradation, with maximum levels accumulating at the end of the long night. Previous evidence shows that elongation under diurnal conditions (as well as in shade) is also subjected to circadian gating. However, the mechanism underlying these phenomena is incompletely understood. Here we show that the PIFs and the core clock component Timing of CAB expression 1 (TOC1) display coincident cobinding to the promoters of predawn-phased, growth-related genes under SD conditions. TOC1 interacts with the PIFs and represses their transcriptional activation activity, antagonizing PIF-induced growth. Given the dynamics of TOC1 abundance (displaying high postdusk levels that progressively decline during the long night), our data suggest that TOC1 functions to provide a direct output from the core clock that transiently constrains the growth-promoting activity of the accumulating PIFs early postdusk, thereby gating growth to predawn, when conditions for cell elongation are optimal. These findings unveil a previously unrecognized mechanism whereby a core circadian clock output signal converges immediately with the phytochrome photosensory pathway to coregulate directly the activity of the PIF transcription factors positioned at the apex of a transcriptional network that regulates a diversity of downstream morphogenic responses. PMID:27071129

  15. Interactive Televised Courses: Student Perceptions of Teaching Effectiveness, with Recommendations.

    ERIC Educational Resources Information Center

    Anderson, Lorraine P.; Kent, Calvin A.

    2002-01-01

    Reviews research on student satisfaction levels in interactive televised courses (ITV). Finds that when other variables are held constant, students rate the effectiveness of the professor's teaching lower when ITV is involved. Offers recommendations regarding effective use of ITV. (EV)

  16. Experienced Elementary Music Teachers' Perceptions of Effective Classroom Interactions

    ERIC Educational Resources Information Center

    Gibbs, Beth Ellen

    2009-01-01

    The purpose of this study was to examine how experienced elementary general music teachers perceived the effectiveness of their instructional interactions with students in the music classroom. The following questions were addressed in this study: What types of interactions do experienced teachers use most frequently and perceive as effective in…

  17. A Course on Effective Teacher-Child Interactions. Research Brief

    ERIC Educational Resources Information Center

    Hamre, Bridget K.; Pianta, Robert C.; Burchinal, Margaret; Field, Samuel; LoCasale-Crouch, Jennifer; Downer, Jason T.; Howes, Carollee; LaParo, Karen; Scott-Little, Catherine

    2012-01-01

    This study found that teachers who were randomly assigned to take a 14-week course on effective teacher-child interactions demonstrated significant changes in beliefs and knowledge about effective practices and provided more stimulating and engaging interactions in the classroom. [This research brief is based on: Hamre, B. K., Pianta, R. C.,…

  18. From a Subtractive to Multiplicative Approach: A concept-driven interactive pathway on the selective absorption of light

    NASA Astrophysics Data System (ADS)

    Viennot, Laurence; de Hosson, Cécile

    2015-01-01

    This research documents the aims and the impact of a teaching experiment on how the absorption of light depends on the thickness of the absorbing medium. This teaching experiment is more specifically characterized as bringing to bear a 'concept-driven interactive pathway'. It is designed to make students analyse the absorption of light by a medium as a selective multiplication (i.e. one depending on the wavelength) of the intensity by a factor smaller than one. Six teaching interviews conducted with fourth-year university students were recorded, transcribed and coded. Their analysis led us to evaluate the importance of the main obstacle expected, that is, of restricting the interpretation of absorption/transmission phenomena to the idea of 'less light', or, equivalently, of seeing a multiplication by a factor smaller than one as just a subtraction. The students' comments at the end of the interview introduce a discussion about the links between their intellectual satisfaction, critical attitude and comprehension of the topic.

  19. miR-124 interacts with the Notch1 signalling pathway and has therapeutic potential against gastric cancer.

    PubMed

    Jiang, Lei; Lin, Tiesu; Xu, Chaochao; Hu, Sunkuan; Pan, Yangyang; Jin, Rong

    2016-02-01

    Aberrant Notch signalling plays an important role in cancer progression. However, little is known about the interaction between miRNA and the Notch signalling pathway and its role in gastric cancer (GC). In this study, we found that miR-124 was down-regulated in GC compared with adjacent normal tissue. Forced expression of miR-124 inhibited GC cell growth, migration and invasion, and induced cell cycle arrest. miR-124 negatively regulated Notch1 signalling by targeting JAG1. miR-124 levels were also shown to be inversely correlated with JAG1 expression in GC. Furthermore, we found that the overexpression of the intracellular domain of Notch1 repressed miR-124 expression, promoted GC cell growth, migration and invasion. Conversely, blocking Notch1 using a γ-secretase inhibitor up-regulated miR-124 expression, inhibited GC cell growth, migration and invasion. In conclusion, our data demonstrates a regulatory feedback loop between miR-124 and Notch1 signalling in GC cells, suggesting that the miR-124/Notch axis may be a potential therapeutic target against GC. PMID:26612211

  20. Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways.

    PubMed

    Guan, Hongtao; Shuaib, Aban; Leon, David Davila De; Angyal, Adrienn; Salazar, Maria; Velasco, Guillermo; Holcombe, Mike; Dower, Steven K; Kiss-Toth, Endre

    2016-01-01

    Spatio-temporal regulation of intracellular signalling networks is key to normal cellular physiology; dysregulation of which leads to disease. The family of three mammalian tribbles proteins has emerged as an important controller of signalling via regulating the activity of mitogen activated protein kinases (MAPK), the PI3-kinase induced signalling network and E3 ubiquitin ligases. However, the importance of potential redundancy in the action of tribbles and how the differences in affinities for the various binding partners may influence signalling control is currently unclear. We report that tribbles proteins can bind to an overlapping set of MAPK-kinases (MAPKK) in live cells and dictate the localisation of the complexes. Binding studies in transfected cells reveal common regulatory mechanisms and suggest that tribbles and MAPKs may interact with MAPKKs in a competitive manner. Computational modelling of the impact of tribbles on MAPK activation suggests a high sensitivity of this system to changes in tribbles levels, highlighting that these proteins are ideally placed to control the dynamics and balance of activation of concurrent signalling pathways. PMID:27600771

  1. Competition between members of the tribbles pseudokinase protein family shapes their interactions with mitogen activated protein kinase pathways

    PubMed Central

    Guan, Hongtao; Shuaib, Aban; Leon, David Davila De; Angyal, Adrienn; Salazar, Maria; Velasco, Guillermo; Holcombe, Mike; Dower, Steven K.; Kiss-Toth, Endre

    2016-01-01

    Spatio-temporal regulation of intracellular signalling networks is key to normal cellular physiology; dysregulation of which leads to disease. The family of three mammalian tribbles proteins has emerged as an important controller of signalling via regulating the activity of mitogen activated protein kinases (MAPK), the PI3-kinase induced signalling network and E3 ubiquitin ligases. However, the importance of potential redundancy in the action of tribbles and how the differences in affinities for the various binding partners may influence signalling control is currently unclear. We report that tribbles proteins can bind to an overlapping set of MAPK-kinases (MAPKK) in live cells and dictate the localisation of the complexes. Binding studies in transfected cells reveal common regulatory mechanisms and suggest that tribbles and MAPKs may interact with MAPKKs in a competitive manner. Computational modelling of the impact of tribbles on MAPK activation suggests a high sensitivity of this system to changes in tribbles levels, highlighting that these proteins are ideally placed to control the dynamics and balance of activation of concurrent signalling pathways. PMID:27600771

  2. Nutrient-Deprived Retinal Progenitors Proliferate in Response to Hypoxia: Interaction of the HIF-1 and mTOR Pathway

    PubMed Central

    Khaliullina, Helena; Love, Nicola K.; Harris, William A.

    2016-01-01

    At a cellular level, nutrients are sensed by the mechanistic Target of Rapamycin (mTOR). The response of cells to hypoxia is regulated via action of the oxygen sensor Hypoxia-Inducible Factor 1 (HIF-1). During development, injury and disease, tissues might face conditions of both low nutrient supply and low oxygen, yet it is not clear how cells adapt to both nutrient restriction and hypoxia, or how mTOR and HIF-1 interact in such conditions. Here we explore this question in vivo with respect to cell proliferation using the ciliary marginal zone (CMZ) of Xenopus. We found that both nutrient-deprivation and hypoxia cause retinal progenitors to decrease their proliferation, yet when nutrient-deprived progenitors are exposed to hypoxia there is an unexpected rise in cell proliferation. This increase, mediated by HIF-1 signalling, is dependent on glutaminolysis and reactivation of the mTOR pathway. We discuss how these findings in non-transformed tissue may also shed light on the ability of cancer cells in poorly vascularised solid tumours to proliferate. PMID:27280081

  3. CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway.

    PubMed

    Ruan, Ye Chun; Wang, Yan; Da Silva, Nicolas; Kim, Bongki; Diao, Rui Ying; Hill, Eric; Brown, Dennis; Chan, Hsiao Chang; Breton, Sylvie

    2014-10-15

    Mutations in CFTR lead to dysfunction of tubular organs, which is currently attributed to impairment of its conductive properties. We now show that CFTR regulates tight junction assembly and epithelial cell differentiation through modulation of the ZO-1-ZONAB pathway. CFTR colocalizes with ZO-1 at the tight junctions of trachea and epididymis, and is expressed before ZO-1 in Wolffian ducts. CFTR interacts with ZO-1 through the CTFR PDZ-binding domain. In a three-dimensional (3D) epithelial cell culture model, CFTR regulates tight junction assembly and is required for tubulogenesis. CFTR inhibition or knockdown reduces ZO-1 expression and induces the translocation of the transcription factor ZONAB (also known as YBX3) from tight junctions to the nucleus, followed by upregulation of the transcription of CCND1 and downregulation of ErbB2 transcription. The epididymal tubules of cftr(-/-) and cftr(ΔF508) mice have reduced ZO-1 levels, increased ZONAB nuclear expression, and decreased epithelial cell differentiation, illustrated by the reduced expression of apical AQP9 and V-ATPase. This study provides a new paradigm for the etiology of diseases associated with CFTR mutations, including cystic fibrosis. PMID:25107366

  4. CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway

    PubMed Central

    Ruan, Ye Chun; Wang, Yan; Da Silva, Nicolas; Kim, Bongki; Diao, Rui Ying; Hill, Eric; Brown, Dennis; Chan, Hsiao Chang; Breton, Sylvie

    2014-01-01

    ABSTRACT Mutations in CFTR lead to dysfunction of tubular organs, which is currently attributed to impairment of its conductive properties. We now show that CFTR regulates tight junction assembly and epithelial cell differentiation through modulation of the ZO-1–ZONAB pathway. CFTR colocalizes with ZO-1 at the tight junctions of trachea and epididymis, and is expressed before ZO-1 in Wolffian ducts. CFTR interacts with ZO-1 through the CTFR PDZ-binding domain. In a three-dimensional (3D) epithelial cell culture model, CFTR regulates tight junction assembly and is required for tubulogenesis. CFTR inhibition or knockdown reduces ZO-1 expression and induces the translocation of the transcription factor ZONAB (also known as YBX3) from tight junctions to the nucleus, followed by upregulation of the transcription of CCND1 and downregulation of ErbB2 transcription. The epididymal tubules of cftr−/− and cftrΔF508 mice have reduced ZO-1 levels, increased ZONAB nuclear expression, and decreased epithelial cell differentiation, illustrated by the reduced expression of apical AQP9 and V-ATPase. This study provides a new paradigm for the etiology of diseases associated with CFTR mutations, including cystic fibrosis. PMID:25107366

  5. Evidence for multiple stressor interactions and effects on coral reefs.

    PubMed

    Ban, Stephen S; Graham, Nicholas A J; Connolly, Sean R

    2014-03-01

    Concern is growing about the potential effects of interacting multiple stressors, especially as the global climate changes. We provide a comprehensive review of multiple stressor interactions in coral reef ecosystems, which are widely considered to be one of the most sensitive ecosystems to global change. First, we synthesized coral reef studies that examined interactions of two or more stressors, highlighting stressor interactions (where one stressor directly influences another) and potentially synergistic effects on response variables (where two stressors interact to produce an effect that is greater than purely additive). For stressor-stressor interactions, we found 176 studies that examined at least 2 of the 13 stressors of interest. Applying network analysis to analyze relationships between stressors, we found that pathogens were exacerbated by more costressors than any other stressor, with ca. 78% of studies reporting an enhancing effect by another stressor. Sedimentation, storms, and water temperature directly affected the largest number of other stressors. Pathogens, nutrients, and crown-of-thorns starfish were the most-influenced stressors. We found 187 studies that examined the effects of two or more stressors on a third dependent variable. The interaction of irradiance and temperature on corals has been the subject of more research (62 studies, 33% of the total) than any other combination of stressors, with many studies reporting a synergistic effect on coral symbiont photosynthetic performance (n = 19). Second, we performed a quantitative meta-analysis of existing literature on this most-studied interaction (irradiance and temperature). We found that the mean effect size of combined treatments was statistically indistinguishable from a purely additive interaction, although it should be noted that the sample size was relatively small (n = 26). Overall, although in aggregate a large body of literature examines stressor effects on coral reefs and coral

  6. Interaction of Aβ(1-42) amyloids with lipids promotes "off-pathway" oligomerization and membrane damage.

    PubMed

    Henry, Sarah; Vignaud, Hélène; Bobo, Claude; Decossas, Marion; Lambert, Oliver; Harte, Etienne; Alves, Isabel D; Cullin, Christophe; Lecomte, Sophie

    2015-03-01

    The toxicity of amyloids, as Aβ(1-42) involved in Alzheimer disease, is a subject under intense scrutiny. Many studies link their toxicity to the existence of various intermediate structures prior to fiber formation and/or their specific interaction with membranes. In this study we focused on the interaction between membrane models and Aβ(1-42) peptides and variants (L34T, mG37C) produced in E. coli and purified in monomeric form. We evaluated the interaction of a toxic stable oligomeric form (oG37C) with membranes as comparison. Using various biophysical techniques as fluorescence and plasmon waveguide resonance, we clearly established that the oG37C interacts strongly with membranes leading to its disruption. All the studied peptides destabilized liposomes and accumulated slowly on the membrane (rate constant 0.02 min(-1)). Only the oG37C exhibited a particular pattern of interaction, comprising two steps: the initial binding followed by membrane reorganization. Cryo-TEM was used to visualize the peptide effect on liposome morphologies. Both oG37C and mG37C lead to PG membrane fragmentation. The PG membrane promotes peptide oligomerization, implicated in membrane disruption. WT (Aβ(1-42)) also perturbs liposome organization with membrane deformation rather than disruption. For all the peptides studied, their interaction with the membranes changes their fibrillization process, with less fibers and more small aggregates being formed. These studies allowed to establish, a correlation between toxicity, fiber formation, and membrane disruption. PMID:25689632

  7. Compound K, a Ginsenoside Metabolite, Inhibits Colon Cancer Growth via Multiple Pathways Including p53-p21 Interactions

    PubMed Central

    Zhang, Zhiyu; Du, Guang-Jian; Wang, Chong-Zhi; Wen, Xiao-Dong; Calway, Tyler; Li, Zejuan; He, Tong-Chuan; Du, Wei; Bissonnette, Marc; Musch, Mark W.; Chang, Eugene B.; Yuan, Chun-Su

    2013-01-01

    Compound K (20-O-beta-d-glucopyranosyl-20(S)-protopanaxadiol, CK), an intestinal bacterial metabolite of ginseng protopanaxadiol saponins, has been shown to inhibit cell growth in a variety of cancers. However, the mechanisms are not completely understood, especially in colorectal cancer (CRC). A xenograft tumor model was used first to examine the anti-CRC effect of CK in vivo. Then, multiple in vitro assays were applied to investigate the anticancer effects of CK including antiproliferation, apoptosis and cell cycle distribution. In addition, a qPCR array and western blot analysis were executed to screen and validate the molecules and pathways involved. We observed that CK significantly inhibited the growth of HCT-116 tumors in an athymic nude mouse xenograft model. CK significantly inhibited the proliferation of human CRC cell lines HCT-116, SW-480, and HT-29 in a dose- and time-dependent manner. We also observed that CK induced cell apoptosis and arrested the cell cycle in the G1 phase in HCT-116 cells. The processes were related to the upregulation of p53/p21, FoxO3a-p27/p15 and Smad3, and downregulation of cdc25A, CDK4/6 and cyclin D1/3. The major regulated targets of CK were cyclin dependent inhibitors, including p21, p27, and p15. These results indicate that CK inhibits transcriptional activation of multiple tumor-promoting pathways in CRC, suggesting that CK could be an active compound in the prevention or treatment of CRC. PMID:23434653

  8. Spin effects in the weak interaction

    SciTech Connect

    Freedman, S.J. Chicago Univ., IL . Dept. of Physics Chicago Univ., IL . Enrico Fermi Inst.)

    1990-01-01

    Modern experiments investigating the beta decay of the neutron and light nuclei are still providing important constraints on the theory of the weak interaction. Beta decay experiments are yielding more precise values for allowed and induced weak coupling constants and putting constraints on possible extensions to the standard electroweak model. Here we emphasize the implications of recent experiments to pin down the strengths of the weak vector and axial vector couplings of the nucleon.

  9. Beam-Plasma Interaction and Nonlinear Effects

    SciTech Connect

    Yoon, Peter H.

    2009-11-10

    This paper presents a survey of perturbative nonlinear plasma theory known as the weak turbulence theory. After the basic concepts and methodology of the weak turbulence theory are outlined in sufficient detail, numerical solutions of the weak turbulence theory obtained in the context of the beam-plasma interaction are compared against particle-in-cell (PIC) numerical simulations. It is demonstrated that theory and PIC simulation are in excellent agreement.

  10. Communication: Dimensionality of the ionic conduction pathways in glass and the mixed-alkali effect.

    PubMed

    Novy, Melissa; Avila-Paredes, Hugo; Kim, Sangtae; Sen, Sabyasachi

    2015-12-28

    A revised empirical relationship between the power law exponent of ac conductivity dispersion and the dimensionality of the ionic conduction pathway is established on the basis of electrical impedance spectroscopic (EIS) measurements on crystalline ionic conductors. These results imply that the "universal" ac conductivity dispersion observed in glassy solids is associated with ionic transport along fractal pathways. EIS measurements on single-alkali glasses indicate that the dimensionality of this pathway D is ∼2.5, while in mixed-alkali glasses, D is lower and goes through a minimum value of ∼2.2 when the concentrations of the two alkalis become equal. D and σ display similar variation with alkali composition, thus suggesting a topological origin of the mixed-alkali effect. PMID:26723583

  11. Interaction and the Online Distance Classroom: Do Instructional Methods Effect the Quality of Interaction?

    ERIC Educational Resources Information Center

    Kanuka, Heather

    2011-01-01

    In this special issue, I bring together two studies to provide a comprehensive overview on diverse and interactive instructional methods aimed to facilitate higher levels of learning. One study explored the effects of group interaction using different instructional strategies focusing on the learning "process" using the Community of Inquiry…

  12. Effects of Ignoring Item Interaction on Item Parameter Estimation and Detection of Interacting Items

    ERIC Educational Resources Information Center

    Chen, Cheng-Te; Wang, Wen-Chung

    2007-01-01

    This study explores the effects of ignoring item interaction on item parameter estimation and the efficiency of using the local dependence index Q[subscript 3] and the SAS NLMIXED procedure to detect item interaction under the three-parameter logistic model and the generalized partial credit model. Through simulations, it was found that ignoring…

  13. Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis

    PubMed Central

    Crosslin, David R.; Shah, Svati H.; Nelson, Sarah C.; Haynes, Carol S.; Connelly, Jessica J.; Gadson, Shera; Goldschmidt-Clermont, Pascal J.; Vance, Jeffery M.; Rose, Jason; Granger, Chris B.; Seo, David; Gregory, Simon G.; Kraus, William E.

    2009-01-01

    Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of human diseases, most particularly asthma. Recently, leukotriene-based inflammation has also been shown to play an important role in atherosclerosis: ALOX5AP and LTA4H, both genes in the leukotriene biosynthesis pathway, have individually been shown to be associated with various cardiovascular disease (CVD) phenotypes. To assess the role of the leukotriene pathway in CVD pathogenesis, we performed genetic association studies of ALOX5AP and LTA4H in a family based study of early onset coronary artery disease (EOCAD) (GENECARD, 1,101 families) and in a non-familial dataset of EOCAD (CATHGEN, 656 cases and 405 controls). We found weak to moderate association between single nucleotide polymorphisms (SNPs) in ALOX5AP and LTA4H with EOCAD. The previously reported four-SNP haplotype (HapA) in ALOX5AP showed association with EOCAD in CATHGEN (P = 0.02), while controlling for age, race and CVD risk factors. HapK, the previously reported ten-SNP haplotype in LTA4H was associated with EOCAD in CATHGEN (P = 0.04). Another previously reported four-SNP haplotype in ALOX5AP (HapB) was not significant in our sample (P = 0.39). The overall lack of (or weak) association of single SNPs as compared with the haplotype results demonstrates the need for analyzing multiple SNPs within each gene in such studies. Interestingly, we detected an association of SNPs in ALOX5 (P < 0.05), the target of ALOX5AP, with CVD. Using a pathway-based approach, we also detected statistical evidence for interactions among ALOX5, ALOX5AP and LTA4H using RNA expression data from a collection of freshly harvested human aortas with varying degrees of atherosclerosis. The GENECARD families did not demonstrate evidence for linkage or association with ALOX5, ALOX5AP or LTA4H. Our results support a modest role for the leukotriene pathway in atherosclerosis pathogenesis, reveal important

  14. Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all.

    PubMed

    Oei, Arlene L; Vriend, Lianne E M; Crezee, Johannes; Franken, Nicolaas A P; Krawczyk, Przemek M

    2015-01-01

    The currently available arsenal of anticancer modalities includes many DNA damaging agents that can kill malignant cells. However, efficient DNA repair mechanisms protect both healthy and cancer cells against the effects of treatment and contribute to the development of drug resistance. Therefore, anti-cancer treatments based on inflicting DNA damage can benefit from inhibition of DNA repair. Hyperthermia - treatment at elevated temperature - considerably affects DNA repair, among other cellular processes, and can thus sensitize (cancer) cells to DNA damaging agents. This effect has been known and clinically applied for many decades, but how heat inhibits DNA repair and which pathways are targeted has not been fully elucidated. In this review we attempt to summarize the known effects of hyperthermia on DNA repair pathways relevant in clinical treatment of cancer. Furthermore, we outline the relationships between the effects of heat on DNA repair and sensitization of cells to various DNA damaging agents. PMID:26245485

  15. Protein-protein interactions in the β-oxidation part of the phenylacetate utilization pathway: crystal structure of the PaaF-PaaG hydratase-isomerase complex.

    PubMed

    Grishin, Andrey M; Ajamian, Eunice; Zhang, Linhua; Rouiller, Isabelle; Bostina, Mihnea; Cygler, Miroslaw

    2012-11-01

    Microbial anaerobic and so-called hybrid pathways for degradation of aromatic compounds contain β-oxidation-like steps. These reactions convert the product of the opening of the aromatic ring to common metabolites. The hybrid phenylacetate degradation pathway is encoded in Escherichia coli by the paa operon containing genes for 10 enzymes. Previously, we have analyzed protein-protein interactions among the enzymes catalyzing the initial oxidation steps in the paa pathway (Grishin, A. M., Ajamian, E., Tao, L., Zhang, L., Menard, R., and Cygler, M. (2011) J. Biol. Chem. 286, 10735-10743). Here we report characterization of interactions between the remaining enzymes of this pathway and show another stable complex, PaaFG, an enoyl-CoA hydratase and enoyl-Coa isomerase, both belonging to the crotonase superfamily. These steps are biochemically similar to the well studied fatty acid β-oxidation, which can be catalyzed by individual monofunctional enzymes, multifunctional enzymes comprising several domains, or enzymatic complexes such as the bacterial fatty acid β-oxidation complex. We have determined the structure of the PaaFG complex and determined that although individually PaaF and PaaG are similar to enzymes from the fatty acid β-oxidation pathway, the structure of the complex is dissimilar from bacterial fatty acid β-oxidation complexes. The PaaFG complex has a four-layered structure composed of homotrimeric discs of PaaF and PaaG. The active sites of PaaF and PaaG are adapted to accept the intermediary components of the Paa pathway, different from those of the fatty acid β-oxidation. The association of PaaF and PaaG into a stable complex might serve to speed up the steps of the pathway following the conversion of phenylacetyl-CoA to a toxic and unstable epoxide-CoA by PaaABCE monooxygenase. PMID:22961985

  16. Nonstandard interaction effects on astrophysical neutrino fluxes

    SciTech Connect

    Blennow, Mattias; Meloni, Davide

    2009-09-15

    We investigate new physics effects in the production and detection of high-energy neutrinos at neutrino telescopes. Analyzing the flavor ratios {phi}{sub {mu}}/{phi}{sub {tau}} and {phi}{sub {mu}}/({phi}{sub {tau}}+{phi}{sub e}), we find that the standard model predictions for them can be sensibly altered by new physics effects in the case of pion sources. However, the experimental precision required to see the effects would be very difficult to obtain.

  17. Interparticle interactions and polarization effects in colloids

    SciTech Connect

    Hayter, J.B.

    1987-01-01

    The physics of simple colloidal systems is usually dominated by three independent length scales: the particle size, the average interparticle distance, and the range of the interparticle potential. The dispersed particles typically have characteristic dimensions in the range 5 to 100 nm, often with spherical or cylindrical symmetry. Dispersion densities vary over volume fractions ranging from 0.5 to 10/sup -4/, with the corresponding mean interparticle distances ranging from about 1 to 10 diameters (in spherical systems). The interaction potential may be very short ranged (hard sphere), very long ranged (Coulomb or dipolar), or anywhere in between (screened Coulomb), and the correlations exhibited in the dispersion may be gas-like, liquid-like or crystalline, depending on the range of the potential relative to the interparticle distance. This rich phase behavior is responsible for the remarkable importance of colloidal studies in many areas of condensed matter physics and biophysics, but it poses often intractable problems in developing the statistical mechanical descriptions necessary for an understanding of scattering data from colloids. This paper will review the considerable recent progress in this field, in the context of SANS experiments on colloids in which the potentials are dominated by either screened Coulomb or magnetic dipolar interactions; in the case of magnetic colloids (ferrofluids), the use of polarization analysis will also be discussed. 32 refs., 4 figs.

  18. Friction Effects in Atom-Surface Interactions

    NASA Astrophysics Data System (ADS)

    Jentschura, Ulrich D.

    2016-05-01

    Atom-surface interactions both have a conservative as well as a dissipative component. A treatment of the dissipative terms requires the use of the fluctuation-dissipation theorem, and the calculation of the imaginary part of the polarizability of an atom is required. The paper will review the recent resolution of a long-standing question regarding the low-frequency asymptotics of the imaginary part, as summarized in and, together with K. Pachucki, G. Lach and M. De Kieviet. The surprising conclusion is that the precise form of the imaginary part for low driving frequency is dominated by a so-called quantum electrodynamic loop correction, where ``correction'' here is not to be taken literally. The one-loop QED term dominates over the tree-level contribution! The findings drastically alter theoretical predictions for non-contact friction, and blackbody friction (due to the atom's interaction with a bath of thermal photons). The basic principle behind the calculation and the methods of nonrelativistic quantum electrodynamics will be discussed. Supported by the NSF (Grant PHY-1403973).

  19. PfIRR Interacts with HrIGF-I and Activates the MAP-kinase and PI3-kinase Signaling Pathways to Regulate Glycogen Metabolism in Pinctada fucata

    PubMed Central

    Shi, Yu; He, Mao-xian

    2016-01-01

    The insulin-induced mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are major intracellular signaling modules and conserved among eukaryotes that are known to regulate diverse cellular processes. However, they have not been investigated in the mollusk species Pinctada fucata. Here, we demonstrate that insulin-related peptide receptor of P. fucata (pfIRR) interacts with human recombinant insulin-like growth factor I (hrIGF-I), and stimulates the MAPK and PI3K signaling pathways in P. fucata oocytes. We also show that inhibition of pfIRR by the inhibitor PQ401 significantly attenuates the basal and hrIGF-I-induced phosphorylation of MAPK and PI3K/Akt at amino acid residues threonine 308 and serine 473. Furthermore, our experiments show that there is cross-talk between the MAPK and PI3K/Akt pathways, in which MAPK kinase positively regulates the PI3K pathway, and PI3K positively regulates the MAPK cascade. Intramuscular injection of hrIGF-I stimulates the PI3K and MAPK pathways to increase the expression of pfirr, protein phosphatase 1, glucokinase, and the phosphorylation of glycogen synthase, decreases the mRNA expression of glycogen synthase kinase-3 beta, decreases glucose levels in hemocytes, and increases glycogen levels in digestive glands. These results suggest that the MAPK and PI3K pathways in P. fucata transmit the hrIGF-I signal to regulate glycogen metabolism. PMID:26911653

  20. Effect Modification and Interaction Terms: It Takes Two to Tango.

    PubMed

    Jupiter, Daniel C

    2016-01-01

    In this Investigators' Corner I look more deeply into the previously discussed phenomenon of effect modification. I revisit an explanation and examples of the phenomenon and then examine how to account for it statistically. Specifically, I show, in detail, how to write a regression equation that includes interaction terms that account for the effect modification. Finally, I look at interpretation of regression coefficients both with and without the presence of effect modification, and the associated interaction terms. PMID:27320193

  1. Effect of the short-range interaction on critical phenomena in elastic interaction systems

    NASA Astrophysics Data System (ADS)

    Nishino, Masamichi; Miyashita, Seiji

    2013-07-01

    The elastic interaction, induced by the lattice distortion due to the difference of the molecular size, causes an effective long-range interaction. In spin-crossover (SC) compounds, local bistable states, i.e., high-spin and low-spin states, have different molecular sizes, and the elastic interaction is important. In bipartite lattices, e.g., the square lattice, the ground state can be two types of phases: ferromagneticlike and antiferromagneticlike phases. In systems like SC compounds, the former phase consists of all small or large molecules, and the latter phase has the configuration of alternating small and large molecules. In fact, both cases are observed in SC systems. In this paper we have studied the effect of the short-range interaction in the elastic system on the properties of those order-disorder phase transitions. We have obtained a phase diagram in the coordinates of the temperature and the strength of the short-range interaction, including the metastable structures. We show that effects of the short-range interaction are essentially different for ferromagneticlike and antiferromagneticlike phase transitions. In the ferromagneticlike transition, the long-range interaction of elasticity is relevant, and the system exhibits a phase transition in the mean-filed universality class. In this case, the long-range interaction strongly enhances the ferromagneticlike order, and it works cooperatively with the short-range interaction. In contrast, in the antiferromagneticlike transition, the elastic interaction slightly enhances the antiferromagneticlike order, but essentially it does not contribute to the ordering, and the system shows a transition in the Ising universality class. We have found that in the border region between ferromagneticlike and antiferromagneticlike phases, the antiferromagneticlike phase has an advantage at finite temperatures. We discuss the critical properties of two-step SC transitions with comparison between the elastic interaction

  2. Possibilities for reducing the aftercavity interaction effect in gyrotrons

    SciTech Connect

    Sinitsyn, O. V.; Nusinovich, G. S.; Antonsen, T. M. Jr.

    2010-08-15

    This paper addresses the problem of aftercavity interaction in gyrotrons. The term ''aftercavity interaction'' is used for the cyclotron resonance interaction between electrons in a spent beam exiting the microwave cavity and traveling electromagnetic waves propagating from the cavity exit into the output part of a gyrotron. Aftercavity interaction may reduce the interaction efficiency by several percent and spoil the energy distribution of spent electrons, thus reducing the possibility of efficient utilization of depressed collectors. We have used a simple theory to find conditions resulting in the reduction of this effect. In particular, we have shown that both the axial waveguide wall profile and magnetic field distribution should be modified in order to weaken the effect of aftercavity interaction. We verified results of our simple analysis with advanced simulations and demonstrated that they are in good agreement. Result of these studies can be beneficial for the gyrotron efficiency enhancement.

  3. Investigation of adverse effects of interactions between herbal drugs and natural blood clotting mechanism.

    PubMed

    Adhyapak, M S; Kachole, M S

    2016-05-01

    Throughout the world, herbal medicines are consumed by most of the patients without considering their adverse effects. Many herbal medicines/plant extracts have been reported to interact with the natural blood clotting system. In continuation to this effort, thirty medicinal plant extracts were allowed to interact with citrated human blood and the clotting time was measured after re-calcification in vitro using Lee and White method. The aq. leaf ext. of Syzygium cumini and Camellia sinensis significantly prolonged the clotting time. In response to the prothrombin time and activated partial thromboplastin time tests, the ext. of C. sinensis showed normal APTT and marginally prolonged the PT to 16.7 s (control-15.2 s) while S. cumini showed normal PT but significantly prolonged the APTT to 66.9 s (control-20.7 s). This suggests that, C. sinensis acts on the extrinsic pathway while S. cumini on the intrinsic pathway. There are some common herbal formulations that are frequently used by the patients which contain above plant materials, like, Syzygium cumin in anti-diabetic formulations, while the ext. of C. sinensis is consumed frequently as beverage in many part of the world. Hence, patients having known bleeding tendency or haemophilia disease should take into account the interaction potential of these plants with the natural blood clotting system while taking herbal formulations containing above plants; specially, the patients suffering from intrinsic pathway factor deficiency should keep a limit on the consumption of S. cumini while extrinsic pathway factor deficiency patients should limit C. sinensis. Also, the medical practitioners should consider the patient's food consumption history before doing any major surgical procedures. PMID:26340850

  4. Role of hippocampal and prefrontal cortical signaling pathways in dextromethorphan effect on morphine-induced memory impairment in rats.

    PubMed

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2016-02-01

    Evidence suggests that dextromethorphan (DM), an NMDA receptor antagonist, induces memory impairment. Considering that DM is widely used in cough-treating medications, and the co-abuse of DM with morphine has recently been reported, the aims of the present study was (1) to investigate whether there is a functional interaction between morphine and DM in passive avoidance learning and (2) to assess the possible role of the hippocampal and prefrontal cortical (PFC) signaling pathways in the effects of the drugs on memory formation. Our findings indicated that post-training or pre-test administration of morphine (2 and 6 mg/kg) or DM (10-30 mg/kg) impaired memory consolidation and retrieval which was associated with the attenuation of the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (p-CAMKII) and cAMP responsive element-binding protein (p-CREB) in the targeted sites. Moreover, the memory impairment induced by post-training administration of morphine was reversed by pre-test administration of the same dose of morphine or DM (30 mg/kg), indicating state-dependent learning (SDL) and a cross-SDL between the drugs. It is important to note that the levels of p-CAMKII/CAMKII and p-CREB/CREB in the hippocampus and the PFC increased in drugs-induced SDL. In addition, DM administration potentiated morphine-induced SDL which was related to the enhanced levels of hippocampal and PFC CAMKII-CREB signaling pathways. It can be concluded that there is a relationship between the hippocampus and the PFC in the effect of DM and/or morphine on memory retrieval. Moreover, a cross SDL can be induced between the co-administration of DM and morphine. Interestingly, CAMKII-CREB signaling pathways also mediate the drugs-induced SDL. PMID:26708494

  5. Novel QCD Effects from Initial and Final State Interactions

    SciTech Connect

    Brodsky, Stanley J.

    2007-09-12

    Initial-state and final-state interactions which are conventionally neglected in the parton model, have a profound effect in QCD hard-scattering reactions. The effects, which arise from gluon exchange between the active and spectator quarks, cause leading-twist single-spin asymmetries, diffractive deep inelastic scattering, diffractive hard hadronic reactions, and the breakdown of the Lam-Tung relation in Drell-Yan reactions. Diffractive deep inelastic scattering also leads to nuclear shadowing and non-universal antishadowing of nuclear structure functions through multiple scattering reactions in the nuclear target. Factorization-breaking effects are particularly important for hard hadron interactions since both initial-state and final-state interactions appear. Related factorization breaking effects can also appear in exclusive electroproduction reactions and in deeply virtual Compton scattering. None of the effects of initial-state and final-state interactions are incorporated in the light-front wavefunctions of the target hadron computed in isolation.

  6. Effects of Peer Tutoring on Young Children's Social Interactions

    ERIC Educational Resources Information Center

    Xu, Yaoying; Gelfer, Jeffrey I.; Sileo, Nancy; Filler, John; Perkins, Peggy G.

    2008-01-01

    This study examined the effects of peer tutoring on children's social interactions and compared social interaction behaviors between children who are English-language learners (ELL) and children who are primary English speakers (PES). Single-subject withdrawal design (ABA) was applied in this study and classwide peer tutoring was used as the…

  7. Effectiveness of Interactive Video to Teach CPR Theory and Skills.

    ERIC Educational Resources Information Center

    Lyness, Ann L.

    This study investigated whether an interactive video system of instruction taught cardiopulmonary resuscitation (CPR) as effectively as traditional instruction. Using standards of the American Heart Association, the study was designed with two randomized groups to be taught either by live instruction or by interactive video. Subjects were 100…

  8. Dietary glycine and threonine interactive effects in broilers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There is little information regarding the interaction of dietary threonine and glycine on potential metabolic sparing effects, live production, or breast meat yield of broilers. To test these potential interactions, 432 one-day-old Ross 308 male broilers were fed a common diet up to 21 days of age a...

  9. Interactive TV: An Effective Instructional Mode for Adult Learners

    ERIC Educational Resources Information Center

    Chen, Li-Ling; Iris, Carole

    2004-01-01

    The inclusion of interactive television (iTV) programs for learning is an emerging genre in education. Literature has concluded that any aspect of learning requires some form of interaction or feedback to be most effective. As television (TV) evolves from being a passive to an active medium, it has the potential to engage learners and reach a mass…

  10. Multilocus analyses of seven candidate genes suggest interacting pathways for obesity-related traits in Brazilian populations.

    PubMed

    Angeli, Cláudia B; Kimura, Lilian; Auricchio, Maria T; Vicente, João P; Mattevi, Vanessa S; Zembrzuski, Verônica M; Hutz, Mara H; Pereira, Alexandre C; Pereira, Tiago V; Mingroni-Netto, Regina C

    2011-06-01

    We investigated whether variants in major candidate genes for food intake and body weight regulation contribute to obesity-related traits under a multilocus perspective. We studied 375 Brazilian subjects from partially isolated African-derived populations (quilombos). Seven variants displaying conflicting results in previous reports and supposedly implicated in the susceptibility of obesity-related phenotypes were investigated: β2-adrenergic receptor (ADRB2) (Arg16Gly), insulin induced gene 2 (INSIG2) (rs7566605), leptin (LEP) (A19G), LEP receptor (LEPR) (Gln223Arg), perilipin (PLIN) (6209T > C), peroxisome proliferator-activated receptor-γ (PPARG) (Pro12Ala), and resistin (RETN) (-420 C > G). Regression models as well as generalized multifactor dimensionality reduction (GMDR) were employed to test the contribution of individual effects and higher-order interactions to BMI and waist-hip ratio (WHR) variation and risk of overweight/obesity. The best multilocus association signal identified in the quilombos was further examined in an independent sample of 334 Brazilian subjects of European ancestry. In quilombos, only the PPARG polymorphism displayed significant individual effects (WHR variation, P = 0.028). No association was observed either with the risk of overweight/obesity (BMI ≥ 25 kg/m2), risk of obesity alone (BMI ≥ 30 kg/m2) or BMI variation. However, GMDR analyses revealed an interaction between the LEPR and ADRB2 polymorphisms (P = 0.009) as well as a third-order effect involving the latter two variants plus INSIG2 (P = 0.034) with overweight/obesity. Assessment of the LEPR-ADRB2 interaction in the second sample indicated a marginally significant association (P = 0.0724), which was further verified to be limited to men (P = 0.0118). Together, our findings suggest evidence for a two-locus interaction between the LEPR Gln223Arg and ADRB2 Arg16Gly variants in the risk of overweight/obesity, and highlight further the importance of multilocus effects in

  11. Regulation of CDKN2B expression by interaction of Arnt with Miz-1 - a basis for functional integration between the HIF and Myc gene regulatory pathways

    PubMed Central

    2014-01-01

    Background Hypoxia- and Myc-dependent transcriptional regulatory pathways are frequently deregulated in cancer cells. These pathways converge in many cellular responses, but the underlying molecular mechanisms are unclear. Methods The ability of Miz-1 and Arnt to interact was identified in a yeast two-hybrid screen. The mode of interaction and the functional consequences of complex formation were analyzed by diverse molecular biology methods, in vitro. Statistical analyses were performed by Student’s t-test and ANOVA. Results In the present study we demonstrate that the aryl hydrocarbon receptor nuclear translocator (Arnt), which is central in hypoxia-induced signaling, forms a complex with Miz-1, an important transcriptional regulator in Myc-mediated transcriptional repression. Overexpression of Arnt induced reporter gene activity driven by the proximal promoter of the cyclin-dependent kinase inhibitor 2B gene (CDKN2B), which is an established target for the Myc/Miz-1 complex. In contrast, mutated forms of Arnt, that were unable to interact with Miz-1, had reduced capability to activate transcription. Moreover, repression of Arnt reduced endogenous CDKN2B expression, and chromatin immunoprecipitation demonstrated that Arnt interacts with the CDKN2B promoter. The transcriptional activity of Arnt was counteracted by Myc, but not by a mutated variant of Myc that is unable to interact with Miz-1, suggesting mutually exclusive interaction of Arnt and Myc with Miz-1. Our results also establish CDKN2B as a hypoxia regulated gene, as endogenous CDKN2B mRNA and protein levels were reduced by hypoxic treatment of U2OS cells. Conclusions Our data reveal a novel mode of regulation by protein-protein interaction that directly ties together, at the transcriptional level, the Myc- and hypoxia-dependent signaling pathways and expands our understanding of the roles of hypoxia and cell cycle alterations during tumorigenesis. PMID:24618291

  12. The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL*

    PubMed Central

    Miles, Jennifer A.; Frost, Mark G.; Carroll, Eilis; Rowe, Michelle L.; Howard, Mark J.; Sidhu, Ateesh; Chaugule, Viduth K.; Alpi, Arno F.; Walden, Helen

    2015-01-01

    The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown. We report here that the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The interaction involves the canonical Ile44 patch on ubiquitin, and a functionally conserved patch on FANCL. We show that the interaction is not necessary for the recognition of the core complex, it does not enhance the interaction between FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro. However, we demonstrate that the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo. PMID:26149689

  13. The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.

    PubMed

    Miles, Jennifer A; Frost, Mark G; Carroll, Eilis; Rowe, Michelle L; Howard, Mark J; Sidhu, Ateesh; Chaugule, Viduth K; Alpi, Arno F; Walden, Helen

    2015-08-21

    The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown. We report here that the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The interaction involves the canonical Ile44 patch on ubiquitin, and a functionally conserved patch on FANCL. We show that the interaction is not necessary for the recognition of the core complex, it does not enhance the interaction between FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro. However, we demonstrate that the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo. PMID:26149689

  14. HSD3B and Gene-Gene Interactions in a Pathway-Based Analysis of Genetic Susceptibility to Bladder Cancer

    PubMed Central

    Andrew, Angeline S.; Hu, Ting; Gu, Jian; Gui, Jiang; Ye, Yuanqing; Marsit, Carmen J.; Kelsey, Karl T.; Schned, Alan R.; Tanyos, Sam A.; Pendleton, Eben M.; Mason, Rebecca A.; Morlock, Elaine V.; Zens, Michael S.; Li, Zhongze; Moore, Jason H.; Wu, Xifeng; Karagas, Margaret R.

    2012-01-01

    Bladder cancer is the 4th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case–control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene–gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3′UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31–2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06–12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40–3.25) than females (OR 1.56 95%CI 0.83–2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3–4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis. PMID:23284679

  15. The effects of teacher fidelity of implementation of pathways to health on student outcomes.

    PubMed

    Little, Melissa A; Riggs, Nathaniel R; Shin, Hee-Sung; Tate, Eleanor B; Pentz, Mary Ann

    2015-03-01

    Previous research has demonstrated the importance of ensuring that programs are implemented as intended by program developers in order to achieve desired program effects. The current study examined implementation fidelity of Pathways to Health (Pathways), a newly developed obesity prevention program for fourth- through sixth-grade children. We explored the associations between self-reported and observed implementation fidelity scores and whether implementation fidelity differed across the first 2 years of program implementation. Additionally, we examined whether implementation fidelity affected program outcomes and whether teacher beliefs were associated with implementation fidelity. The program was better received, and implementation fidelity had more effects on program outcomes in fifth grade than in fourth grade. Findings suggest that implementation in school-based obesity programs may affect junk food intake and intentions to eat healthfully and exercise. School support was associated with implementation fidelity, suggesting that prevention programs may benefit from including a component that boosts school-wide support. PMID:23739725

  16. The effect of diet interventions on hypothalamic nutrient sensing pathways in rodents.

    PubMed

    Rijnsburger, Merel; Belegri, Evita; Eggels, Leslie; Unmehopa, Unga A; Boelen, Anita; Serlie, Mireille J; la Fleur, Susanne E

    2016-08-01

    The hypothalamus plays a fundamental role in regulating homeostatic processes including regulation of food intake. Food intake is driven in part by energy balance, which is sensed by specific brain structures through signaling molecules such as nutrients and hormones. Both circulating glucose and fatty acids decrease food intake via a central mechanism involving the hypothalamus and brain stem. Besides playing a role in signaling energy status, glucose and fatty acids serve as fuel for neurons. This review focuses on the effects of glucose and fatty acids on hypothalamic pathways involved in regulation of energy metabolism as well as on the role of the family of peroxisome proliferator activated receptors (PPARs) which are implicated in regulation of central energy homeostasis. We further discuss the effects of different hypercaloric diets on these pathways. PMID:27083123

  17. INTERACTION BETWEEN METHYL MERCURY AND RADIATION EFFECTS ON NERVOUS SYSTEMS

    EPA Science Inventory

    The interaction between methyl mercury and ionizing radiation was investigated in a series of experiments using rats, hamsters, and squirrel monkeys to study the effects produced and possible mechanisms of action. Parameters evaluated included several measurements of behavior, br...

  18. Effective Interaction: Communicating with and about People with Disabilities

    MedlinePlus

    ... with Disabilities in the Workplace ODEP - Office of Disability Employment Policy Disability Employment Policy Resources by Topic Choose a Disability ... Effective Interaction: Communicating With and About People with Disabilities in the Workplace As children, we are curious — ...

  19. Bag of Marbles controls the size and organization of the Drosophila hematopoietic niche through interactions with the Insulin-like growth factor pathway and Retinoblastoma-family protein.

    PubMed

    Tokusumi, Tsuyoshi; Tokusumi, Yumiko; Hopkins, Dawn W; Schulz, Robert A

    2015-07-01

    Bag of Marbles (Bam) is known to function as a positive regulator of hematopoietic progenitor maintenance in the lymph gland blood cell-forming organ during Drosophila hematopoiesis. Here, we demonstrate a key function for Bam in cells of the lymph gland posterior signaling center (PSC), a cellular domain proven to function as a hematopoietic niche. Bam is expressed in PSC cells, and gene loss-of-function results in PSC overgrowth and disorganization, indicating that Bam plays a crucial role in controlling the proper development of the niche. It was previously shown that Insulin receptor (InR) pathway signaling is essential for proper PSC cell proliferation. We analyzed PSC cell number in lymph glands double-mutant for bam and InR pathway genes, and observed that bam genetically interacts with pathway members in the formation of a normal PSC. The elF4A protein is a translation factor downstream of InR pathway signaling, and functional knockdown of this crucial regulator rescued the bam PSC overgrowth phenotype, further supporting the cooperative function of Bam with InR pathway members. Additionally, we documented that the Retinoblastoma-family protein (Rbf), a proven regulator of cell proliferation, was present in cells of the PSC, with a bam function-dependent expression. By contrast, perturbation of Decapentaplegic or Wingless signaling failed to affect Rbf niche cell expression. Together, these findings indicate that InR pathway-Bam-Rbf functional interactions represent a newly identified means to regulate the correct size and organization of the PSC hematopoietic niche. PMID:26041767

  20. Effect of particle interactions on thermoremanent magnetization

    NASA Astrophysics Data System (ADS)

    Newell, A. J.; Niemerg, M.; Bates, D.

    2013-12-01

    Paleomagnetism has a dizzying array of protocols for determining the strength of the Earth's magnetic field in the past from measurements of the magnetic memory in rocks. Some, such as variants of the Thellier-Thellier method, try to isolate the signal from an "ideal" fraction of magnetic minerals, discarding the contribution of "non-ideal" minerals; others, like the multi-specimen method, try to glean useful information from all of the minerals. The "ideal" remanence carriers behave like single-domain (SD) magnets with uniaxial anisotropy, and their behavior is predicted by Louis Néel's theory of thermoremanent magnetization (TRM). Non-ideal carriers are not at all well understood, but every paleointensity method relies on assumptions about their nature to either remove their signal or make use of it. One way to explore the boundary between ideal and non-ideal is to look at the behavior of SD magnets as they are brought increasingly close together, thus increasing the strength of the magnetostatic coupling between them. Magnetostatic coupling greatly increases the complexity of such a system. Instead of just two stable states, many must be found. Instead of one energy barrier, there is a network of connections between stable states over energy barriers. Instead of one rate for the relaxation of a system towards equilibrium, there are several. It is particularly difficult to find the transition states at the top of the energy barriers. We have developed software that does all of the above. A method from algebraic geometry called homotopy continuation is used to find all stable states and transition states. The software can track changes in these states with magnetic field, temperature, or other external variables. We use it to model TRM acquisition in small systems of interacting particles, and examine its behavior under various paleointensity tests.

  1. Aerosol-cloud interactions: effect on precipitation

    NASA Astrophysics Data System (ADS)

    Takle, Jasmine; Maheskumar, R.

    2016-05-01

    Aerosols are tiny suspended particle in the atmosphere with high variability in time and space, play a major role in modulating the cloud properties and thereby precipitation. To understand the aerosol induced Invigoration effect predictors like aerosol optical depth, cloud optical depth, cloud top temperature, cloud effective radii, ice water path, retrieved from the Moderate resolution Imaging Spectroradiometer (MODIS) level-3 aqua satellite data were analysed for pre monsoon April-May and post monsoon October-November months over the Indian subcontinent 8 ° N to 33° N, 65 °E to 100 °E during the period 2003-2013. Apart from the above data, mesoscale dynamical parameters such as vertical wind shear of horizontal wind, relative humidity, were also considered to understand their role in invigoration. Case studies have been carried out for the regions having heavy rainfall events & minimal rainfall events during high Aerosol optical depths occasions respectively. Analysis revealed that the heavy rainfall which occurred in this region with higher optical depths might be due to invigoration effect of aerosols wherein the dynamical as well as thermodynamical parameters were also found favourable. Minimal rainfall events were also observed most probably due to the suppression of rain formation/delay in precipitation due to high amount of aerosol concentration in these regions. Prominent 36 such cases were studied all over India during Pre & Post monsoon months.

  2. Effects of Website Interactivity on Online Retail Shopping Behavior

    NASA Astrophysics Data System (ADS)

    Islam, Hafizul

    Motivations to engage in retail online shopping can include both utilitarian and hedonic shopping dimensions. To cater to these consumers, online retailers can create a cognitively and esthetically rich shopping environment, through sophisticated levels of interactive web utilities and features, offering not only utilitarian benefits and attributes but also providing hedonic benefits of enjoyment. Since the effect of interactive websites has proven to stimulate online consumer’s perceptions, this study presumes that websites with multimedia rich interactive utilities and features can influence online consumers’ shopping motivations and entice them to modify or even transform their original shopping predispositions by providing them with attractive and enhanced interactive features and controls, thus generating a positive attitude towards products and services offered by the retailer. This study seeks to explore the effects of Web interactivity on online consumer behavior through an attitudinal model of technology acceptance.

  3. LncRNA MT1JP functions as a tumor suppressor by interacting with TIAR to modulate the p53 pathway

    PubMed Central

    Li, Jing; Wei, Guifeng; Chen, Xiaomin; Lu, Youyong; Guo, Mingzhou; Luo, Jianjun; Chen, Runsheng

    2016-01-01

    Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play important roles in transcriptional regulation, whereas the extent to which the lncRNAs also function at the posttranscriptional level is less known. In the present study, we report a lncRNA named MT1JP which acts as a tumor suppressor through a posttranscriptional mechanism. We found that MT1JP is differentially expressed in tumor tissues by analyzing data from a customized microarray applied to 76 pairs of matched normal and cancer tissue samples. By associating with the RNA-binding protein TIAR, MT1JP enhanced the translation of the master transcription factor p53, thereby regulating a series of pathways involving p53, such as the cell cycle, apoptosis and proliferation. When MT1JP was down-regulated, the protein level of p53 declined, which in turn accelerated cell deterioration and tumor formation. Moreover, differential expression of MT1JP in cancerous and normal tissues suggests that it may be a promising prognostic marker and a therapeutic target. Taken together, we identified MT1JP as a critical factor in restraining cell transformation by modulating p53 translation through interactions with TIAR, and this finding is likely to shed new light on future investigations about posttranscriptional or translational effects of lncRNAs during cell transformation. PMID:26909858

  4. Crystal Structure of Vancosaminyltransferase GtfD from the Vancomycin Biosynthetic Pathway: Interactions with Acceptor and Nucleotide Ligands

    SciTech Connect

    Mulichak, A.M.; Lu, W.; Losey, H.C.; Walsh, C.T.; Garavito, R.M.

    2010-03-08

    The TDP-vancosaminyltransferase GtfD catalyzes the attachment of L-vancosamine to a monoglucosylated heptapeptide intermediate during the final stage of vancomycin biosynthesis. Glycosyltransferases from this and similar antibiotic pathways are potential tools for the design of new compounds that are effective against vancomycin resistant bacterial strains. We have determined the X-ray crystal structure of GtfD as a complex with TDP and the natural glycopeptide substrate at 2.0 {angstrom} resolution. GtfD, a member of the bidomain GT-B glycosyltransferase superfamily, binds TDP in the interdomain cleft, while the aglycone acceptor binds in a deep crevice in the N-terminal domain. However, the two domains are more interdependent in terms of substrate binding and overall structure than was evident in the structures of closely related glycosyltransferases GtfA and GtfB. Structural and kinetic analyses support the identification of Asp13 as a catalytic general base, with a possible secondary role for Thr10. Several residues have also been identified as being involved in donor sugar binding and recognition.

  5. Effects of estradiol and genistein on the insulin signaling pathway in the cerebral cortex of aged female rats.

    PubMed

    Morán, Javier; Garrido, Pablo; Cabello, Estefanía; Alonso, Ana; González, Celestino

    2014-10-01

    Menopause leads to a decrease in estrogen production that increases central insulin resistance, contributing to the development of neurodegenerative diseases. We have evaluated the influence of aging and estradiol or genistein treatments on some key stages of the insulin signaling pathway in the cerebral cortex. Young and aged female Wistar rats were ovariectomized and treated acutely with 17β-estradiol (1.4μg/kg body weight), two doses of genistein (10 or 40mg/kg body weight), or vehicle. The cortical expression of several key insulin signaling pathway components was analyzed by western blotting. Our results showed an age-related deterioration in the interactions between the regulatory subunit of phosphatidylinositol 3-kinase (p85α) and the activated form of insulin receptor substrate 1 (p-IRS1tyr612), as well as between p85α and the 46kDa isoform of the estrogen receptor α (ERα46). Moreover, aging also decreased the translocation of glucose transporter-4 (GLUT4) to the plasma membrane. 17β-Estradiol but not genistein reduced the negative impact of aging on central insulin sensitivity by favoring this GLUT4 translocation, and therefore could be neuroprotective against the associated neurodegenerative diseases. However, protein kinase B (Akt) activation by genistein suggests that other possible mechanisms are involved in the neuroprotective effects of this phytoestrogen during the aging process. PMID:25086228

  6. A cyclopalladated complex interacts with mitochondrial membrane thiol-groups and induces the apoptotic intrinsic pathway in murine and cisplatin-resistant human tumor cells

    PubMed Central

    2011-01-01

    Background Systemic therapy for cancer metastatic lesions is difficult and generally renders a poor clinical response. Structural analogs of cisplatin, the most widely used synthetic metal complexes, show toxic side-effects and tumor cell resistance. Recently, palladium complexes with increased stability are being investigated to circumvent these limitations, and a biphosphinic cyclopalladated complex {Pd2 [S(-)C2, N-dmpa]2 (μ-dppe)Cl2} named C7a efficiently controls the subcutaneous development of B16F10-Nex2 murine melanoma in syngeneic mice. Presently, we investigated the melanoma cell killing mechanism induced by C7a, and extended preclinical studies. Methods B16F10-Nex2 cells were treated in vitro with C7a in the presence/absence of DTT, and several parameters related to apoptosis induction were evaluated. Preclinical studies were performed, and mice were endovenously inoculated with B16F10-Nex2 cells, intraperitoneally treated with C7a, and lung metastatic nodules were counted. The cytotoxic effects and the respiratory metabolism were also determined in human tumor cell lines treated in vitro with C7a. Results Cyclopalladated complex interacts with thiol groups on the mitochondrial membrane proteins, causes dissipation of the mitochondrial membrane potential, and induces Bax translocation from the cytosol to mitochondria, colocalizing with a mitochondrial tracker. C7a also induced an increase in cytosolic calcium concentration, mainly from intracellular compartments, and a significant decrease in the ATP levels. Activation of effector caspases, chromatin condensation and DNA degradation, suggested that C7a activates the apoptotic intrinsic pathway in murine melanoma cells. In the preclinical studies, the C7a complex protected against murine metastatic melanoma and induced death in several human tumor cell lineages in vitro, including cisplatin-resistant ones. The mitochondria-dependent cell death was also induced by C7a in human tumor cells. Conclusions The

  7. [Non-steroidal antirheumatics: side-effects and interactions].

    PubMed

    Felder, M

    1982-08-28

    Side effects of non-steroidal antirheumatic drugs (NSAD) may occur in any organ system, since the prostaglandins, the synthesis of which is inhibited by NSAD, play a role in numerous adverse cellular processes throughout the body. Besides these physiologic regulations there are adverse effects of NSAD, such as bone marrow aplasia, of unexplained etiology. The interactions of NSAD are of clinical relevance in drug types such as the salicylates, pyrazolons and fenamic acids (e.g. interactions with cumarin derivatives). The clinically relevant interactions of NSAD are discussed in detail. PMID:6982512

  8. Condition-specific genetic interaction maps reveal crosstalk between the cAMP/PKA and the HOG MAPK pathways in the activation of the general stress response

    PubMed Central

    Gutin, Jenia; Sadeh, Amit; Rahat, Ayelet; Aharoni, Amir; Friedman, Nir

    2015-01-01

    Cells must quickly respond and efficiently adapt to environmental changes. The yeast Saccharomyces cerevisiae has multiple pathways that respond to specific environmental insults, as well as a generic stress response program. The later is regulated by two transcription factors, Msn2 and Msn4, that integrate information from upstream pathways to produce fast, tunable, and robust response to different environmental changes. To understand this integration, we employed a systematic approach to genetically dissect the contribution of various cellular pathways to Msn2/4 regulation under a range of stress and growth conditions. We established a high-throughput liquid handling and automated flow cytometry system and measured GFP levels in 68 single-knockout and 1,566 double-knockout strains that carry an HSP12-GFP allele as a reporter for Msn2/4 activity. Based on the expression of this Msn2/4 reporter in five different conditions, we identified numerous genetic and epistatic interactions between different components in the network upstream to Msn2/4. Our analysis gains new insights into the functional specialization of the RAS paralogs in the repression of stress response and identifies a three-way crosstalk between the Mediator complex, the HOG MAPK pathway, and the cAMP/PKA pathway. PMID:26446933

  9. Condition-specific genetic interaction maps reveal crosstalk between the cAMP/PKA and the HOG MAPK pathways in the activation of the general stress response.

    PubMed

    Gutin, Jenia; Sadeh, Amit; Rahat, Ayelet; Aharoni, Amir; Friedman, Nir

    2015-10-01

    Cells must quickly respond and efficiently adapt to environmental changes. The yeast Saccharomyces cerevisiae has multiple pathways that respond to specific environmental insults, as well as a generic stress response program. The later is regulated by two transcription factors, Msn2 and Msn4, that integrate information from upstream pathways to produce fast, tunable, and robust response to different environmental changes. To understand this integration, we employed a systematic approach to genetically dissect the contribution of various cellular pathways to Msn2/4 regulation under a range of stress and growth conditions. We established a high-throughput liquid handling and automated flow cytometry system and measured GFP levels in 68 single-knockout and 1,566 double-knockout strains that carry an HSP12-GFP allele as a reporter for Msn2/4 activity. Based on the expression of this Msn2/4 reporter in five different conditions, we identified numerous genetic and epistatic interactions between different components in the network upstream to Msn2/4. Our analysis gains new insights into the functional specialization of the RAS paralogs in the repression of stress response and identifies a three-way crosstalk between the Mediator complex, the HOG MAPK pathway, and the cAMP/PKA pathway. PMID:26446933

  10. Clinical Care Pathways for Patients With Hepatitis C: Reducing Critical Barriers to Effective Treatment

    PubMed Central

    Howes, Nik; Lattimore, Sam; Irving, William Lucien; Thomson, Brian James

    2016-01-01

    Background. Engagement of individuals infected with hepatitis C virus (HCV) with care pathways remains a major barrier to realizing the benefits of new and more effective antiviral therapies. After an exploratory study, we have undertaken an evidence-based redesign of care pathways for HCV, including the following: (1) reflex testing of anti-HCV-positive samples for HCV RNA; (2) annotation of laboratory results to recommend referral of actively infected patients to specialist clinics; (3) educational programs for primary care physicians and nurses; and (4) the establishment of needs-driven community clinics in substance misuse services. Methods. In this study, we conducted a retrospective cohort study of progression through care pathways of individuals with a new diagnosis of HCV infection made between January 2010 and January 2012. We also analyzed patient flow through new care pathways and compared this with our baseline study of identical design. Results. A total of 28 980 samples were tested for anti-HCV antibody during the study period and yielded 273 unique patients with a new diagnosis of HCV infection. Of these, 38% were tested in general practice, 21% were tested in substance misuse services, 23% were tested in secondary care, and 18% were tested in local prisons. Overall, 80% of patients were referred to specialist clinics, 70% attended for assessment, and 38% commenced treatment, in comparison to 49%, 27%, and 10%, respectively, in the baseline study. Referral rates from all testing sources improved. Conclusions. This study provides timely evidence that progression through care pathways can be enhanced, and it demonstrates reduction of key barriers to eradication of HCV. PMID:26900576

  11. Land cover effects on infiltration and preferential flow pathways in the high rainfall zone of Madagascar

    NASA Astrophysics Data System (ADS)

    Zwartendijk, Bob; van Meerveld, Ilja; Ravelona, Maafaka; Razakamanarivo, Herintsitohaina; Ghimire, Chandra; Bruijnzeel, Sampurno; Jones, Julia

    2015-04-01

    Shortened slash-and-burn cycles exhaust agricultural land and have resulted in extensive tracts of highly degraded land across the tropics. Land degradation typically results in decreased rainfall infiltration due to a reduced field-saturated hydraulic conductivity of the topsoil because of a progressive decline in soil organic matter, exposure to raindrop impact, surface sealing and compaction. This results, in turn, in enhanced surface runoff and erosion, and consequently less subsurface flow and groundwater recharge. On the other hand, natural vegetation regrowth or active reforestation can lead to a renewed accumulation of soil organic matter, macropore development and increased infiltration rates. As part of the P4GES project (Can Paying 4 Global Ecosystem Services values reduce poverty?; www.p4ges.org), we study the effects of land use change and reforestation on water resources in the Corridor Ankeniheny-Zahamena (CAZ) in eastern Madagascar. In this poster, we present the results of infiltration and preferential flow measurements in four different land uses in the southern part of the CAZ: (i) closed canopy forest, (ii) 3-14 year-old regrowth on fallow land (savokas), (iii) exhausted and severely degraded land (tany maty), and (iv) recently reforested sites (6-8 years old). The results show that infiltrability increases significantly after several years of forest regrowth after land abandonment, but it remains unclear whether active replanting decreases the time required for restoration of soil hydrological functioning. Preferential flow pathways differed strikingly between the respective land cover types: infiltration in mature forests was predominantly characterized by macropore flow (preferential flow pathways), whereas infiltration in exhausted agricultural land was dominated by matrix flow (few preferential flow pathways). Occurrence of preferential flow pathways in reforestation and fallow sites varied considerably. These results suggest that land

  12. Clinical Care Pathways for Patients With Hepatitis C: Reducing Critical Barriers to Effective Treatment.

    PubMed

    Howes, Nik; Lattimore, Sam; Irving, William Lucien; Thomson, Brian James

    2016-01-01

    Background.  Engagement of individuals infected with hepatitis C virus (HCV) with care pathways remains a major barrier to realizing the benefits of new and more effective antiviral therapies. After an exploratory study, we have undertaken an evidence-based redesign of care pathways for HCV, including the following: (1) reflex testing of anti-HCV-positive samples for HCV RNA; (2) annotation of laboratory results to recommend referral of actively infected patients to specialist clinics; (3) educational programs for primary care physicians and nurses; and (4) the establishment of needs-driven community clinics in substance misuse services. Methods.  In this study, we conducted a retrospective cohort study of progression through care pathways of individuals with a new diagnosis of HCV infection made between January 2010 and January 2012. We also analyzed patient flow through new care pathways and compared this with our baseline study of identical design. Results.  A total of 28 980 samples were tested for anti-HCV antibody during the study period and yielded 273 unique patients with a new diagnosis of HCV infection. Of these, 38% were tested in general practice, 21% were tested in substance misuse services, 23% were tested in secondary care, and 18% were tested in local prisons. Overall, 80% of patients were referred to specialist clinics, 70% attended for assessment, and 38% commenced treatment, in comparison to 49%, 27%, and 10%, respectively, in the baseline study. Referral rates from all testing sources improved. Conclusions.  This study provides timely evidence that progression through care pathways can be enhanced, and it demonstrates reduction of key barriers to eradication of HCV. PMID:26900576

  13. Nematode endogenous small RNA pathways

    PubMed Central

    Hoogstrate, Suzanne W; Volkers, Rita JM; Sterken, Mark G; Kammenga, Jan E; Snoek, L Basten

    2014-01-01

    The discovery of small RNA silencing pathways has greatly extended our knowledge of gene regulation. Small RNAs have been presumed to play a role in every field of biology because they affect many biological processes via regulation of gene expression and chromatin remodeling. Most well-known examples of affected processes are development, fertility, and maintenance of genome stability. Here we review the role of the three main endogenous small RNA silencing pathways in Caenorhabditis elegans: microRNAs, endogenous small interfering RNAs, and PIWI-interacting RNAs. After providing an entry-level overview on how these pathways function, we discuss research on other nematode species providing insight into the evolution of these small RNA pathways. In understanding the differences between the endogenous small RNA pathways and their evolution, a more comprehensive picture is formed of the functions and effects of small RNAs. PMID:25340013

  14. Upregulation of extrinsic apoptotic pathway in curcumin-mediated antiproliferative effect on human pancreatic carcinogenesis.

    PubMed

    Youns, Mahmoud; Fathy, Gihan Mahmoud

    2013-12-01

    Pancreatic cancer is one of the most lethal human cancers, with almost identical incidence and mortality rates. Curcumin, derived from the rhizome of Curcuma longa, has a long history of use as coloring agent and for a wide variety of disorders. Here, the antiproliferative activity of curcumin and its modulatory effect on gene expression of pancreatic cancer cell lines were investigated. The effect of curcumin on cellular proliferation and viability was monitored by sulphurhodamine B assay. Apoptotic effect was evaluated by flow cytometry and further confirmed by measuring amount of cytoplasmic histone-associated DNA fragments. Analysis of gene expression was performed with and without curcumin treatment using microarray expression profiling techniques. Array results were confirmed by real-time PCR. ingenuity pathway analysis (IPA) has been used to classify the list of differentially expressed genes and to indentify common biomarkergenes modulating the chemopreventive effect of curcumin. Results showed that curcumin induces growth arrest and apoptosis in pancreatic cancer cell lines. Its effect was more obvious on the highly COX-2 expressing cell line. Additionally, the expression of 366 and 356 cancer-related genes, involved in regulation of apoptosis, cell cycle, metastasis, was significantly altered after curcumin treatment in BxPC-3 and MiaPaCa-2 cells, respectively. Our results suggested that up-regulation of the extrinsic apoptotic pathway was among signaling pathways modulating the growth inhibitory effects of curcumin on pancreatic cancer cells. Curcumin effect was mediated through activation of TNFR, CASP 8, CASP3, BID, BAX, and down-regulation of NFκB, NDRG 1, and BCL2L10 genes. PMID:23794119

  15. Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways

    PubMed Central

    Nölting, Svenja; Maurer, Julian; Spöttl, Gerald; Aristizabal Prada, Elke Tatjana; Reuther, Clemens; Young, Karen; Korbonits, Márta; Göke, Burkhard; Grossman, Ashley; Auernhammer, Christoph J.

    2015-01-01

    Background The mTORC1-inhibitor everolimus shows limited efficacy in treating patients with gastro-entero-pancreatic or pulmonary neuroendocrine tumors (NETs), and poor outcome in patients with malignant pheochromocytoma or hepatic carcinoma. We speculated that any effect may be enhanced by antogonising other signaling pathways. Methods Therefore, we tested the effect of lovastatin—known to inhibit both ERK and AKT signaling—and everolimus, separately and in combination, on cell viability and signaling pathways in human midgut (GOT), pancreatic (BON1), and pulmonary (H727) NET, hepatocellular carcinoma (HepG2, Huh7), and mouse pheochromocytoma (MPC, MTT) cell lines. Results Lovastatin and everolimus separately significantly reduced cell viability in H727, HepG2, Huh7, MPC and MTT cells at clinically relevant doses (P ≤ 0.05). However, high doses of lovastatin were necessary to affect GOT or BON1 cell viability. Clinically relevant doses of both drugs showed additive anti-tumor effects in H727, HepG2, Huh7, MPC and MTT cells (P ≤ 0.05), but not in BON1 or GOT cells. In all cell lines investigated, lovastatin inhibited EGFR and AKT signaling. Subsequently, combination treatment more strongly inhibited EGFR and AKT signaling than everolimus alone, or at least attenuated everolimus-induced EGFR or AKT activation. Vice versa, everolimus constantly decreased pp70S6K and combination treatment more strongly decreased pp70S6K than lovastatin alone, or attenuated lovastatin-induced p70S6K activation: in BON1 cells lovastatin-induced EGFR inhibition was least pronounced, possibly explaining the low efficacy and consequent absent additive effect. Conclusion In summary, clinically relevant doses of lovastatin and everolimus were effective separately and showed additive effects in 5 out of 7 cell lines. Our findings emphasize the importance of targeting several interacting signaling pathways simultaneously when attempting to attenuate tumor growth. However, the variable

  16. Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma

    PubMed Central

    Atefi, Mohammad; Avramis, Earl; Lassen, Amanda; Wong, Deborah; Robert, Lidia; Foulad, David; Cerniglia, Michael; Titz, Bjoern; Chodon, Thinle; Graeber, Thomas G.; Comin-Anduix, Begonya; Ribas, Antoni

    2014-01-01

    Purpose PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition. Experimental Design Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors. The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated. Results No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, while the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines the effects of BRAF, MEK and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INFγ. In PD-L1-exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines. Conclusions In melanoma cell lines, including BRAF inhibitor-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1-exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. PMID:24812408

  17. Multipole expansion in plasmas: Effective interaction potentials between compound particles

    NASA Astrophysics Data System (ADS)

    Ramazanov, T. S.; Moldabekov, Zh. A.; Gabdullin, M. T.

    2016-05-01

    In this paper, the multipole expansion method is used to determine effective interaction potentials between particles in both classical dusty plasma and dense quantum plasma. In particular, formulas for interactions of dipole-dipole and charge-dipole pairs in a classical nondegenerate plasma as well as in degenerate quantum and semiclassical plasmas were derived. The potentials describe interactions between atoms, atoms and charged particles, dust particles in the complex plasma, atoms and electrons in the degenerate plasma, and metals. Correctness of the results obtained from the multipole expansion is confirmed by their agreement with the results based on other methods of statistical physics and dielectric response function. It is shown that the method of multipole expansion can be used to derive effective interaction potentials of compound particles, if the effect of the medium on the potential of individual particles comprising compound particles is known.

  18. Relativistic AC gyromagnetic effects in ultraintense laser-matter interaction.

    PubMed

    Geindre, J P; Audebert, P; Marjoribanks, R S

    2006-08-25

    We demonstrate that in ultraintense ultrafast laser-matter interaction, the interplay of laser-induced oscillating space-charge fields with laser E and B fields can strongly affect whether the interaction is relativistic or not: stronger laser fields may not in fact produce more relativistic plasma interactions. We show that there exists a regime of interaction, in the relation of laser intensity and incident angle, for which the Brunel effect of electron acceleration is strongly suppressed by AC gyromagnetic fields, at a frequency different from the laser field. Analytically and with 1.5D particle-in-cell modeling, we show that from gyromagnetic effects, even in the absence of usual J x B second-harmonic contributions, there are strong effects on the harmonic emission and on the generation of attosecond pulses. PMID:17026310

  19. Study of pathway cross-talk interactions with NF-κB leading to its activation via ubiquitination or phosphorylation: A brief review.

    PubMed

    Ghosh, Sayantan; Dass, J Febin Prabhu

    2016-06-10

    NFκB has been known to be a necessary transcription factor for the functioning of nearly all cells in a living organism. For its proper functioning, it talks to several other molecular cofactors and interacts with their functionalities resulting in a convoluted cross talking mesh of signalling networks. To completely understand the working of nuclear factor-kappa B protein, one needs to understand the interactions that occur during its lifecycle, with cofactors from various biological processes. This study attempts to elaborate and bridge the gaps on the cross-talk interactions that NFkB is a part of, during its activation pathway. For this Cytoscape and its various plugins (Cytocopter, Allegro, AgilentLitSearch and Styles) are employed. Other related pathways were also collated and analysed for cross-talk between NfκB and interacting molecules. NFκB was found to mainly interact with E3 ubiquitin ligase, NIK, RIP, TCR, IRAK-1, TLR, TRAF-6, NLR and IL-1, details of which are discussed as a part of this study. PMID:26968890

  20. Multiple biomarker tissue arrays: A computational approach to identifying protein-protein interactions in the EGFR/ERK signalling pathway

    PubMed Central

    2012-01-01

    Background Many studies have demonstrated genetic and environmental factors that lead to renal cell carcinoma (RCC) and that occur during a protracted period of tumourigenesis. It appears suitable to identify and characterise potential molecular markers that appear during tumourigenesis and that might provide rapid and effective possibilities for the early detection of RCC. EGFR activation induces cell cycle progression, inhibition of apoptosis and angiogenesis, promotion of invasion/metastasis, and other tumour promoting activities. Over-expression of EGFR is thought to play an important role in tumour initiation and progression of RCC because up-regulation of EGFR has been associated with high grade cancers and a worse prognosis. Methods Characterisation of the protein profile interacting with EGFR was performed using the following: an immunohistochemical (IHC) study of EGFR, a comprehensive computational study of EGFR protein-protein interactions, an analysis correlating the expression levels of EGFR with other significant markers in the tumourigenicity of RCC, and finally, an analysis of the utility of EGFR for prognosis in a cohort of patients with renal cell carcinoma. Results The cases that showed a higher level of this protein fell within the clear cell histological subtype (p = 0.001). The EGFR significance statistic was found with respect to a worse prognosis. In vivo significant correlations were found with PDGFR-β, Flk-1, Hif1-α, proteins related to differentiation (such as DLL3 and DLL4 ligands), and certain metabolic proteins such as Glut5. In silico significant associations gave us a panel of 32 EGFR-interacting proteins (EIP) using the APID and STRING databases. Conclusions This work summarises the multifaceted role of EGFR in the pathology of RCC, and it identifies EIPs that could help to provide mechanistic explanations for the different behaviours observed in tumours. PMID:22937740

  1. Coevolution and the Effects of Climate Change on Interacting Species

    PubMed Central

    Northfield, Tobin D.; Ives, Anthony R.

    2013-01-01

    Background Recent studies suggest that environmental changes may tip the balance between interacting species, leading to the extinction of one or more species. While it is recognized that evolution will play a role in determining how environmental changes directly affect species, the interactions among species force us to consider the coevolutionary responses of species to environmental changes. Methodology/Principle Findings We use simple models of competition, predation, and mutualism to organize and synthesize the ways coevolution modifies species interactions when climatic changes favor one species over another. In cases where species have conflicting interests (i.e., selection for increased interspecific interaction strength on one species is detrimental to the other), we show that coevolution reduces the effects of climate change, leading to smaller changes in abundances and reduced chances of extinction. Conversely, when species have nonconflicting interests (i.e., selection for increased interspecific interaction strength on one species benefits the other), coevolution increases the effects of climate change. Conclusions/Significance Coevolution sets up feedback loops that either dampen or amplify the effect of environmental change on species abundances depending on whether coevolution has conflicting or nonconflicting effects on species interactions. Thus, gaining a better understanding of the coevolutionary processes between interacting species is critical for understanding how communities respond to a changing climate. We suggest experimental methods to determine which types of coevolution (conflicting or nonconflicting) drive species interactions, which should lead to better understanding of the effects of coevolution on species adaptation. Conducting these experiments across environmental gradients will test our predictions of the effects of environmental change and coevolution on ecological communities. PMID:24167443

  2. Pubertal Effects on Adjustment in Girls: Moving from Demonstrating Effects to Identifying Pathways

    ERIC Educational Resources Information Center

    Graber, Julia A.; Brooks-Gunn, Jeanne; Warren, Michelle P.

    2006-01-01

    The present investigation examines mediated pathways from pubertal development to changes in depressive affect and aggression. Participants were 100 white girls who were between the ages of 10 and 14 (M=12.13, SD=0.80); girls were from well-educated, middle-to upper-middle class families, and attended private schools in a major northeastern urban…

  3. Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

    SciTech Connect

    O'Neill, Peter; Anderson, Jennifer

    2014-10-02

    The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental

  4. Veterinary team interactions, part 2: the personal effect.

    PubMed

    Kinnison, T; Guile, D; May, S A

    2015-11-28

    Modern veterinary practices consist of multiple professions/occupations, often spread over multiple branches. Within these teams are identifiable 'key people' who are central to information and resource flow. Key people are frequently the appointed leaders, such as practice managers, but also include emergent leaders. Veterinary surgeons are commonly involved in the flow of higher order interactions such as problem solving, while administrators are often involved in information interactions. These key people are repeatedly boundary spanners, sharing resources across physical boundaries such as branches. Their marginal status (belonging to multiple groups) also allows them to interact across professional boundaries. Lower order interactions including asking for information and advice are often interprofessional; however, higher order interactions tend to be intraprofessional. Analysis of interaction reciprocity between professions demonstrated the prevalence of a profession based hierarchy, with veterinary surgeons at the top. Being social outside of work with a colleague is also linked to work based interactions. The results of this paper demonstrate the need for practices to consider key people and support them appropriately. Further to this, they suggest that, to promote an effective team, interactions should be based on experience as much as professional status, and that social interactions should be encouraged. PMID:26489995

  5. Veterinary team interactions, part one: the practice effect.

    PubMed

    Kinnison, T; May, S A; Guile, D

    2015-10-24

    Veterinary practices have evolved since the era of solo practitioners working on one site. Today veterinary practices tend to include veterinary surgeons, veterinary nurses, receptionists and business managers, leading to the notion of the veterinary team and the rise of interprofessional working. In addition, practices have grown in size and frequently include several branches, creating a distributed team. Research regarding veterinary teamwork is lacking. This paper uses Social Network Analysis (SNA) to address this issue. SNA measures interactions between members of a network. The types of interactions in practice and the effects of practice size and location (branches) are considered. Information sharing and asking for advice are straightforward, lower order interactions. Problem solving and being influenced by another are complex, higher order interactions. Smaller practices have higher densities of interactions, implying a more cohesive team. However, individuals in smaller practices still do not interact with everyone and therefore actively choose with whom to interact. Practices with little staff rotation across branches experience limited interactions across locations. The results of this study have implications for practices aiming to expand their team, either in a single site or by acquiring more branches. Suggestions for ways to maintain and improve interactions are made. PMID:26446881

  6. Obstacle Effects on the River sea Interaction

    NASA Astrophysics Data System (ADS)

    Hwang, J.; Park, Y.

    2008-12-01

    The river discharged flow behavior in the ROFI (Regions of Freshwater Influence; Simpson, 1997) is studied using FVCOM (Chen et al, 2006), an unstructured grid primitive equation model. In the present study we can resolve detailed motion near the river mouth and consider the effect of an obstacle (a sea mount or an island) placed in front of the river mouth. The unstructured grid zooms up the behavior of a bulge which was widely observed in earlier estuarine model studies and we could investigate the separation of the bulge by the anti-cyclonic motion due to the river discharge. An obstacle of a sea mount seems to play a similar role as the core of a bulge, but in the case with an island as an obstacle, totally different flow patterns were observed compared with other cases, since island can affect the surface motions. With the same geometrical conditions, we also consider tide, which enhances vertical mixing and changes flow patterns induced by the river discharge.

  7. Molecular Signaling Pathways Behind the Biological Effects of Salvia Species Diterpenes in Neuropharmacology and Cardiology.

    PubMed

    Akaberi, M; Iranshahi, M; Mehri, S

    2016-06-01

    The genus Salvia, from the Lamiaceae family, has diverse biological properties that are primarily attributable to their diterpene contents. There is no comprehensive review on the molecular signaling pathways of these active components. In this review, we investigated the molecular targets of bioactive Salvia diterpenes responsible for the treatment of nervous and cardiovascular diseases. The effects on different pathways, including apoptosis signaling, oxidative stress phenomena, the accumulation of amyloid beta plaques, and tau phosphorylation, have all been considered to be mechanisms of the anti-Alzheimer properties of Salvia diterpenes. Additionally, effects on the benzodiazepine and kappa opioid receptors and neuroprotective effects are noted as neuropharmacological properties of Salvia diterpenes, including tanshinone IIA, salvinorin A, cryptotanshinone, and miltirone. Tanshinone IIA, as the primary diterpene of Salvia miltiorrhiza, has beneficial activities in heart diseases because of its ability to scavenge free radicals and its effects on transcription factors, such as nuclear transcription factor-kappa B (NF-κB) and the mitogen-activated protein kinases (MAPKs). Additionally, tanshinone IIA has also been proposed to have cardioprotective properties including antiarrhythmic activities and effects on myocardial infarction. With respect to the potential therapeutic effects of Salvia diterpenes, comprehensive clinical trials are warranted to evaluate these valuable molecules as lead compounds. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26988179

  8. Behavioral effects of clozapine: Involvement of trace amine pathways in C. elegans and M. musculus

    PubMed Central

    Karmacharya, Rakesh; Lynn, Spencer K.; Demarco, Sarah; Ortiz, Angelica; Wang, Xin; Lundy, Miriam Y.; Xie, Zhihua; Cohen, Bruce M.; Miller, Gregory M.; Buttner, Edgar A.

    2011-01-01

    Clozapine is an antipsychotic medication with superior efficacy in treatment-refractory schizophrenia. The molecular basis of clozapine’s therapeutic profile is not well understood. We studied behavioral effects of clozapine in Caenorhabditis elegans to identify novel pathways that modulate clozapine’s biological effects. Clozapine stimulated egg laying in C. elegans in a dose-dependent manner. This effect was clozapine-specific, as it was not observed with exposure to a typical antipsychotic, haloperidol or an atypical antipsychotic, olanzapine. A candidate gene screen of biogenic amine neurotransmitter systems identified signaling pathways that mediate this clozapine-specific effect on egg laying. Specifically, we found that clozapine-induced increase in egg laying requires tyramine biosynthesis. To test the implications of this finding across species, we explored whether trace amine systems modulate clozapine’s behavioral effects in mammals by studying trace amine-associated receptor 1 (TAAR1) knockout mice. Clozapine increased pre-pulse inhibition (PPI) in wild-type mice. This increase in PPI was abrogated in TAAR1 knockout mice, implicating TAAR1 in clozapine-induced PPI enhancement. In transfected mammalian cell lines, we found no TAAR activation by antipsychotics, suggesting that modulation of trace amine signaling in mice does not occur directly at the receptor itself. In summary, we report a heretofore-unknown role for trace amine systems in clozapine-mediated effects across two species: C. elegans and mice. PMID:21529784

  9. An Association Map on the Effect of Flavonoids on the Signaling Pathways in Colorectal Cancer

    PubMed Central

    Koosha, Sanaz; Alshawsh, Mohammed A.; Looi, Chung Yeng; Seyedan, Atefehalsadat; Mohamed, Zahurin

    2016-01-01

    Colorectal cancer (CRC) is the third most common type of cancer in the world, causing thousands of deaths annually. Although chemotherapy is known to be an effective treatment to combat colon cancer, it produces severe side effects. Natural products, on the other hand, appear to generate fewer side effects than do chemotherapeutic drugs. Flavonoids are polyphenolic compounds found in various fruits and vegetables known to possess antioxidant activities, and the literature shows that several of these flavonoids have anti-CRC propertiesFlavonoids are classified into five main subclasses: flavonols, flavanones, flavones, flavan-3-ols, and flavanonols. Of these subclasses, the flavanonols have a minimum effect against CRC, whereas the flavones play an important role. The main targets for the inhibitory effect of flavonoids on CRC signaling pathways are caspase; nuclear factor kappa B; mitogen-activated protein kinase/p38; matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9; p53; β-catenin; cyclin-dependent kinase (CDK)2 and CDK4; and cyclins A, B, D, and E. In this review article, we summarize the in vitro and in vivo studies that have been performed since 2000 on the anti-CRC properties of flavonoids. We also describe the signaling pathways affected by flavonoids that have been found to be involved in CRC. Some flavonoids have the potential to be an effective alternative to chemotherapeutic drugs in the treatment of colon cancer; well-controlled clinical studies should, however, be conducted to support this proposal. PMID:27226778

  10. Mediators, Receptors, and Signalling Pathways in the Anti-Inflammatory and Antihyperalgesic Effects of Acupuncture

    PubMed Central

    McDonald, John L.; Cripps, Allan W.; Smith, Peter K.

    2015-01-01

    Acupuncture has been used for millennia to treat allergic diseases including both intermittent rhinitis and persistent rhinitis. Besides the research on the efficacy and safety of acupuncture treatment for allergic rhinitis, research has also investigated how acupuncture might modulate immune function to exert anti-inflammatory effects. A proposed model has previously hypothesized that acupuncture might downregulate proinflammatory neuropeptides, proinflammatory cytokines, and neurotrophins, modulating transient receptor potential vallinoid (TRPV1), a G-protein coupled receptor which plays a central role in allergic rhinitis. Recent research has been largely supportive of this model. New advances in research include the discovery of a novel cholinergic anti-inflammatory pathway activated by acupuncture. A chemokine-mediated proliferation of opioid-containing macrophages in inflamed tissues, in response to acupuncture, has also been demonstrated for the first time. Further research on the complex cross talk between receptors during inflammation is also helping to elucidate the mediators and signalling pathways activated by acupuncture. PMID:26339274

  11. The effect of aquaporin 5 overexpression on the Ras signaling pathway

    SciTech Connect

    Woo, Janghee; Lee, Juna; Kim, Myoung Sook; Jang, Se Jin; Sidransky, David; Moon, Chulso

    2008-03-07

    Human aquaporin 5 (AQP5) has been shown to be overexpressed in multiple cancers, such as pancreatic cancer and colon cancer. Furthermore, it has been reported that ectopic expression of AQP5 leads to many phenotypic changes characteristic of transformation. However, the biochemical mechanism leading to transformation in AQP5-overexpressing cells has not been clearly elucidated. In this report, the overexpression of AQP5 in NIH3T3 cells demonstrated a significant effect on Ras activity and, thus, cell proliferation. Furthermore, this influence was shown to be mediated by phosphorylation of the PKA consensus site of AQP5. This is the first evidence demonstrating an association between AQP5 and a signaling pathway, namely the Ras signal transduction pathway, which may be the basis of the oncogenic properties seen in AQP-overexpressing cells.

  12. Effect of aluminum (III) on the conversion of dopachrome in the melanin synthesis pathway

    NASA Astrophysics Data System (ADS)

    Di, Junwei; Bi, Shuping

    2003-06-01

    The effect of aluminum ions on the kinetics and mode of the conversion of dopachrome (DC) in acidic environment has been studied using UV-Vis spectrophotometric and cyclic voltammetric methods. The DC conversion step is an important reaction in melanogenesis. Aluminum ions catalyze greatly the decarboxylative transformation of DC to give 5,6-dihydroxyindole (DHI) rather than 5,6-dihydroxyindole-2-carboxylic acid (DHICA) at pH 5.5, which enhance the ratio of formation DHI/DHICA in melanin synthesis pathway. The kinetics of DC conversion catalyzed by aluminum ions is dependent on the concentration of DC and aluminum ions. These results provide evidence that aluminum ions could play a role in the synthesis of melanin pathway in acidic condition through catalyzing the DC decarboxylative transformation to yield DHI and influence the melanin structure and properties.

  13. The effect of point defects on diffusion pathway within α-Fe

    NASA Astrophysics Data System (ADS)

    Sakuraya, Seiji; Takahashi, Keisuke; Hashimoto, Naoyuki; Ohnuki, Somei

    2015-05-01

    The diffusion mechanism of point defects within α-Fe with a single vacancy is investigated using the density functional theory. Calculation reveals that H has a slight effect towards Fe diffusion to a vacancy. He has a strong binding with a vacancy; therefore, Fe diffusion is unlikely to happen. The diffusion of C and N from a vacancy has a high barrier. However, Fe diffusion to a vacancy decreases if the C and N diffuse from a vacancy. Thus, the effect of interstitial atoms within α-Fe with a single vacancy towards diffusion and a possible diffusion pathway is discussed.

  14. Interaction mechanisms and biological effects of static magnetic fields

    SciTech Connect

    Tenforde, T.S.

    1994-06-01

    Mechanisms through which static magnetic fields interact with living systems are described and illustrated by selected experimental observations. These mechanisms include electrodynamic interactions with moving, ionic charges (blood flow and nerve impulse conduction), magnetomechanical interactions (orientation and translation of molecules structures and magnetic particles), and interactions with electronic spin states in charge transfer reactions (photo-induced electron transfer in photosynthesis). A general summary is also presented of the biological effects of static magnetic fields. There is convincing experimental evidence for magnetoreception mechanisms in several classes of lower organisms, including bacteria and marine organisms. However, in more highly evolved species of animals, there is no evidence that the interactions of static magnetic fields with flux densities up to 2 Tesla (1 Tesla [T] = 10{sup 4} Gauss) produce either behavioral or physiolocical alterations. These results, based on controlled studies with laboratory animals, are consistent with the outcome of recent epidemiological surveys on human populations exposed occupationally to static magnetic fields.

  15. Nuclear Effects in Neutrino Interactions at Low Momentum Transfer

    SciTech Connect

    Miltenberger, Ethan Ryan

    2015-05-01

    This is a study to identify predicted effects of the carbon nucleus environment on neutrino - nucleus interactions with low momentum transfer. A large sample of neutrino interaction data collected by the MINERvA experiment is analyzed to show the distribution of charged hadron energy in a region with low momentum transfer. These distributions reveal a major discrepancy between the data and a popular interaction model with only the simplest Fermi gas nuclear effects. Detailed analysis of systematic uncertainties due to energy scale and resolution can account for only a little of the discrepancy. Two additional nuclear model effects, a suppression/screening effect (RPA), and the addition of a meson exchange current process (MEC), are shown to improve the description of the data.

  16. Acute interactive motoric effects of permethrin and xylene

    SciTech Connect

    Durnam, M.R.

    1992-01-01

    The potential interactive motoric effects of permethrin (a type I pyrethroid pesticide) and xylene (an aromatic hydrocarbon solvent) were assessed in male CD-I mice following acute exposure. The hypothesis was that these two compounds would interact (the effects would be more than additive) to disrupt motor performance on inverted screen tent performance and/or locomotor activity. The data obtained from this experiment do not support this hypothesis. The results failed to show a significant interaction between the permethrin and xylene on either task, however, the combination of these compounds altered the time course of motoric effects. The peak effect on the inverted screen test occurred earlier for xylene and permethrin than for permethrin alone. The xylene probably increased the rate of absorption of xylene. On locomotor activity, permethrin and xylene when given separately increased activity, however, the highest dose combination of permethrin and xylene produced a strong decrease in activity at all time points.

  17. Effective spin-spin interaction in neutron matter

    SciTech Connect

    Zverev, M.V.; Khafizov, R.U.; Khodel, V.A.; Shaginyan, V.R.

    1995-09-01

    A set of equations for calculating the effective-interaction matrix R{sup ik}(q, {omega}) and the response function X{sup ik}(q, {omega}) is derived. These equations take into account the spin degrees of freedom of infinite neutron matter. For isotropic neutron matter with the Bethe interaction, the effective spin-spin interaction g(k) is calculated in the local approximation of the functional approach in the density range from {rho} = 0.17 to 25 fm{sup -3}. It is shown that this interaction weakly depends on the density within the range under consideration and that neither ferromagnetic nor antiferromagnetic phase transitions occur in the system. 7 refs., 2 figs.

  18. Evaluating Differential Effects Using Regression Interactions and Regression Mixture Models

    ERIC Educational Resources Information Center

    Van Horn, M. Lee; Jaki, Thomas; Masyn, Katherine; Howe, George; Feaster, Daniel J.; Lamont, Andrea E.; George, Melissa R. W.; Kim, Minjung

    2015-01-01

    Research increasingly emphasizes understanding differential effects. This article focuses on understanding regression mixture models, which are relatively new statistical methods for assessing differential effects by comparing results to using an interactive term in linear regression. The research questions which each model answers, their…

  19. The effects of organic solvents on the folding pathway and associated thermodynamics of proteins: a microscopic view.

    PubMed

    Yu, Yuqi; Wang, Jinan; Shao, Qiang; Shi, Jiye; Zhu, Weiliang

    2016-01-01

    Protein folding is subject to the effects of solvation environment. A variety of organic solvents are used as additives for in vitro refolding of denatured proteins. Examination of the solvent effects on protein folding could be of fundamental importance to understand the molecular interactions in determining protein structure. This article investigated the folding of α-helix and β-hairpin structures in water and the solutions of two representative refolding additives (methanol (MeOH) and 1-Ethyl-3-methylimidazolium chloride (EMIM-Cl) ionic liquid) using REMD simulations. For both α-helix and β-hairpin in MeOH/water solution or α-helix in EMIM-Cl/water solution, the transient structures along the folding pathway are consistent with the counterparts in water but the relative statistical weights are changed, leading to the decrease in the overall folding free energy barrier. Accordingly, MeOH promotes the folding of both α-helix and β-hairpin but EMIM-Cl ionic liquid only promotes the folding of α-helix, consistent with experimental observations. The present study reveals for the first time the trivial effects on folding route but significant effects on folding thermodynamics from MeOH and EMIM-Cl, explaining the function of protein refolding additives and testifying the validity of the folding mechanism revealed by in vitro protein folding study using refolding additives. PMID:26775871

  20. The effects of organic solvents on the folding pathway and associated thermodynamics of proteins: a microscopic view

    PubMed Central

    Yu, Yuqi; Wang, Jinan; Shao, Qiang; Shi, Jiye; Zhu, Weiliang

    2016-01-01

    Protein folding is subject to the effects of solvation environment. A variety of organic solvents are used as additives for in vitro refolding of denatured proteins. Examination of the solvent effects on protein folding could be of fundamental importance to understand the molecular interactions in determining protein structure. This article investigated the folding of α-helix and β-hairpin structures in water and the solutions of two representative refolding additives (methanol (MeOH) and 1-Ethyl-3-methylimidazolium chloride (EMIM-Cl) ionic liquid) using REMD simulations. For both α-helix and β-hairpin in MeOH/water solution or α-helix in EMIM-Cl/water solution, the transient structures along the folding pathway are consistent with the counterparts in water but the relative statistical weights are changed, leading to the decrease in the overall folding free energy barrier. Accordingly, MeOH promotes the folding of both α-helix and β-hairpin but EMIM-Cl ionic liquid only promotes the folding of α-helix, consistent with experimental observations. The present study reveals for the first time the trivial effects on folding route but significant effects on folding thermodynamics from MeOH and EMIM-Cl, explaining the function of protein refolding additives and testifying the validity of the folding mechanism revealed by in vitro protein folding study using refolding additives. PMID:26775871

  1. Indirect Genetic Effects and the Dynamics of Social Interactions

    PubMed Central

    Trubenová, Barbora; Novak, Sebastian; Hager, Reinmar

    2015-01-01

    Background Indirect genetic effects (IGEs) occur when genes expressed in one individual alter the expression of traits in social partners. Previous studies focused on the evolutionary consequences and evolutionary dynamics of IGEs, using equilibrium solutions to predict phenotypes in subsequent generations. However, whether or not such steady states may be reached may depend on the dynamics of interactions themselves. Results In our study, we focus on the dynamics of social interactions and indirect genetic effects and investigate how they modify phenotypes over time. Unlike previous IGE studies, we do not analyse evolutionary dynamics; rather we consider within-individual phenotypic changes, also referred to as phenotypic plasticity. We analyse iterative interactions, when individuals interact in a series of discontinuous events, and investigate the stability of steady state solutions and the dependence on model parameters, such as population size, strength, and the nature of interactions. We show that for interactions where a feedback loop occurs, the possible parameter space of interaction strength is fairly limited, affecting the evolutionary consequences of IGEs. We discuss the implications of our results for current IGE model predictions and their limitations. PMID:25993124

  2. Aerodynamic Interaction Effects of a Helicopter Rotor and Fuselage

    NASA Technical Reports Server (NTRS)

    Boyd, David D., Jr.

    1999-01-01

    A three year Cooperative Research Agreements made in each of the three years between the Subsonic Aerodynamics Branch of the NASA Langley Research Center and the Virginia Polytechnic Institute and State University (Va. Tech) has been completed. This document presents results from this three year endeavor. The goal of creating an efficient method to compute unsteady interactional effects between a helicopter rotor and fuselage has been accomplished. This paper also includes appendices to support these findings. The topics are: 1) Rotor-Fuselage Interactions Aerodynamics: An Unsteady Rotor Model; and 2) Rotor/Fuselage Unsteady Interactional Aerodynamics: A New Computational Model.

  3. Coulomb interaction effects on the Majorana states in quantum wires.

    PubMed

    Manolescu, A; Marinescu, D C; Stanescu, T D

    2014-04-30

    The stability of the Majorana modes in the presence of a repulsive interaction is studied in the standard semiconductor wire-metallic superconductor configuration. The effects of short-range Coulomb interaction, which is incorporated using a purely repulsive δ-function to model the strong screening effect due to the presence of the superconductor, are determined within a Hartree-Fock approximation of the effective Bogoliubov-De Gennes Hamiltonian that describes the low-energy physics of the wire. Through a numerical diagonalization procedure we obtain interaction corrections to the single particle eigenstates and calculate the extended topological phase diagram in terms of the chemical potential and the Zeeman energy. We find that, for a fixed Zeeman energy, the interaction shifts the phase boundaries to a higher chemical potential, whereas for a fixed chemical potential this shift can occur either at lower or higher Zeeman energies. These effects can be interpreted as a renormalization of the g-factor due to the interaction. The minimum Zeeman energy needed to realize Majorana fermions decreases with the increasing strength of the Coulomb repulsion. Furthermore, we find that in wires with multi-band occupancy this effect can be enhanced by increasing the chemical potential, i.e. by occupying higher energy bands. PMID:24722427

  4. A High-Throughput Screening Strategy to Identify Protein-Protein Interaction Inhibitors That Block the Fanconi Anemia DNA Repair Pathway.

    PubMed

    Voter, Andrew F; Manthei, Kelly A; Keck, James L

    2016-07-01

    Induction of the Fanconi anemia (FA) DNA repair pathway is a common mechanism by which tumors evolve resistance to DNA crosslinking chemotherapies. Proper execution of the FA pathway requires interaction between the FA complementation group M protein (FANCM) and the RecQ-mediated genome instability protein (RMI) complex, and mutations that disrupt FANCM/RMI interactions sensitize cells to DNA crosslinking agents. Inhibitors that block FANCM/RMI complex formation could be useful therapeutics for resensitizing tumors that have acquired chemotherapeutic resistance. To identify such inhibitors, we have developed and validated high-throughput fluorescence polarization and proximity assays that are sensitive to inhibitors that disrupt interactions between the RMI complex and its binding site on FANCM (a peptide referred to as MM2). A pilot screen of 74,807 small molecules was performed using the fluorescence polarization assay. Hits from the primary screen were further tested using the proximity assay, and an orthogonal proximity assay was used to assess inhibitor selectivity. Direct physical interaction between the RMI complex and the most selective inhibitor identified through the screening process was measured by surface plasmon resonance and isothermal titration calorimetry. Observation of direct binding by this small molecule validates the screening protocol. PMID:26962873

  5. Interaction between Major Nitrogen Regulatory Protein NIT2 and Pathway-Specific Regulatory Factor NIT4 Is Required for Their Synergistic Activation of Gene Expression in Neurospora crassa

    PubMed Central

    Feng, Bo; Marzluf, George A.

    1998-01-01

    In Neurospora crassa, the major nitrogen regulatory protein, NIT2, a member of the GATA family of transcription factors, controls positively the expression of numerous genes which specify nitrogen catabolic enzymes. Expression of the highly regulated structural gene nit-3, which encodes nitrate reductase, is dependent upon a synergistic interaction of NIT2 with a pathway-specific control protein, NIT4, a member of the GAL4 family of fungal regulatory factors. The NIT2 and NIT4 proteins both bind at specific recognition elements in the nit-3 promoter, but, in addition, we show that a direct protein-protein interaction between NIT2 and NIT4 is essential for optimal expression of the nit-3 structural gene. Neurospora possesses at least five different GATA factors which control different areas of cellular function, but which have a similar DNA binding specificity. Significantly, only NIT2, of the several Neurospora GATA factors examined, interacts with NIT4. We propose that protein-protein interactions of the individual GATA factors with additional pathway-specific regulatory factors determine each of their specific regulatory functions. PMID:9632783

  6. Reactivity of Single-Walled Carbon Nanotubes in the Diels-Alder Cycloaddition Reaction: Distortion-Interaction Analysis along the Reaction Pathway.

    PubMed

    Li, Yingzi; Osuna, Sílvia; Garcia-Borràs, Marc; Qi, Xiaotian; Liu, Song; Houk, Kendall N; Lan, Yu

    2016-08-26

    Diels-Alder cycloaddition is one of the most powerful tools for the functionalization of single-walled carbon nanotubes (SWCNTs). Density functional theory at the B3-LYP level of theory has been used to investigate the reactivity of different-diameter SWCNTs (4-9,5) in Diels-Alder reactions with 1,3-butadiene; the reactivity was found to decrease with increasing SWCNT diameter. Distortion/interaction analysis along the whole reaction pathway was found to be a better way to explore the reactivity of this type of reaction. The difference in interaction energy along the reaction pathway is larger than that of the corresponding distortion energy. However, the distortion energy plots for these reactions show the same trend. Therefore, the formation of the transition state can be determined from the interaction energy. A lower interaction energy leads to an earlier transition state, which indicates a lower activation energy. The computational results also indicate that the original distortion of the SWCNTs leads to an increase in the reactivity of the SWCNTs. PMID:27465519

  7. Targeting the ataxia telangiectasia mutated pathway for effective therapy against hirsutine-resistant breast cancer cells

    PubMed Central

    LOU, CHENGHUA; YOKOYAMA, SATORU; ABDELHAMED, SHERIF; SAIKI, IKUO; HAYAKAWA, YOSHIHIRO

    2016-01-01

    The present authors have recently demonstrated that hirsutine, one of the major alkaloids in Uncaria species, promotes cell apoptosis by inducing DNA damage and suppresses metastasis of breast cancer cells. Despite its potent anti-cancer activity, certain types of human breast cancer cells exhibit resistance to hirsutine. To maximize the clinical utility of hirsutine therapy against breast cancer, it is critical to explore the underlying mechanism that protects hirsutine-resistant breast cancer cell lines. To identify potential targets for overcoming hirsutine-resistance, the present study investigated a library of kinase inhibitors in combination with hirsutine treatment in the hirsutine-resistant human breast carcinoma MCF-7 cell line. Amongst the 96 compounds tested, inhibitors of the ataxia telangiectasia mutated (ATM) pathway sensitized MCF-7 cells to hirsutine-induced cell death along with a sustained DNA damage response. This sensitization of MCF-7 cells to the hirsutine-induced DNA damage response by interfering with the ATM pathway did not require p53. Instead, radical oxygen species generation was significantly increased in hirsute and ATM inhibitor-treated MCF-7 cells. In conclusion, the present findings suggest the importance of the ATM pathway for optimizing the anti-cancer effect of hirsutine in breast cancer cells. PMID:27347141

  8. Association between the Interaction of Key Genes Involved in Effector T-Cell Pathways and Susceptibility to Developallergic Rhinitis: A Population-Based Case-Control Association Study

    PubMed Central

    Zhang, Yuan; Li, Jingyun; Wang, Chengshuo; Zhang, Luo

    2015-01-01

    Background Evidence suggests that interaction between key genes mediating signaling and transcriptional networks involving effector T-cell responses may influence an individual’s susceptibility to develop allergic rhinitis(AR). Objective The aim of this study was todetermine whether specific interactions between key genes involved in effector T-cell pathways are associated with an individual’s susceptibility to develop AR in Han Chinese subjects. Method A cohort of 489 patients with AR and 421 healthy controls was enrolled from the Han Chinese population in Beijing, China. AR was established by questionnaire and clinical examination, and peripheral blood was drawn from all subjects for DNA extraction. A total of 96 single nucleotide polymorphisms (SNPs) in 26 reprehensive candidate genes involved in T helper 1 (Th1), Th2, Th17, Th9 and T regulatory cell pathways were selected from the International Haplotype Mappingdatabase for Han Chinese in Beijing (CHB) population, and IlluminaGoldenGate assay was conducted for SNP genotyping. The PLINK software package was used to perform statistical analyses. Results Simple SNP-phenotype association analysis using logistic regression showed SNP rs8193036 in IL17A gene, rs2569254 in IL-12 and rs1898413 in RORα weresignificantlyassociatedwith AR.Simple SNP-phenotype association analysis with genetic models demonstrated thatrs2569254 in IL-12, rs1031508 in STAT4, and rs3741809 in IL-26 were likely to be recessive, rs8193036 in IL17A allelic, rs897200in STAT4 genotypic, and rs1898413 in RORα dominant. Epistasis analyses exhibited that 83 SNPs in 23 genes were significantly interactive; of which 59 interactions/SNP pairs demonstrated OR values higher than 2 or lower than 0.5, and 12 interactions/SNP pairs OR values higher than 4 or lower than 0.25. STAT3, RORα and IL-26, involved in Th17 pathway,were the mostfrequentlyinteractive genes. Conclusion This study suggests that interactions between several SNPs in key genes

  9. Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species.

    PubMed

    Oja, Terhi; San Martin Galindo, Paola; Taguchi, Takaaki; Manner, Suvi; Vuorela, Pia M; Ichinose, Koji; Metsä-Ketelä, Mikko; Fallarero, Adyary

    2015-10-01

    Streptomyces bacteria are renowned for their ability to produce bioactive secondary metabolites. Recently, synthetic biology has enabled the production of intermediates and shunt products, which may have altered biological activities compared to the end products of the pathways. Here, we have evaluated the potential of recently isolated alnumycins and other closely related pyranonaphthoquinone (PNQ) polyketides against Staphylococcus aureus biofilms. The antimicrobial potency of the compounds against planktonic cells and biofilms was determined by redox dye-based viability staining, and the antibiofilm efficacy of the compounds was confirmed by viable counting. A novel antistaphylococcal polyketide, alnumycin D, was identified. Unexpectedly, the C-ribosylated pathway shunt product alnumycin D was more active against planktonic and biofilm cells than the pathway end product alnumycin A, where a ribose unit has been converted into a dioxane moiety. The evaluation of the antibiofilm potential of other alnumycins revealed that the presence of the ribose moiety in pyranose form is essential for high activity against preformed biofilms. Furthermore, the antibiofilm potential of other closely related PNQ polyketides was examined. Based on their previously reported activity against planktonic S. aureus cells, granaticin B, kalafungin, and medermycin were also selected for testing, and among them, granaticin B was found to be the most potent against preformed biofilms. The most active antibiofilm PNQs, alnumycin D and granaticin B, share several structural features that may be important for their antibiofilm activity. They are uncharged, glycosylated, and also contain a similar oxygenation pattern of the lateral naphthoquinone ring. These findings highlight the potential of antibiotic biosynthetic pathways as a source of effective antibiofilm compounds. PMID:26195520

  10. Effective Antibiofilm Polyketides against Staphylococcus aureus from the Pyranonaphthoquinone Biosynthetic Pathways of Streptomyces Species

    PubMed Central

    San Martin Galindo, Paola; Taguchi, Takaaki; Manner, Suvi; Vuorela, Pia M.; Ichinose, Koji; Metsä-Ketelä, Mikko

    2015-01-01

    Streptomyces bacteria are renowned for their ability to produce bioactive secondary metabolites. Recently, synthetic biology has enabled the production of intermediates and shunt products, which may have altered biological activities compared to the end products of the pathways. Here, we have evaluated the potential of recently isolated alnumycins and other closely related pyranonaphthoquinone (PNQ) polyketides against Staphylococcus aureus biofilms. The antimicrobial potency of the compounds against planktonic cells and biofilms was determined by redox dye-based viability staining, and the antibiofilm efficacy of the compounds was confirmed by viable counting. A novel antistaphylococcal polyketide, alnumycin D, was identified. Unexpectedly, the C-ribosylated pathway shunt product alnumycin D was more active against planktonic and biofilm cells than the pathway end product alnumycin A, where a ribose unit has been converted into a dioxane moiety. The evaluation of the antibiofilm potential of other alnumycins revealed that the presence of the ribose moiety in pyranose form is essential for high activity against preformed biofilms. Furthermore, the antibiofilm potential of other closely related PNQ polyketides was examined. Based on their previously reported activity against planktonic S. aureus cells, granaticin B, kalafungin, and medermycin were also selected for testing, and among them, granaticin B was found to be the most potent against preformed biofilms. The most active antibiofilm PNQs, alnumycin D and granaticin B, share several structural features that may be important for their antibiofilm activity. They are uncharged, glycosylated, and also contain a similar oxygenation pattern of the lateral naphthoquinone ring. These findings highlight the potential of antibiotic biosynthetic pathways as a source of effective antibiofilm compounds. PMID:26195520

  11. The Group B Streptococcus–Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways

    PubMed Central

    Pietrocola, Giampiero; Rindi, Simonetta; Rosini, Roberto; Buccato, Scilla

    2016-01-01

    The group B Streptococcus (GBS) is a leading cause of neonatal invasive disease. GBS bacteria are surrounded by a thick capsular polysaccharide that is a potent inhibitor of complement deposition via the alternative pathway. Several of its surface molecules can however activate the classical and lectin complement pathways, rendering this species still vulnerable to phagocytic killing. In this study we have identified a novel secreted protein named complement interfering protein (CIP) that downregulates complement activation via the classical and lectin pathways, but not the alternative pathway. The CIP protein showed high affinity toward C4b and inhibited its interaction with C2, presumably preventing the formation of the C4bC2a convertase. Addition of recombinant CIP to GBS cip-negative bacteria resulted in decreased deposition of C3b on their surface and in diminished phagocytic killing in a whole-blood assay. Our data reveal a novel strategy exploited by GBS to counteract innate immunity and could be valuable for the development of anti-infective agents against this important pathogen. PMID:26608922

  12. The Group B Streptococcus-Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways.

    PubMed

    Pietrocola, Giampiero; Rindi, Simonetta; Rosini, Roberto; Buccato, Scilla; Speziale, Pietro; Margarit, Immaculada

    2016-01-01

    The group B Streptococcus (GBS) is a leading cause of neonatal invasive disease. GBS bacteria are surrounded by a thick capsular polysaccharide that is a potent inhibitor of complement deposition via the alternative pathway. Several of its surface molecules can however activate the classical and lectin complement pathways, rendering this species still vulnerable to phagocytic killing. In this study we have identified a novel secreted protein named complement interfering protein (CIP) that downregulates complement activation via the classical and lectin pathways, but not the alternative pathway. The CIP protein showed high affinity toward C4b and inhibited its interaction with C2, presumably preventing the formation of the C4bC2a convertase. Addition of recombinant CIP to GBS cip-negative bacteria resulted in decreased deposition of C3b on their surface and in diminished phagocytic killing in a whole-blood assay. Our data reveal a novel strategy exploited by GBS to counteract innate immunity and could be valuable for the development of anti-infective agents against this important pathogen. PMID:26608922

  13. Photonic Aharonov-Bohm effect in photon-phonon interactions.

    PubMed

    Li, Enbang; Eggleton, Benjamin J; Fang, Kejie; Fan, Shanhui

    2014-01-01

    The Aharonov-Bohm effect is one of the most intriguing phenomena in both classical and quantum physics, and associates with a number of important and fundamental issues in quantum mechanics. The Aharonov-Bohm effects of charged particles have been experimentally demonstrated and found applications in various fields. Recently, attention has also focused on the Aharonov-Bohm effect for neutral particles, such as photons. Here we propose to utilize the photon-phonon interactions to demonstrate that photonic Aharonov-Bohm effects do exist for photons. By introducing nonreciprocal phases for photons, we observe experimentally a gauge potential for photons in the visible range based on the photon-phonon interactions in acousto-optic crystals, and demonstrate the photonic Aharonov-Bohm effect. The results presented here point to new possibilities to control and manipulate photons by designing an effective gauge potential. PMID:24476790

  14. Photonic Aharonov–Bohm effect in photon–phonon interactions

    PubMed Central

    Li, Enbang; Eggleton, Benjamin J.; Fang, Kejie; Fan, Shanhui

    2014-01-01

    The Aharonov–Bohm effect is one of the most intriguing phenomena in both classical and quantum physics, and associates with a number of important and fundamental issues in quantum mechanics. The Aharonov–Bohm effects of charged particles have been experimentally demonstrated and found applications in various fields. Recently, attention has also focused on the Aharonov–Bohm effect for neutral particles, such as photons. Here we propose to utilize the photon–phonon interactions to demonstrate that photonic Aharonov–Bohm effects do exist for photons. By introducing nonreciprocal phases for photons, we observe experimentally a gauge potential for photons in the visible range based on the photon–phonon interactions in acousto-optic crystals, and demonstrate the photonic Aharonov–Bohm effect. The results presented here point to new possibilities to control and manipulate photons by designing an effective gauge potential. PMID:24476790

  15. Effective long-distance interaction from short-distance interaction in a periodically driven one-dimensional classical system

    NASA Astrophysics Data System (ADS)

    Guo, Lingzhen; Liu, Modan; Marthaler, Michael

    2016-05-01

    We study the classical dynamics of many interacting particles in a periodically driven one-dimensional (1D) system. We show that under the rotating wave approximation (RWA), a short-distance 1D interaction (δ function or hard-core interaction) becomes a long-distance two-dimensional (2D) interaction which only depends on the distance in the phase space of the rotating frame. The RWA interaction describes the effect of the interaction on the slowly changing amplitude and phase of the oscillating particles, while the fast oscillations take on the role of a force carrier, which allows for interaction over much larger effective distances.

  16. The Alström Syndrome Protein, ALMS1, Interacts with α-Actinin and Components of the Endosome Recycling Pathway

    PubMed Central

    Collin, Gayle B.; Marshall, Jan D.; King, Benjamin L.; Milan, Gabriella; Maffei, Pietro; Jagger, Daniel J.; Naggert, Jürgen K.

    2012-01-01

    Alström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS. PMID:22693585

  17. Climate-chemical interactions and greenhouse effects of trace gases

    NASA Technical Reports Server (NTRS)

    Shi, Guang-Yu; Fan, Xiao-Biao

    1994-01-01

    A completely coupled one-dimensional radiative-convective (RC) and photochemical-diffusion (PC) model has been developed recently and used to study the climate-chemical interactions. The importance of radiative-chemical interactions within the troposphere and stratosphere has been examined in some detail. We find that increases of radiatively and/or chemically active trace gases such as CO2, CH4 and N2O have both the direct effects and the indirect effects on climate change by changing the atmospheric O3 profile through their interaction with chemical processes in the atmosphere. It is also found that the climatic effect of ozone depends strongly on its vertical distribution throughout the troposphere and stratosphere, as well on its column amount in the atmosphere.

  18. Effective field theory of thermal Casimir interactions between anisotropic particles

    NASA Astrophysics Data System (ADS)

    Haussman, Robert C.; Deserno, Markus

    2014-06-01

    We employ an effective field theory (EFT) approach to study thermal Casimir interactions between objects bound to a fluctuating fluid surface or interface dominated by surface tension, with a focus on the effects of particle anisotropy. The EFT prescription disentangles the constraints imposed by the particles' boundaries from the calculation of the interaction free energy by constructing an equivalent point particle description. The finite-size information is captured in a derivative expansion that encodes the particles' response to external fields. The coefficients of the expansion terms correspond to generalized tensorial polarizabilities and are found by matching the results of a linear response boundary value problem computed in both the full and effective theories. We demonstrate the versatility of the EFT approach by constructing the general effective Hamiltonian for a collection of particles of arbitrary shapes. Taking advantage of the conformal symmetry of the Hamiltonian, we discuss a straightforward conformal mapping procedure to systematically determine the polarizabilities and derive a complete description for elliptical particles. We compute the pairwise interaction energies to several orders for nonidentical ellipses as well as their leading-order triplet interactions and discuss the resulting preferred pair and multibody configurations. Furthermore, we elaborate on the complications that arise with pinned particle boundary conditions and show that the powerlike corrections expected from dimensional analysis are exponentially suppressed by the leading-order interaction energies.

  19. Effective field theory of thermal Casimir interactions between anisotropic particles.

    PubMed

    Haussman, Robert C; Deserno, Markus

    2014-06-01

    We employ an effective field theory (EFT) approach to study thermal Casimir interactions between objects bound to a fluctuating fluid surface or interface dominated by surface tension, with a focus on the effects of particle anisotropy. The EFT prescription disentangles the constraints imposed by the particles' boundaries from the calculation of the interaction free energy by constructing an equivalent point particle description. The finite-size information is captured in a derivative expansion that encodes the particles' response to external fields. The coefficients of the expansion terms correspond to generalized tensorial polarizabilities and are found by matching the results of a linear response boundary value problem computed in both the full and effective theories. We demonstrate the versatility of the EFT approach by constructing the general effective Hamiltonian for a collection of particles of arbitrary shapes. Taking advantage of the conformal symmetry of the Hamiltonian, we discuss a straightforward conformal mapping procedure to systematically determine the polarizabilities and derive a complete description for elliptical particles. We compute the pairwise interaction energies to several orders for nonidentical ellipses as well as their leading-order triplet interactions and discuss the resulting preferred pair and multibody configurations. Furthermore, we elaborate on the complications that arise with pinned particle boundary conditions and show that the powerlike corrections expected from dimensional analysis are exponentially suppressed by the leading-order interaction energies. PMID:25019720

  20. Effect of interparticle interaction on magnetic hyperthermia in ferrofluids

    NASA Astrophysics Data System (ADS)

    Zubarev, A. Yu.; Iskakova, L.; Abu-Bakr, A. F.

    2015-11-01

    The work deals with the theoretical study of effect of magnetic interaction between single-domain ferromagnetic particles on the hyperthermia effect produced by these particles under the action of oscillating magnetic field. We consider a homogeneous (without heterogeneous aggregates) ferrofluid consisting of identical spherical Brownian particles. Effects of the particles diameter and their magnetic properties on the intensity of the heat production are studied.

  1. Effect of verteporfin-PDT on the Notch signaling pathway in cholangiocarcinoma (CCA) cell lines

    NASA Astrophysics Data System (ADS)

    Cerec, Virginie; Andreola, Fausto; Pereira, Stephen P.

    2009-06-01

    Accumulating preclinical and clinical evidence supports a pro-oncogenic function for Notch signaling in several solid tumors. Therefore, Notch inhibitory agents, such as gamma-secretase inhibitors (GSI), are being investigated as cancer therapeutic agents and a potential adjuvant to conventional chemo/radiotherapy. To date, no in vitro data are available on the cellular response and effect of either photodynamic therapy (PDT) or GSI on human cholangiocarcinoma (CCA). Consequently, we aimed to study the: (i) constitutive expression of Notch signaling pathway in CCA cell lines; (ii) response to Verteporfin-PDT and to GSI, as single agents on CCA cell lines; (iii) effect of Verteporfin-PDT on Notch signaling pathway expression. Expression of Notch signaling components was studied in two cholangiocarcinoma cell lines, HuCCT1 and TFK-1 (intra- and extrahepatic, respectively). No difference in basal expression of Notch1, 2 and Jagged1 was observed in either cell line. In contrast, Notch3 was found to be weakly and highly expressed in HuCCT1 and TFK-1 cells, respectively - supporting our recent microarray data which showed Notch3 overexpression in biliary brushings from patients with extrahepatic CCA. HuCCT1 and TFK-1 differentially responded to Verteporfin-PDT treatment; preliminary data showed no clear effect of GSI on proliferation/apoptosis in either cell line following short exposure (6 and 24h). Following Verteporfin-PDT, Notch1, 2 and Jagged-1 expression was down-regulated in both cell lines, while Notch3 expression was unaffected in HuCCT1 cells and down-regulated in TFK-1 cells. The Notch signaling pathway could represent a potential target for combination therapy in CCA treatment.

  2. Synergistic effects of curcumin and bevacizumab on cell signaling pathways in hepatocellular carcinoma.

    PubMed

    Gao, Jian-Zhi; DU, Jing-Li; Wang, Yong-Ling; Li, Jia; Wei, Li-Xin; Guo, Ming-Zhou

    2015-01-01

    The aim of the present study was to explore the effects of curcumin in combination with bevacizumab on the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)/K-ras pathway in hepatocellular carcinoma. A total of 30 Sprague Dawley (SD) rats were randomly divided into five groups: Control, model, curcumin, VEGF blocker, and curcumin + VEGF blocker groups. The mRNA levels of VEGF and VEGFR in all groups were subsequently measured by quantitative reverse transcriptase-polymerase chain reaction and the protein expression of K-ras was detected by western blot analysis. Compared with the control group, the mRNA levels of VEGF and VEGFR were revealed to be significantly increased in the model, curcumin and VEGF blocker groups. The VEGF mRNA levels in the curcumin, VEGF blocker and curcumin + VEGF blocker groups were all decreased when compared with the model group. In addition, the VEGF mRNA levels in the curcumin + VEGF blocker group were significantly lower compared with the curcumin group (P<0.05). The VEGF mRNA levels in the curcumin, VEGF blocker and curcumin + VEGF blocker groups were decreased when compared with the model group (P=0.0001). No significant differences in VEGF mRNA levels were identified between the VEGF blocker and curcumin groups (P=0.863), whereas the VEGF mRNA levels in the curcumin + VEGF blocker group were significantly lower than that of the curcumin group (P=0.025). Curcumin and the VEGF blocker are each capable of inhibiting hepatocellular carcinoma progression by regulating the VEGF/VEGFR/K-ras pathway. The combination of the two compounds has a synergistic effect on the inhibition of the effects of the VEGF signaling pathways in hepatocellular carcinoma progression. PMID:25435978

  3. Synergistic effects of curcumin and bevacizumab on cell signaling pathways in hepatocellular carcinoma

    PubMed Central

    GAO, JIAN-ZHI; DU, JING-LI; WANG, YONG-LING; LI, JIA; WEI, LI-XIN; GUO, MING-ZHOU

    2015-01-01

    The aim of the present study was to explore the effects of curcumin in combination with bevacizumab on the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)/K-ras pathway in hepatocellular carcinoma. A total of 30 Sprague Dawley (SD) rats were randomly divided into five groups: Control, model, curcumin, VEGF blocker, and curcumin + VEGF blocker groups. The mRNA levels of VEGF and VEGFR in all groups were subsequently measured by quantitative reverse transcriptase-polymerase chain reaction and the protein expression of K-ras was detected by western blot analysis. Compared with the control group, the mRNA levels of VEGF and VEGFR were revealed to be significantly increased in the model, curcumin and VEGF blocker groups. The VEGF mRNA levels in the curcumin, VEGF blocker and curcumin + VEGF blocker groups were all decreased when compared with the model group. In addition, the VEGF mRNA levels in the curcumin + VEGF blocker group were significantly lower compared with the curcumin group (P<0.05). The VEGF mRNA levels in the curcumin, VEGF blocker and curcumin + VEGF blocker groups were decreased when compared with the model group (P=0.0001). No significant differences in VEGF mRNA levels were identified between the VEGF blocker and curcumin groups (P=0.863), whereas the VEGF mRNA levels in the curcumin + VEGF blocker group were significantly lower than that of the curcumin group (P=0.025). Curcumin and the VEGF blocker are each capable of inhibiting hepatocellular carcinoma progression by regulating the VEGF/VEGFR/K-ras pathway. The combination of the two compounds has a synergistic effect on the inhibition of the effects of the VEGF signaling pathways in hepatocellular carcinoma progression. PMID:25435978

  4. [Effect of narcotic analgesics on impulse conduction along the afferent pathways of visceral nerves].

    PubMed

    Churiukanov, V V; Sinitsyn, L N

    1976-06-01

    Experiments were conducted on chloralose-anesthetized cats. The action of morphine and promedol upon the potentials of the cortical and subcortical structures occurring after the visceral nerve stimulation was studied. Morphine proved to depress the potentials evoked by stimulation of the inferior cardiac and vagus nerves, in the specific, associative and nonspecific structures of the brain; promedol produced an analogous effect. Morphine also inhibited the potentials occurring after the stimulation of the splanchnic nerve in the associative and nonspecific structures; depression of the responses in the specific pathways was less pronounced. PMID:953307

  5. The effect of fetal growth and nutrient stresses on steroid pathways.

    PubMed

    Stirrat, Laura I; Reynolds, Rebecca M

    2016-06-01

    The early life environment is a crucial time for establishing the trajectory of future health. Low birthweight is considered a marker of an adverse in utero environment and predisposes to cardio-metabolic disease later in life. It has been proposed that this is mediated by glucocorticoids, with life-long activation of the HPA axis. Here we review the evidence to support this hypothesis, with particular emphasis on the effects of fetal growth and nutrient stresses in utero on steroid pathways of the HPA axis. A better understanding of the mechanisms underlying these processes could help to optimize in utero health, and identify individuals at greatest risk of future disease. PMID:26196121

  6. PI3K/Akt signaling pathway is involved in the neurotrophic effect of senegenin.

    PubMed

    Pi, Ting; Zhou, Xiao-Wen; Cai, Liang; Zhang, Wei; Su, Chao-Fen; Wu, Wu-Tian; Ren, Xiao-Ming; Luo, Huan-Min

    2016-02-01

    Neurodegenerative diseases are frequently associated with the loss of synapses and neurons. Senegenin, extracted from the Chinese herb Polygala tenuifolia Willd, was previously found to promote neurite outgrowth and neuronal survival in primary cultured rat cortical neurons. The aim of the present study was to investigate the underlying mechanisms of senegenin-induced neurotrophic effects on rat cortical neurons. Primary cortical rat neurons were treated with various pharmacological antagonists and with or without senegenin, and subjected to MTT and western blot analysis to explore the effects of senegenin on cell survival as well as the activation of signaling pathways. Neurite outgrowth and neuronal survival induced by senegenin were significantly inhibited by A2A receptor antagonist ZM241385 and specific phosphoinositide-3 kinase (PI3K) inhibitor LY294002, but not by tropomyosin receptor kinase A receptor inhibitor K252a, mitogen-activated protein kinase kinase inhibitor PD98059 or protein kinase C inhibitor GÖ6976. Furthermore, senegenin enhanced the phosphorylation of Akt, which was blocked by LY294002. The present study revealed that the PI3K/Akt signaling pathway may be involved in the neurotrophic effects of senegenin. PMID:26647727

  7. The mechanisms for desensitization effect of synthetic polymers on BCHMX: Physical models and decomposition pathways.

    PubMed

    Yan, Qi-Long; Zeman, Svatopluk; Zhang, Xiao-Hong; Málek, Jiří; Xie, Wu-Xi

    2015-08-30

    The project involves determination of the activation energies and physical models for thermolysis of BCHMX and its PBXs. The initial decomposition pathways were also proposed on the basis of molecular dynamic simulation. The goal is to find the mutual relationships among the physical models, decomposition pathways, and the impact sensitivities for BCHMX and its PBXs. It has been shown that the physical model of the first step of BCHMX thermolysis is close to first order and the second step is governed by a first order autocatalytic model, which turns to "2D or 3D Nucleation and Growth" models under the effect of polymeric binders probably due to their hindrances on topochemical reaction of BCHMX. Simulation results show that the scission of N-NO2 is the initial step for BCHMX pyrolysis, followed by HONO and HNO eliminations, where the latter is due to nitro-nitrite rearrangement. Under the effect of hydrocarbon polymers, the HONO/HON elimination and collapse of ring structure of BCHMX occur earlier without changing the time for N-NO2 scission, which might be the reason why those polymers have little effect on the thermal stability of BCHMX, while they could make it decompose almost in a single complex step. PMID:25867587

  8. The antitumor effects of geraniol: Modulation of cancer hallmark pathways (Review).

    PubMed

    Cho, Minsoo; So, Insuk; Chun, Jung Nyeo; Jeon, Ju-Hong

    2016-05-01

    Geraniol is a dietary monoterpene alcohol that is found in the essential oils of aromatic plants. To date, experimental evidence supports the therapeutic or preventive effects of geraniol on different types of cancer, such as breast, lung, colon, prostate, pancreatic, and hepatic cancer, and has revealed the mechanistic basis for its pharmacological actions. In addition, geraniol sensitizes tumor cells to commonly used chemotherapy agents. Geraniol controls a variety of signaling molecules and pathways that represent tumor hallmarks; these actions of geraniol constrain the ability of tumor cells to acquire adaptive resistance against anticancer drugs. In the present review, we emphasize that geraniol is a promising compound or chemical moiety for the development of a safe and effective multi-targeted anticancer agent. We summarize the current knowledge of the effects of geraniol on target molecules and pathways in cancer cells. Our review provides novel insight into the challenges and perspectives with regard to geraniol research and to its application in future clinical investigation. PMID:26983575

  9. The antitumor effects of geraniol: Modulation of cancer hallmark pathways (Review)

    PubMed Central

    CHO, MINSOO; SO, INSUK; CHUN, JUNG NYEO; JEON, JU-HONG

    2016-01-01

    Geraniol is a dietary monoterpene alcohol that is found in the essential oils of aromatic plants. To date, experimental evidence supports the therapeutic or preventive effects of geraniol on different types of cancer, such as breast, lung, colon, prostate, pancreatic, and hepatic cancer, and has revealed the mechanistic basis for its pharmacological actions. In addition, geraniol sensitizes tumor cells to commonly used chemotherapy agents. Geraniol controls a variety of signaling molecules and pathways that represent tumor hallmarks; these actions of geraniol constrain the ability of tumor cells to acquire adaptive resistance against anticancer drugs. In the present review, we emphasize that geraniol is a promising compound or chemical moiety for the development of a safe and effective multi-targeted anticancer agent. We summarize the current knowledge of the effects of geraniol on target molecules and pathways in cancer cells. Our review provides novel insight into the challenges and perspectives with regard to geraniol research and to its application in future clinical investigation. PMID:26983575

  10. Effect of neostigmine on organ injury in murine endotoxemia: missing facts about the cholinergic antiinflammatory pathway.

    PubMed

    Akinci, Seda B; Ulu, Nadir; Yondem, Omer Z; Firat, Pinar; Guc, M Oguz; Kanbak, Meral; Aypar, Ulku

    2005-11-01

    Electrical and pharmacologic stimulation of the efferent cholinergic antiinflammatory pathway suppress the systemic inflammatory response and can prevent lethal endotoxemia. Neostigmine, a cholinergic agent, has not been tested to determine if it can prevent histopathologic organ injury in endotoxemia. In the present study, the effects of neostigmine treatment on the histopathologic organ injury inflicted by Escherichia coli endotoxin in a mouse model of septic shock was investigated. Endotoxemia in mice caused weight loss and increased spleen, liver, and lung weight. When the organs were examined for histopathologic injury, endotoxemia increased interstitial inflammation in the lungs, liver injury, and organ injury in general terms; neostigmine, at a dose of 0.1 mg/kg, failed to attenuate these effects. Although the simultaneous administration of neostigmine at a dose of 0.3 mg/kg and endotoxin decreased interstitial inflammation in the lungs, vacuolar degeneration in the liver, and total liver injury, mortality was increased with this dose in the presence of endotoxemia. We conclude that neostigmine at a dose of 0.1 mg/kg was not protective against histopathologic organ injury in mice with endotoxemia, and a higher dose (0.3 mg/kg) was not tolerated probably owing to nonspecific parasympathetic action including cardiovascular effects. Further studies are required to determine the contribution of sites in the cholinergic antiinflammatory pathway. PMID:16222449

  11. Leptin exerts proliferative and anti-apoptotic effects on goose granulosa cells through the PI3K/Akt/mTOR signaling pathway.

    PubMed

    Wen, Rui; Hu, Shenqiang; Xiao, Qihai; Han, Chunchun; Gan, Chao; Gou, Hua; Liu, Hehe; Li, Liang; Xu, Hengyong; He, Hua; Wang, Jiwen

    2015-05-01

    Leptin was known as a pivotal regulator for the control of food intake and energy expenditure. However, leptin has also been found to be involved in the regulation of female reproductive system through interactions with pathways in the hypothalamic-hypophyseal axis and direct action at the ovarian level. In the present study, granulosa cells from goose ovarian preovulatory (F1-F3) follicles were cultured with leptin (0, 1, 10 or 100ng/ml). The proliferative and anti-apoptotic actions of leptin in granulosa cells were revealed by CCK-8, BrdU and TUNEL assays. Quantitative real-time PCR and Western blot analyses further indicated that leptin treatment led to increased expression of cyclin D1, cyclin D2, cyclin D3 and bcl-2, and decreased expression of p21 and caspase-3. The effects were involved in the activation of the PI3K/Akt/mTOR signaling pathway, as leptin treatment enhanced the expression of PI3K, Akt1, Akt2, Raptor, mTOR, S6K and p-S6K. Moreover, blockade of the PI3K/Akt/mTOR pathway attenuated the influences of leptin on proliferation and apoptosis of granulosa cells, considering that activated factors by leptin were inhibited in the presence of either 20μM LY294002 (a PI3K inhibitor) or 10μM rapamycin (an mTOR inhibitor). In addition, leptin had a modulatory effect on the expression of its receptor at the transcriptional and translational levels, and blockade of PI3K/Akt/mTOR inhibited both basal and leptin-induced Lepr gene and protein expression. These findings suggest that leptin exerts its proliferative and anti-apoptotic effects on goose granulosa cells through the PI3K/Akt/mTOR signaling pathway via interaction with its receptor. PMID:25576904

  12. The Effects of Real-Time Interactive Multimedia Teleradiology System

    PubMed Central

    Al-Safadi, Lilac

    2016-01-01

    This study describes the design of a real-time interactive multimedia teleradiology system and assesses how the system is used by referring physicians in point-of-care situations and supports or hinders aspects of physician-radiologist interaction. We developed a real-time multimedia teleradiology management system that automates the transfer of images and radiologists' reports and surveyed physicians to triangulate the findings and to verify the realism and results of the experiment. The web-based survey was delivered to 150 physicians from a range of specialties. The survey was completed by 72% of physicians. Data showed a correlation between rich interactivity, satisfaction, and effectiveness. The results of our experiments suggest that real-time multimedia teleradiology systems are valued by referring physicians and may have the potential for enhancing their practice and improving patient care and highlight the critical role of multimedia technologies to provide real-time multimode interactivity in current medical care. PMID:27294118

  13. Effect of hydrogenation on interaction force among carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Fallah, Ahmadreza; Nakayama, Yoshikazu

    2013-04-01

    Hydrogenation of carbon nanotubes (CNTs) was achieved with flowing hydrogen gas and heating CNTs up to 800 °C. Electron microcopy images show the etching effect of the hydrogen as well as the appearance of defects after hydrogenation. Infrared spectroscopy confirmed the presence of CHx groups on the sidewalls of the functionalized CNTs. Raman spectra of the pristine and hydrogenated samples revealed a transition from graphitic to a disordered and defected structure by increasing the hydrogenation time. We measured the interaction force among CNTs in the pristine and hydrogenated samples. Results showed that the interaction force is reduced sharply upon hydrogenation. After examination of the relation between different experimentally obtained results and the interaction force trend, we discuss how hydrogenation affects the interaction force among CNTs by increasing roughness and formation of repulsive dipoles on the CNT surface.

  14. Interaction of Notch Signaling Modulator Numb with α-Adaptin Regulates Endocytosis of Notch Pathway Components and Cell Fate Determination of Neural Stem Cells*

    PubMed Central

    Song, Yan; Lu, Bingwei

    2012-01-01

    The ability to balance self-renewal and differentiation is a hallmark of stem cells. In Drosophila neural stem cells (NSCs), Numb/Notch (N) signaling plays a key role in this process. However, the molecular and cellular mechanisms underlying Numb function in a stem cell setting remain poorly defined. Here we show that α-Adaptin (α-Ada), a subunit of the endocytic AP-2 complex, interacts with Numb through a new mode of interaction to regulate NSC homeostasis. In α-ada mutants, N pathway component Sanpodo and the N receptor itself exhibited altered trafficking, and N signaling was up-regulated in the intermediate progenitors of type II NSC lineages, leading to their transformation into ectopic NSCs. Surprisingly, although the Ear domain of α-Ada interacts with the C terminus of Numb and is important for α-Ada function in the sensory organ precursor lineage, it was dispensable in the NSCs. Instead, α-Ada could regulate Sanpodo, N trafficking, and NSC homeostasis by interacting with Numb through new domains in both proteins previously not known to mediate their interaction. This interaction could be bypassed when α-Ada was directly fused to the phospho-tyrosine binding domain of Numb. Our results identify a critical role for the AP-2-mediated endocytosis in regulating NSC behavior and reveal a new mechanism by which Numb regulates NSC behavior through N. These findings are likely to have important implications for cancer biology. PMID:22474327

  15. Kaolin Foliar Application Has a Stimulatory Effect on Phenylpropanoid and Flavonoid Pathways in Grape Berries.

    PubMed

    Conde, Artur; Pimentel, Diana; Neves, Andreia; Dinis, Lia-Tânia; Bernardo, Sara; Correia, Carlos M; Gerós, Hernâni; Moutinho-Pereira, José

    2016-01-01

    Drought, elevated air temperature, and high evaporative demand are increasingly frequent during summer in grape growing areas like the Mediterranean basin, limiting grapevine productivity and berry quality. The foliar exogenous application of kaolin, a radiation-reflecting inert mineral, has proven effective in mitigating the negative impacts of these abiotic stresses in grapevine and other fruit crops, however, little is known about its influence on the composition of the grape berry and on key molecular mechanisms and metabolic pathways notably important for grape berry quality parameters. Here, we performed a thorough molecular and biochemical analysis to assess how foliar application of kaolin influences major secondary metabolism pathways associated with berry quality-traits, leading to biosynthesis of phenolics and anthocyanins, with a focus on the phenylpropanoid, flavonoid (both flavonol- and anthocyanin-biosynthetic) and stilbenoid pathways. In grape berries from different ripening stages, targeted transcriptional analysis by qPCR revealed that several genes involved in these pathways-VvPAL1, VvC4H1, VvSTSs, VvCHS1, VvFLS1, VvDFR, and VvUFGT-were more expressed in response to the foliar kaolin treatment, particularly in the latter maturation phases. In agreement, enzymatic activities of phenylalanine ammonia lyase (PAL), flavonol synthase (FLS), and UDP-glucose:flavonoid 3-O-glucosyltransferase (UFGT) were about two-fold higher in mature or fully mature berries from kaolin-treated plants, suggesting regulation also at a transcriptional level. The expression of the glutathione S-transferase VvGST4, and of the tonoplast anthocyanin transporters VvMATE1 and VvABCC1 were also all significantly increased at véraison and in mature berries, thus, when anthocyanins start to accumulate in the vacuole, in agreement with previously observed higher total concentrations of phenolics and anthocyanins in berries from kaolin-treated plants, especially at full maturity

  16. Pleiotrophin Exerts Its Migration and Invasion Effect through the Neuropilin-1 Pathway

    PubMed Central

    Elahouel, Rania; Blanc, Charly; Carpentier, Gilles; Frechault, Sophie; Cascone, Ilaria; Destouches, Damien; Delbé, Jean; Courty, José; Hamma-Kourbali, Yamina

    2015-01-01

    Pleiotrophin (PTN) is a pleiotropic growth factor that exhibits angiogenic properties and is involved in tumor growth and metastasis. Although it has been shown that PTN is expressed in tumor cells, few studies have investigated its receptors and their involvement in cell migration and invasion. Neuropilin-1 (NRP-1) is a receptor for multiple growth factors that mediates cell motility and plays an important role in angiogenesis and tumor progression. Here we provide evidence for the first time that NRP-1 is crucial for biological activities of PTN. We found that PTN interacted directly with NRP-1 through its thrombospondin type-I repeat domains. Importantly, binding of PTN to NRP-1 stimulated the internalization and recycling of NRP-1 at the cell surface. Invalidation of NRP-1 by RNA interference in human carcinoma cells inhibited PTN-induced intracellular signaling of the serine-threonine kinase, mitogen-activated protein MAP kinase, and focal adhesion kinase pathways. Accordingly, NRP-1 silencing or blocking by antibody inhibited PTN-induced human umbilical vein endothelial cell migration and tumor cell invasion. These results suggest that NRP-1/PTN interaction provides a novel mechanism for controlling the response of endothelial and tumoral cells to PTN and may explain, at least in part, how PTN contributes to tumor angiogenesis and cancer progression. PMID:26408254

  17. Pleiotrophin exerts its migration and invasion effect through the neuropilin-1 pathway.

    PubMed

    Elahouel, Rania; Blanc, Charly; Carpentier, Gilles; Frechault, Sophie; Cascone, Ilaria; Destouches, Damien; Delbé, Jean; Courty, José; Hamma-Kourbali, Yamina

    2015-08-01

    Pleiotrophin (PTN) is a pleiotropic growth factor that exhibits angiogenic properties and is involved in tumor growth and metastasis. Although it has been shown that PTN is expressed in tumor cells, few studies have investigated its receptors and their involvement in cell migration and invasion. Neuropilin-1 (NRP-1) is a receptor for multiple growth factors that mediates cell motility and plays an important role in angiogenesis and tumor progression. Here we provide evidence for the first time that NRP-1 is crucial for biological activities of PTN. We found that PTN interacted directly with NRP-1 through its thrombospondin type-I repeat domains. Importantly, binding of PTN to NRP-1 stimulated the internalization and recycling of NRP-1 at the cell surface. Invalidation of NRP-1 by RNA interference in human carcinoma cells inhibited PTN-induced intracellular signaling of the serine-threonine kinase, mitogen-activated protein MAP kinase, and focal adhesion kinase pathways. Accordingly, NRP-1 silencing or blocking by antibody inhibited PTN-induced human umbilical vein endothelial cell migration and tumor cell invasion. These results suggest that NRP-1/PTN interaction provides a novel mechanism for controlling the response of endothelial and tumoral cells to PTN and may explain, at least in part, how PTN contributes to tumor angiogenesis and cancer progression. PMID:26408254

  18. Evaluating differential effects using regression interactions and regression mixture models

    PubMed Central

    Van Horn, M. Lee; Jaki, Thomas; Masyn, Katherine; Howe, George; Feaster, Daniel J.; Lamont, Andrea E.; George, Melissa R. W.; Kim, Minjung

    2015-01-01

    Research increasingly emphasizes understanding differential effects. This paper focuses on understanding regression mixture models, a relatively new statistical methods for assessing differential effects by comparing results to using an interactive term in linear regression. The research questions which each model answers, their formulation, and their assumptions are compared using Monte Carlo simulations and real data analysis. The capabilities of regression mixture models are described and specific issues to be addressed when conducting regression mixtures are proposed. The paper aims to clarify the role that regression mixtures can take in the estimation of differential effects and increase awareness of the benefits and potential pitfalls of this approach. Regression mixture models are shown to be a potentially effective exploratory method for finding differential effects when these effects can be defined by a small number of classes of respondents who share a typical relationship between a predictor and an outcome. It is also shown that the comparison between regression mixture models and interactions becomes substantially more complex as the number of classes increases. It is argued that regression interactions are well suited for direct tests of specific hypotheses about differential effects and regression mixtures provide a useful approach for exploring effect heterogeneity given adequate samples and study design. PMID:26556903

  19. Integrated Sachs-Wolfe effect in interacting dark energy models

    SciTech Connect

    Olivares, German; Pavon, Diego; Atrio-Barandela, Fernando

    2008-05-15

    Models with dark energy decaying into dark matter have been proposed in cosmology to solve the coincidence problem. We study the effect of such coupling on the cosmic microwave background temperature anisotropies. The interaction changes the rate of evolution of the metric potentials and the growth rate of matter density perturbations and modifies the integrated Sachs-Wolfe component of cosmic microwave background temperature anisotropies, enhancing the effect. Cross correlation of galaxy catalogs with cosmic microwave background maps provides a model-independent test to constrain the interaction. We particularize our analysis for a specific interacting model and show that galaxy catalogs with median redshifts z{sub m}=0.1-0.9 can rule out models with an interaction parameter strength of c{sup 2}{approx_equal}0.1 better than 99.95% confidence level. Values of c{sup 2}{<=}0.01 are compatible with the data and may account for the possible discrepancy between the fraction of dark energy derived from Wilkinson microwave anisotropy probe 3 yr data and the fraction obtained from the integrated Sachs-Wolfe effect. Measuring the fraction of dark energy by these two methods could provide evidence of an interaction.

  20. Effects of an electric field on interaction of aromatic systems.

    PubMed

    Youn, Il Seung; Cho, Woo Jong; Kim, Kwang S

    2016-04-30

    The effect of uniform external electric field on the interactions between small aromatic compounds and an argon atom is investigated using post-HF (MP2, SCS-MP2, and CCSD(T)) and density functional (PBE0-D3, PBE0-TS, and vdW-DF2) methods. The electric field effect is quantified by the difference of interaction energy calculated in the presence and absence of the electric field. All the post-HF methods describe electric field effects accurately although the interaction energy itself is overestimated by MP2. The electric field effect is explained by classical electrostatic models, where the permanent dipole moment from mutual polarization mainly determines its sign. The size of π-conjugated system does not have significant effect on the electric field dependence. We found out that PBE0-based methods give reasonable interaction energies and electric field response in every case, while vdW-DF2 sometimes shows spurious artifact owing to its sensitivity toward the real space electron density. © 2015 Wiley Periodicals, Inc. PMID:26696236

  1. Cost-effectiveness analysis of a postoperative clinical care pathway in head and neck surgery with microvascular reconstruction

    PubMed Central

    2013-01-01

    Background The objective of this study is to evaluate the cost-effectiveness of a postoperative clinical care pathway for patients undergoing major head and neck oncologic surgery with microvascular reconstruction. Methods This is a comparative trial of a prospective treatment group managed on a postoperative clinical care pathway and a historical group managed prior to pathway implementation. Effectiveness outcomes evaluated were total hospital days, return to OR, readmission to ICU and rate of pulmonary complications. Costing perspective was from the government payer. Results 118 patients were included in the study. All outcomes demonstrated that the postoperative pathway group was both more effective and less costly, and is therefore a dominant clinical intervention. The overall mean pre- and post-pathway costs are $22,733 and $16,564 per patient, respectively. The incremental cost reduction associated with the postoperative pathway was $6,169 per patient. Conclusion Implementing the postoperative clinical care pathway in patients undergoing head and neck oncologic surgery with reconstruction resulted in improved clinical outcomes and reduced costs. PMID:24351020

  2. Biofluid mechanics of the human reproductive process: modelling of the complex interaction and pathway to the oocytes.

    PubMed

    Foo, Jong Yong Abdiel; Lim, Chu Sing

    2008-11-01

    Recent revelations in the human reproductive process have fuelled much interest in this field of study. In particular, the once prevailing view of large numbers of ejaculated sperms racing towards the egg has been refuted recently. This is opposed to the current views derived from numerous clinical findings that state that only a very small number of sperms will ever enter the oviduct. It is believed that these few sperms must have been guided to make the long, tedious and obstructed journey to the egg. For a mature spermatozoon, its hyperactivated swimming motility upon capacitation plays an important role in the fertilization of a mature egg. Likewise, the female genital tract also provides guiding mechanisms to complement the survival of normal hydrodynamic profile sperms and thus promotes an eventual sperm-egg interaction. Understanding these mechanisms can be essential for the derivation of assisted conception techniques especially those in vitro. With the aid of computational models and simulation, suitability and effectiveness of novel assisted conception methodology can be assessed, particularly for those yet to be ready for clinical trials. This review discusses the possible bioengineering models and the mechanisms by which human spermatozoa are guided to the egg. PMID:18652708

  3. Methylmercury causes neuronal cell death through the suppression of the TrkA pathway: In vitro and in vivo effects of TrkA pathway activators

    SciTech Connect

    Fujimura, Masatake; Usuki, Fusako

    2015-02-01

    Methylmercury (MeHg) is an environmental toxin which induces cell death specific for the nervous systems. Here we show that MeHg causes neuronal cell death through the suppression of the tropomyosin receptor kinase A (TrkA) pathway, and that compounds activating the TrkA pathway prevent MeHg-induced nerve damage in vitro and in vivo. We first investigated the mechanism of MeHg-induced neurotoxicity in differentiating neurons using PC12 cells. Exposure to 100 nM MeHg for 1 day induced apoptosis in differentiating PC12 cells. Further, MeHg-induced apoptosis was preceded by inhibition of neurite extension, as determined by ELISA analyses of the neurite-specific protein neurofilament triplet H protein (NF-H). To determine the mechanism of MeHg-induced apoptosis, we evaluated the effects of MeHg on the TrkA pathway, which is known to regulate neuronal differentiation and viability. Western blot analysis demonstrated that, like the TrkA phosphorylation inhibitor K252a, MeHg inhibited phosphorylation of TrkA and its downstream effectors. Furthermore, GM1 ganglioside and its analog MCC-257, which enhance TrkA phosphorylation, overcame the effect of MeHg in neurons, supporting the involvement of the TrkA pathway in MeHg-induced nerve damage. Finally, we demonstrated that MCC-257 rescued the clinical sign and pathological changes in MeHg-exposed rats. These findings indicate that MeHg-induced apoptosis in neuron is triggered by inhibition of the TrkA pathway, and that GM1 ganglioside and MCC-257 effectively prevent MeHg-induced nerve damage. - Highlights: • Exposure to 100 nM MeHg for 1 day induced apoptosis in differentiating PC12 cells. • Inhibition of neurite extension was involved in MeHg-induced apoptosis. • Like the TrkA phosphorylation inhibitor, MeHg inhibited phosphorylation of TrkA. • GM1 ganglioside and its analog effectively prevented MeHg-induced nerve damage.

  4. Interactions between the Isolated-Interactive Elements Effect and Levels of Learner Expertise: Experimental Evidence from an Accountancy Class

    ERIC Educational Resources Information Center

    Blayney, Paul; Kalyuga, Slava; Sweller, John

    2010-01-01

    This study investigated interactions between the isolated-interactive elements effect and levels of learner expertise with first year undergraduate university accounting students. The isolated-interactive elements effect occurs when learning is facilitated by initially presenting elements of information sequentially in an isolated form rather than…

  5. Differential impact of cumulative SES risk on methylation of protein–protein interaction pathways as a function of SLC6A4 genetic variation in African American young adults☆

    PubMed Central

    Beach, Steven R.H.; Dogan, Meeshanthini V.; Brody, Gene H.; Philibert, Robert A.

    2013-01-01

    Exposure to cumulative SES risk in childhood may interact with variability at the serotonin transporter linked polymorphic region (5HTTLPR) to alter DNA methylation across interacting sets of proteins. DNA was obtained from 388 African Americans at age 19. Genotype at the 5HTTLPR was determined, and methylation ratios for C-phosphate-G (CpG) residues were assessed. Exposure to cumulative SES risk was determined using repeated parental reports at ages 11–13. At high SES risk, CpG methylation patterns indicated altered cellular stress response in women, but not men, who carried a short allele at the 5HTTLPR. These changes in methylation patterns may lead to increases in mental and physical health risks. No genotype effect emerged for either women or men at low SES risk. Methylation patterns provide guidance in identifying pathways by which genetic susceptibility is transformed into adverse outcomes years later. PMID:24192273

  6. Differential impact of cumulative SES risk on methylation of protein-protein interaction pathways as a function of SLC6A4 genetic variation in African American young adults.

    PubMed

    Beach, Steven R H; Dogan, Meeshanthini V; Brody, Gene H; Philibert, Robert A

    2014-02-01

    Exposure to cumulative SES risk in childhood may interact with variability at the serotonin transporter linked polymorphic region (5HTTLPR) to alter DNA methylation across interacting sets of proteins. DNA was obtained from 388 African Americans at age 19. Genotype at the 5HTTLPR was determined, and methylation ratios for C-phosphate-G (CpG) residues were assessed. Exposure to cumulative SES risk was determined using repeated parental reports at ages 11-13. At high SES risk, CpG methylation patterns indicated altered cellular stress response in women, but not men, who carried a short allele at the 5HTTLPR. These changes in methylation patterns may lead to increases in mental and physical health risks. No genotype effect emerged for either women or men at low SES risk. Methylation patterns provide guidance in identifying pathways by which genetic susceptibility is transformed into adverse outcomes years later. PMID:24192273

  7. Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1.

    PubMed

    Hirata, Yasuko; Brems, Hilde; Suzuki, Mayu; Kanamori, Mitsuhiro; Okada, Masahiro; Morita, Rimpei; Llano-Rivas, Isabel; Ose, Toyoyuki; Messiaen, Ludwine; Legius, Eric; Yoshimura, Akihiko

    2016-02-12

    Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius syndrome, which consists of symptoms of multiple café-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing α-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120(GAP). Several mutations in these N- and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome. PMID:26635368

  8. Adverse Outcome Pathways and Ecological Risk Assessment: Bridging to Population Level Effects, Journal Article

    EPA Science Inventory

    The viability of populations of plants and animals is a key focus for environmental regulation. Population-level responses integrate the cumulative effects of chemical stressors on individuals as those individuals interact with and are affected by their con-specifics, competitor...

  9. Adverse Outcome Pathways and Ecological Risk Assessment: Bridging to Population Level Effects

    EPA Science Inventory

    The viability of populations of plants and animals is a key focus for environmental regulation. Population-level responses integrate the cumulative effects of chemical stressors on individuals as those individuals interact with and are affected by their con-specifics, competitor...

  10. Effect Of Interaction On Apertures Of Multisegmented Natural Veins

    NASA Astrophysics Data System (ADS)

    Sim, Y.; Germanovich, L. N.; Vermilye, J. M.

    2003-12-01

    Echelons of multisegmented fluid-driven natural fractures (such as dikes, veins, and sometimes joints) with consecutive overlapping are one of the most common types of structures in the Earth­_s crust. The mechanical behavior of these fractures is quite different from that of single fractures, because of the interaction between the segments. In this work we compute the apertures of a highly segmented calcite vein, with 71 segments, in siltstone (Culpeper Quarry, Virginia) described by Vermilye and Scholz [1995]. The effect of elastic interaction between the segments is considered at three different special scales and accurately evaluated by solving the corresponding system of singular integral equations. For comparison, the case of ignored interaction is also considered. Our results unambiguously suggest that the effect of interaction highly affects the vein apertures. By using two net pressures in the vein as fitting parameters, it is possible to obtain an excellent match of the computed and measured apertures (based on 3,000 data points). This indicates two episodes in the history of vein evolution. Based on the performed simulation, a concept of effective fracture (vein) has been suggested. This is a single fracture of the same overall size (length) as the real vein. It is also pressurized by two net pressures that are determined by fitting the field data. As a result, practically the same net pressures are obtained as by accounting for the full interaction between the vein segments. The concept of effective fracture allows the sufficiently accurate computation of the vein (fracture) apertures, but without considering the interaction between the multiple segments.

  11. Effects of cerivastatin on adrenergic pathways, hypertrophic growth and TGFbeta expression in adult ventricular cardiomyocytes.

    PubMed

    Maxeiner, Hagen; Abdallah, Yaser; Kuhlmann, Christoph Rüdiger Wolfram; Schlüter, Klaus-Dieter; Wenzel, Sibylle

    2012-05-01

    The effects of statin treatment in the setting of heart failure have already been shown. Nevertheless, there is little knowledge about its influence on adrenergic pathways in cardiomyocytes. Therefore, this study investigated the impact of cerivastatin on adrenoceptor-mediated signalling pathways in isolated adult ventricular cardiomyocytes. It focused on two endpoints: hypertrophic growth and TGFbeta expression. Cultured cardiomyocytes were used to study rac activation (analysed by its translocation into the membrane fraction), ROS formation (H(2)DCF fluorescence) and hypertrophic growth ((14)C-phenylalanine incorporation). Alpha- and beta-adrenoceptor stimulation showed significant differences regarding rac activation, ROS formation, and p38 MAP kinase activation. Both alpha- and beta-adrenoceptor stimulation induced TGFbeta expression. Upon activation of alpha-adrenergic signalling - although ROS formation was not influenced by cerivastatin - TGFbeta expression decreased. Following beta stimulation, TGFbeta expression as well as rac and p38 MAP kinase activation were reduced after pre-treatment with cerivastatin. Statin treatment did not show any influence on hypertrophic growth. In summary, this study clearly demonstrates the ability of adrenoceptor stimulation to increase TGFbeta expression. One component of the beneficial effects of statin therapy on heart failure might therefore be due to a dominant reduction and inhibition of TGFbeta, which is involved in many pathophysiological processes in cardiomyocytes. PMID:22365145

  12. Effects of Ghrelin on the Proteolytic Pathways of Alzheimer's Disease Neuronal Cells.

    PubMed

    Cecarini, Valentina; Bonfili, Laura; Cuccioloni, Massimiliano; Keller, Jeffrey N; Bruce-Keller, Annadora J; Eleuteri, Anna Maria

    2016-07-01

    Ghrelin is an orexigenic hormone with a role in the onset and progression of neurodegenerative disorders. It has been recently associated to Alzheimer's disease (AD) for its neuroprotective and anti-apoptotic activity. In the present study, we dissected the effect of ghrelin treatment on the two major intracellular proteolytic pathways, the ubiquitin-proteasome system (UPS) and autophagy, in cellular models of AD (namely SH-SY5Y neuroblastoma cells stably transfected with either the wild-type AβPP gene or the 717 valine-to-glycine AβPP-mutated gene). Ghrelin showed a growth-promoting effect on neuronal cells inducing also time-dependent modifications of the growth hormone secretagogue receptor type 1 (GHS-R1) expression. Interestingly, we demonstrated for the first time that ghrelin was able to activate the proteasome in neural cells playing also a role in the interplay between the UPS and autophagy. Our data provide a novel mechanism by which circulating hormones control neural homeostasis through the regulation of proteolytic pathways implicated in AD. PMID:26033219

  13. Time-dependent effects of treadmill exercise on aversive memory and cyclooxygenase pathway function.