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Sample records for identifies critical pathways

  1. Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis.

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    Meng, Yu-Xiu; Liu, Quan-Hong; Chen, Deng-Hong; Meng, Ying

    2017-06-01

    Despite advances in neonatal care, sepsis remains a major cause of morbidity and mortality in neonates worldwide. Pathway cross-talk analysis might contribute to the inference of the driving forces in bacterial sepsis and facilitate a better understanding of underlying pathogenesis of neonatal sepsis. This study aimed to explore the critical pathways associated with the progression of neonatal sepsis by the pathway cross-talk analysis. By integrating neonatal transcriptome data with known pathway data and protein-protein interaction data, we systematically uncovered the disease pathway cross-talks and constructed a disease pathway cross-talk network for neonatal sepsis. Then, attract method was employed to explore the dysregulated pathways associated with neonatal sepsis. To determine the critical pathways in neonatal sepsis, rank product (RP) algorithm, centrality analysis and impact factor (IF) were introduced sequentially, which synthetically considered the differential expression of genes and pathways, pathways cross-talks and pathway parameters in the network. The dysregulated pathways with the highest IF values as well as RPpathways in neonatal sepsis. By integrating three kinds of data, only 6919 common genes were included to perform the pathway cross-talk analysis. By statistic analysis, a total of 1249 significant pathway cross-talks were selected to construct the pathway cross-talk network. Moreover, 47 dys-regulated pathways were identified via attract method, 20 pathways were identified under RPpathways with the highest IF were also screened from the pathway cross-talk network. Among them, we selected 8 common pathways, i.e. critical pathways. In this study, we systematically tracked 8 critical pathways involved in neonatal sepsis by integrating attract method and pathway cross-talk network. These pathways might be responsible for the host response in infection, and of great value for advancing diagnosis and therapy of neonatal sepsis. Copyright © 2017

  2. Protecting Critical Infrastructure by Identifying Pathways of Exposure to Risk

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    Philip O’Neill

    2013-08-01

    Full Text Available Increasingly, our critical infrastructure is managed and controlled by computers and the information networks that connect them. Cyber-terrorists and other malicious actors understand the economic and social impact that a successful attack on these systems could have. While it is imperative that we defend against such attacks, it is equally imperative that we realize how best to react to them. This article presents the strongest-path method of analyzing all potential pathways of exposure to risk – no matter how indirect or circuitous they may be – in a network model of infrastructure and operations. The method makes direct use of expert knowledge about entities and dependency relationships without the need for any simulation or any other models. By using path analysis in a directed graph model of critical infrastructure, planners can model and assess the effects of a potential attack and develop resilient responses.

  3. A cross-study gene set enrichment analysis identifies critical pathways in endometriosis

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    Bai Chunyan

    2009-09-01

    Full Text Available Abstract Background Endometriosis is an enigmatic disease. Gene expression profiling of endometriosis has been used in several studies, but few studies went further to classify subtypes of endometriosis based on expression patterns and to identify possible pathways involved in endometriosis. Some of the observed pathways are more inconsistent between the studies, and these candidate pathways presumably only represent a fraction of the pathways involved in endometriosis. Methods We applied a standardised microarray preprocessing and gene set enrichment analysis to six independent studies, and demonstrated increased concordance between these gene datasets. Results We find 16 up-regulated and 19 down-regulated pathways common in ovarian endometriosis data sets, 22 up-regulated and one down-regulated pathway common in peritoneal endometriosis data sets. Among them, 12 up-regulated and 1 down-regulated were found consistent between ovarian and peritoneal endometriosis. The main canonical pathways identified are related to immunological and inflammatory disease. Early secretory phase has the most over-represented pathways in the three uterine cycle phases. There are no overlapping significant pathways between the dataset from human endometrial endothelial cells and the datasets from ovarian endometriosis which used whole tissues. Conclusion The study of complex diseases through pathway analysis is able to highlight genes weakly connected to the phenotype which may be difficult to detect by using classical univariate statistics. By standardised microarray preprocessing and GSEA, we have increased the concordance in identifying many biological mechanisms involved in endometriosis. The identified gene pathways will shed light on the understanding of endometriosis and promote the development of novel therapies.

  4. A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components.

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    Raghunath, Arathi; Sambarey, Awanti; Sharma, Neha; Mahadevan, Usha; Chandra, Nagasuma

    2015-04-29

    Ultraviolet radiations (UV) serve as an environmental stress for human skin, and result in melanogenesis, with the pigment melanin having protective effects against UV induced damage. This involves a dynamic and complex regulation of various biological processes that results in the expression of melanin in the outer most layers of the epidermis, where it can exert its protective effect. A comprehensive understanding of the underlying cross talk among different signalling molecules and cell types is only possible through a systems perspective. Increasing incidences of both melanoma and non-melanoma skin cancers necessitate the need to better comprehend UV mediated effects on skin pigmentation at a systems level, so as to ultimately evolve knowledge-based strategies for efficient protection and prevention of skin diseases. A network model for UV-mediated skin pigmentation in the epidermis was constructed and subjected to shortest path analysis. Virtual knock-outs were carried out to identify essential signalling components. We describe a network model for UV-mediated skin pigmentation in the epidermis. The model consists of 265 components (nodes) and 429 directed interactions among them, capturing the manner in which one component influences the other and channels information. Through shortest path analysis, we identify novel signalling pathways relevant to pigmentation. Virtual knock-outs or perturbations of specific nodes in the network have led to the identification of alternate modes of signalling as well as enabled determining essential nodes in the process. The model presented provides a comprehensive picture of UV mediated signalling manifesting in human skin pigmentation. A systems perspective helps provide a holistic purview of interconnections and complexity in the processes leading to pigmentation. The model described here is extensive yet amenable to expansion as new data is gathered. Through this study, we provide a list of important proteins essential

  5. Exploring critical pathways for urban water management to identify robust strategies under deep uncertainties.

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    Urich, Christian; Rauch, Wolfgang

    2014-12-01

    Long-term projections for key drivers needed in urban water infrastructure planning such as climate change, population growth, and socio-economic changes are deeply uncertain. Traditional planning approaches heavily rely on these projections, which, if a projection stays unfulfilled, can lead to problematic infrastructure decisions causing high operational costs and/or lock-in effects. New approaches based on exploratory modelling take a fundamentally different view. Aim of these is, to identify an adaptation strategy that performs well under many future scenarios, instead of optimising a strategy for a handful. However, a modelling tool to support strategic planning to test the implication of adaptation strategies under deeply uncertain conditions for urban water management does not exist yet. This paper presents a first step towards a new generation of such strategic planning tools, by combing innovative modelling tools, which coevolve the urban environment and urban water infrastructure under many different future scenarios, with robust decision making. The developed approach is applied to the city of Innsbruck, Austria, which is spatially explicitly evolved 20 years into the future under 1000 scenarios to test the robustness of different adaptation strategies. Key findings of this paper show that: (1) Such an approach can be used to successfully identify parameter ranges of key drivers in which a desired performance criterion is not fulfilled, which is an important indicator for the robustness of an adaptation strategy; and (2) Analysis of the rich dataset gives new insights into the adaptive responses of agents to key drivers in the urban system by modifying a strategy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Critical nodes in signalling pathways

    DEFF Research Database (Denmark)

    Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

    2006-01-01

    Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role...

  7. CSGene: a literature-based database for cell senescence genes and its application to identify critical cell aging pathways and associated diseases.

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    Zhao, M; Chen, L; Qu, H

    2016-01-14

    Cell senescence is a cellular process in which normal diploid cells cease to replicate and is a major driving force for human cancers and aging-associated diseases. Recent studies on cell senescence have identified many new genetic components and pathways that control cell aging. However, there is no comprehensive resource for cell senescence that integrates various genetic studies and relationships with cell senescence, and the risk associated with complex diseases such as cancer is still unexplored. We have developed the first literature-based gene resource for exploring cell senescence genes, CSGene. We complied 504 experimentally verified genes from public data resources and published literature. Pathway analyses highlighted the prominent roles of cell senescence genes in the control of rRNA gene transcription and unusual rDNA repeat that constitute a center for the stability of the whole genome. We also found a strong association of cell senescence with HIV-1 infection and viral carcinogenesis that are mainly related to promoter/enhancer binding and chromatin modification processes. Moreover, pan-cancer mutation and network analysis also identified common cell aging mechanisms in cancers and uncovered a highly modular network structure. These results highlight the utility of CSGene for elucidating the complex cellular events of cell senescence.

  8. Identifying pathways affected by cancer mutations.

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    Iengar, Prathima

    2017-12-16

    Mutations in 15 cancers, sourced from the COSMIC Whole Genomes database, and 297 human pathways, arranged into pathway groups based on the processes they orchestrate, and sourced from the KEGG pathway database, have together been used to identify pathways affected by cancer mutations. Genes studied in ≥15, and mutated in ≥10 samples of a cancer have been considered recurrently mutated, and pathways with recurrently mutated genes have been considered affected in the cancer. Novel doughnut plots have been presented which enable visualization of the extent to which pathways and genes, in each pathway group, are targeted, in each cancer. The 'organismal systems' pathway group (including organism-level pathways; e.g., nervous system) is the most targeted, more than even the well-recognized signal transduction, cell-cycle and apoptosis, and DNA repair pathway groups. The important, yet poorly-recognized, role played by the group merits attention. Pathways affected in ≥7 cancers yielded insights into processes affected. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Identifying Critical States through the Relevance Index

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    Andrea Roli

    2017-02-01

    Full Text Available The identification of critical states is a major task in complex systems, and the availability of measures to detect such conditions is of utmost importance. In general, criticality refers to the existence of two qualitatively different behaviors that the same system can exhibit, depending on the values of some parameters. In this paper, we show that the relevance index may be effectively used to identify critical states in complex systems. The relevance index was originally developed to identify relevant sets of variables in dynamical systems, but in this paper, we show that it is also able to capture features of criticality. The index is applied to two prominent examples showing slightly different meanings of criticality, namely the Ising model and random Boolean networks. Results show that this index is maximized at critical states and is robust with respect to system size and sampling effort. It can therefore be used to detect criticality.

  10. Historical emissions critical for mapping decarbonization pathways

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    Majkut, J.; Kopp, R. E.; Sarmiento, J. L.; Oppenheimer, M.

    2016-12-01

    Policymakers have set a goal of limiting temperature increase from human influence on the climate. This motivates the identification of decarbonization pathways to stabilize atmospheric concentrations of CO2. In this context, the future behavior of CO2 sources and sinks define the CO2 emissions necessary to meet warming thresholds with specified probabilities. We adopt a simple model of the atmosphere-land-ocean carbon balance to reflect uncertainty in how natural CO2 sinks will respond to increasing atmospheric CO2 and temperature. Bayesian inversion is used to estimate the probability distributions of selected parameters of the carbon model. Prior probability distributions are chosen to reflect the behavior of CMIP5 models. We then update these prior distributions by running historical simulations of the global carbon cycle and inverting with observationally-based inventories and fluxes of anthropogenic carbon in the ocean and atmosphere. The result is a best-estimate of historical CO2 sources and sinks and a model of how CO2 sources and sinks will vary in the future under various emissions scenarios, with uncertainty. By linking the carbon model to a simple climate model, we calculate emissions pathways and carbon budgets consistent with meeting specific temperature thresholds and identify key factors that contribute to remaining uncertainty. In particular, we show how the assumed history of CO2 emissions from land use change (LUC) critically impacts estimates of the strength of the land CO2 sink via CO2 fertilization. Different estimates of historical LUC emissions taken from the literature lead to significantly different parameterizations of the carbon system. High historical CO2 emissions from LUC lead to a more robust CO2 fertilization effect, significantly lower future atmospheric CO2 concentrations, and an increased amount of CO2 that can be emitted to satisfy temperature stabilization targets. Thus, in our model, historical LUC emissions have a

  11. Identifying pathways of teachers’ PCK development

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    Wongsopawiro, Dirk S.; Zwart, Rosanne C.; van Driel, Jan H.

    2017-01-01

    This paper describes a method of analysing teacher growth in the context of science education. It focuses on the identification of pathways in the development of secondary school teachers’ pedagogical content knowledge (PCK) by the use of the interconnected model of teachers’ professional growth

  12. A novel method to identify hub pathways of rheumatoid arthritis based on differential pathway networks.

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    Wei, Shi-Tong; Sun, Yong-Hua; Zong, Shi-Hua

    2017-09-01

    The aim of the current study was to identify hub pathways of rheumatoid arthritis (RA) using a novel method based on differential pathway network (DPN) analysis. The present study proposed a DPN where protein‑protein interaction (PPI) network was integrated with pathway‑pathway interactions. Pathway data was obtained from background PPI network and the Reactome pathway database. Subsequently, pathway interactions were extracted from the pathway data by building randomized gene‑gene interactions and a weight value was assigned to each pathway interaction using Spearman correlation coefficient (SCC) to identify differential pathway interactions. Differential pathway interactions were visualized using Cytoscape to construct a DPN. Topological analysis was conducted to identify hub pathways that possessed the top 5% degree distribution of DPN. Modules of DPN were mined according to ClusterONE. A total of 855 pathways were selected to build pathway interactions. By filtrating pathway interactions of weight values >0.7, a DPN with 312 nodes and 791 edges was obtained. Topological degree analysis revealed 15 hub pathways, such as heparan sulfate/heparin‑glycosaminoglycan (HS‑GAG) degradation, HS‑GAG metabolism and keratan sulfate degradation for RA based on DPN. Furthermore, hub pathways were also important in modules, which validated the significance of hub pathways. In conclusion, the proposed method is a computationally efficient way to identify hub pathways of RA, which identified 15 hub pathways that may be potential biomarkers and provide insight to future investigation and treatment of RA.

  13. CRITICAL RADIONUCLIDE AND PATHWAY ANALYSIS FOR THE SAVANNAH RIVER SITE

    Energy Technology Data Exchange (ETDEWEB)

    Jannik, T.

    2011-08-30

    This report is an update to the analysis, Assessment of SRS Radiological Liquid and Airborne Contaminants and Pathways, that was performed in 1997. An electronic version of this large original report is included in the attached CD to this report. During the operational history (1954 to the present) of the Savannah River Site (SRS), many different radionuclides have been released to the environment from the various production facilities. However, as will be shown by this updated radiological critical contaminant/critical pathway analysis, only a small number of the released radionuclides have been significant contributors to potential doses and risks to offsite people. The analysis covers radiological releases to the atmosphere and to surface waters, the principal media that carry contaminants offsite. These releases potentially result in exposure to offsite people. The groundwater monitoring performed at the site shows that an estimated 5 to 10% of SRS has been contaminated by radionuclides, no evidence exists from the extensive monitoring performed that groundwater contaminated with these constituents has migrated off the site (SRS 2011). Therefore, with the notable exception of radiological source terms originating from shallow surface water migration into site streams, onsite groundwater was not considered as a potential exposure pathway to offsite people. In addition, in response to the Department of Energy's (DOE) Order 435.1, several Performance Assessments (WSRC 2008; LWO 2009; SRR 2010; SRR 2011) and a Comprehensive SRS Composite Analysis (SRNO 2010) have recently been completed at SRS. The critical radionuclides and pathways identified in these extensive reports are discussed and, where applicable, included in this analysis.

  14. Automated network analysis identifies core pathways in glioblastoma.

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    Ethan Cerami

    2010-02-01

    Full Text Available Glioblastoma multiforme (GBM is the most common and aggressive type of brain tumor in humans and the first cancer with comprehensive genomic profiles mapped by The Cancer Genome Atlas (TCGA project. A central challenge in large-scale genome projects, such as the TCGA GBM project, is the ability to distinguish cancer-causing "driver" mutations from passively selected "passenger" mutations.In contrast to a purely frequency based approach to identifying driver mutations in cancer, we propose an automated network-based approach for identifying candidate oncogenic processes and driver genes. The approach is based on the hypothesis that cellular networks contain functional modules, and that tumors target specific modules critical to their growth. Key elements in the approach include combined analysis of sequence mutations and DNA copy number alterations; use of a unified molecular interaction network consisting of both protein-protein interactions and signaling pathways; and identification and statistical assessment of network modules, i.e. cohesive groups of genes of interest with a higher density of interactions within groups than between groups.We confirm and extend the observation that GBM alterations tend to occur within specific functional modules, in spite of considerable patient-to-patient variation, and that two of the largest modules involve signaling via p53, Rb, PI3K and receptor protein kinases. We also identify new candidate drivers in GBM, including AGAP2/CENTG1, a putative oncogene and an activator of the PI3K pathway; and, three additional significantly altered modules, including one involved in microtubule organization. To facilitate the application of our network-based approach to additional cancer types, we make the method freely available as part of a software tool called NetBox.

  15. Integrated Analysis Identifies Interaction Patterns between Small Molecules and Pathways

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    Li, Yan; Li, Weiguo; Chen, Xin; Sun, Jiatong; Chen, Huan; Lv, Sali

    2014-01-01

    Previous studies have indicated that the downstream proteins in a key pathway can be potential drug targets and that the pathway can play an important role in the action of drugs. So pathways could be considered as targets of small molecules. A link map between small molecules and pathways was constructed using gene expression profile, pathways, and gene expression of cancer cell line intervened by small molecules and then we analysed the topological characteristics of the link map. Three link patterns were identified based on different drug discovery implications for breast, liver, and lung cancer. Furthermore, molecules that significantly targeted the same pathways tended to treat the same diseases. These results can provide a valuable reference for identifying drug candidates and targets in molecularly targeted therapy. PMID:25114931

  16. Using Proteomics to 1) Identify the Bone Marrow Homing Receptors Expressed on Human Hematopoietic Stem Cells and 2) Elucidate Critical Signaling Pathways Responsible for the Blockage of Hematopoietic Differentiation in Leukemia

    KAUST Repository

    Chin, Chee J.

    2011-05-22

    Successful hematopoiesis requires the trafficking of hematopoietic stem/progenitor cells (HSPCs) to their bone marrow (BM) niche, where they can differentiate to produce all blood lineages. Leukemia arises when there is a blockage of differentiation and uncontrolled proliferation in the hematopoietic cells during their development. To refine therapies for leukemia, this study sought to improve the homing of healthy donor HSPCs for better transplantation and to find new candidates for differentiating and blocking proliferation in leukemic cells. Characterizing the molecular effectors mediating cell migration forms the basis for improving clinical transplantation of HSPCs. E-selectin/ligand interactions play a critical role in the homing of HSPCs to the BM, however, the identity of E-selectin ligands remains elusive. We aimed to use mass spectrometry (MS) to fully analyze the E-selectin ligands expressed on HSPCs. Immunoprecipitation studies coupled with MS confirmed the expression of three known E-selectin ligands, the hematopoietic cell E-/L-selectin ligand (HCELL), P-selectin glycoprotein ligand-1 (PSGL-1) and CD43, and revealed the presence of many interesting candidates on HSPCs-like cell line and on primary human BM CD34+ cells. The MS dataset represents a rich resource for further characterization of E-selectin ligands, which will lead to improvement of HSPCs transplantation. 4 Understanding the critical pathways underlying the initiation and maintenance of leukemia plays a key role in treating acute myeloid leukemia (AML). Ligation of the glycoprotein, CD44, using monoclonal antibodies or its natural ligand, hyaluronic acid, drives the differentiation of immature leukemic cells towards mature terminally differentiated cells, inhibits their proliferation and in some case induces their apoptosis. The aim of this study is to characterize the phosphoproteome of AML cells in response to CD44-induced differentiation. This will afford novel insights into the

  17. Decreasing medical complications for total knee arthroplasty: Effect of Critical Pathways on Outcomes

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    Solomon Daniel H

    2010-07-01

    Full Text Available Abstract Background Studies on critical pathway use have demonstrated decreased length of stay and cost without compromise in quality of care. However, pathway effectiveness is difficult to determine given methodological flaws, such as small or single center cohorts. We studied the effect of critical pathways on total knee replacement outcomes in a large population-based study. Methods We identified hospitals in four US states that performed total knee replacements. We sent a questionnaire to surgical administrators in these hospitals including items about critical pathway use and hospital characteristics potentially related to outcomes. Patient data were obtained from Medicare claims, including demographics, comorbidities, 90-day postoperative complications and length of hospital stay. The principal outcome measure was the risk of having one or more postoperative complications. Results Two hundred ninety five hospitals (73% responded to the questionnaire, with 201 reporting the use of critical pathways. 9,157 Medicare beneficiaries underwent TKR in these hospitals with a mean age of 74 years (± 5.8. After adjusting for both patient and hospital related variables, patients in hospitals with pathways were 32% less likely to have a postoperative complication compared to patients in hospitals without pathways (OR 0.68, 95% CI 0.50-0.92. Patients managed on a critical pathway had an average length of stay 0.5 days (95% CI 0.3-0.6 shorter than patients not managed on a pathway. Conclusion Medicare patients undergoing total knee replacement surgery in hospitals that used critical pathways had fewer postoperative complications than patients in hospitals without pathways, even after adjusting for patient and hospital related factors. This study has helped to establish that critical pathway use is associated with lower rates of postoperative mortality and complications following total knee replacement after adjusting for measured variables.

  18. Using Proteomics To Elucidate Critical Signaling Pathways

    KAUST Repository

    Ahmed, Heba

    2012-11-01

    Despite important advances in the therapy of acute myeloid leukemia (AML) the majority of patients will die from their disease (Appelbaum, Rowe, Radich, & Dick, 2001). Characterization of the aberrant molecular pathways responsible for this malignancy provides a platform to discover alternative treatments to help alter the fate of patients. AML is characterized by a blockage in the differentiation of myeloid cells resulting in the accumulation of highly proliferating immature hematopoietic cells. Since treatments such as chemotherapy rarely destroy the leukemic cells entirely, differentiation induction therapy has become a very attractive treatment option. Interestingly, previous experiments have shown that ligation of CD44, a cell surface glycoprotein strongly expressed on all AML cells, with anti-CD44 monoclonal antibodies (mAbs) could reverse this block in differentiation of leukemic blasts regardless of the AML subtype. To expand the understanding of the cellular regulation and circuitry involved, we aim to apply quantitative phosphoproteomics to monitor dynamic changes in phosphorylation state in response to anti-CD44 treatment. Protein phosphorylation and dephosphorylation is a highly controlled biochemical process that responds to various intracellular and extracellular stimuli. As phosphorylation is a dynamic process, quantification of these phosphorylation events would be vastly insightful. The main objective of this project is to determine the differentiation-dependent phosphoproteome of AML cells upon treatment of cells with the anti-CD44 mAb.In these experiments, optimization of protein extraction, phosphopeptide enrichment and data processing and analysis has been achieved. The primary results show successful phosphoproteome extraction complemented with efficient phosphopeptide enrichment and informative data processing. Further quantification with stable isotope labeling techniques is anticipated to provide candidates for targeted therapy.

  19. The node-weighted Steiner tree approach to identify elements of cancer-related signaling pathways.

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    Sun, Yahui; Ma, Chenkai; Halgamuge, Saman

    2017-12-28

    Cancer constitutes a momentous health burden in our society. Critical information on cancer may be hidden in its signaling pathways. However, even though a large amount of money has been spent on cancer research, some critical information on cancer-related signaling pathways still remains elusive. Hence, new works towards a complete understanding of cancer-related signaling pathways will greatly benefit the prevention, diagnosis, and treatment of cancer. We propose the node-weighted Steiner tree approach to identify important elements of cancer-related signaling pathways at the level of proteins. This new approach has advantages over previous approaches since it is fast in processing large protein-protein interaction networks. We apply this new approach to identify important elements of two well-known cancer-related signaling pathways: PI3K/Akt and MAPK. First, we generate a node-weighted protein-protein interaction network using protein and signaling pathway data. Second, we modify and use two preprocessing techniques and a state-of-the-art Steiner tree algorithm to identify a subnetwork in the generated network. Third, we propose two new metrics to select important elements from this subnetwork. On a commonly used personal computer, this new approach takes less than 2 s to identify the important elements of PI3K/Akt and MAPK signaling pathways in a large node-weighted protein-protein interaction network with 16,843 vertices and 1,736,922 edges. We further analyze and demonstrate the significance of these identified elements to cancer signal transduction by exploring previously reported experimental evidences. Our node-weighted Steiner tree approach is shown to be both fast and effective to identify important elements of cancer-related signaling pathways. Furthermore, it may provide new perspectives into the identification of signaling pathways for other human diseases.

  20. Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders.

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    Ileena Mitra

    2017-01-01

    Full Text Available Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies, we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02. We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10-16, with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.

  1. Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus.

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    Aterido, Adrià; Julià, Antonio; Carreira, Patricia; Blanco, Ricardo; López-Longo, José Javier; Venegas, José Javier Pérez; Olivé, Àlex; Andreu, José Luís; Aguirre-Zamorano, Maria Ángeles; Vela, Paloma; Nolla, Joan M; Marenco-de la Fuente, José Luís; Zea, Antonio; Pego, José María; Freire, Mercedes; Díez, Elvira; López-Lasanta, María; López-Corbeto, Mireia; Palau, Núria; Tortosa, Raül; Gelpí, Josep Lluís; Absher, Devin; Myers, Richard M; Fernández-Nebro, Antonio; Marsal, Sara

    2017-06-15

    Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR ) oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis

  2. Identifying critical thinking indicators and critical thinker attributes in nursing practice.

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    Chao, Shu-Yuan; Liu, Hsing-Yuan; Wu, Ming-Chang; Clark, Mary Jo; Tan, Jung-Ying

    2013-09-01

    Critical thinking is an essential skill in the nursing process. Although several studies have evaluated the critical thinking skills of nurses, there is limited information related to the indicators of critical thinking or evaluation of critical thinking in the context of the nursing process. This study investigated the potential indicators of critical thinking and the attributes of critical thinkers in clinical nursing practice. Knowledge of these indicators can aid the development of tools to assess nursing students' critical thinking skills. The study was conducted between September 2009 and August 2010. In phase 1, a literature review and four focus groups were conducted to identify the indicators of critical thinking in the context of nursing and the attributes of critical thinkers. In phase 2, 30 nursing professionals participated in a modified Delphi research survey to establish consensus and the appropriateness of each indicator and attribute identified in phase 1. We identified 37 indicators of critical thinking and 10 attributes of critical thinkers. The indicators were categorized into five subscales within the context of the nursing process toreflect nursing clinical practice: assessment, 16 indicators of ability to apply professional knowledge and skills to analyze and interpret patient problems; diagnosis, five indicators of ability to propose preliminary suppositions; planning, five indicators of ability to develop problem-solving strategies; implementation, five indicators of ability to implement planning; and evaluation, six indicators of ability to self-assess and reflect. The study operationalized critical thinking into a practical indicator suitable for nursing contexts in which critical thinking is required for clinical problem solving. Identified indicators and attributes can assist clinical instructors to evaluate student critical thought skills and development-related teaching strategies.

  3. Genetic screens to identify new Notch pathway mutants in Drosophila.

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    Giagtzoglou, Nikolaos

    2014-01-01

    Notch signaling controls a wide range of developmental processes, including proliferation, apoptosis, and cell fate specification during both development and adult tissue homeostasis. The functional versatility of the Notch signaling pathway is tightly linked with the complexity of its regulation in different cellular contexts. To unravel the complexity of Notch signaling, it is important to identify the different components of the Notch signaling pathway. A powerful strategy to accomplish this task is based on genetic screens. Given that the developmental context of signaling is important, these screens should be customized to specific cell populations or tissues. Here, I describe how to perform F1 clonal forward genetic screens in Drosophila to identify novel components of the Notch signaling pathway. These screens combine a classical EMS (ethyl methanesulfonate) chemical mutagenesis protocol along with clonal analysis via FRT-mediated mitotic recombination. These F1 clonal screens allow rapid phenotypic screening within clones of mutant cells induced at specific developmental stages and in tissues of interest, bypassing the pleiotropic effects of isolated mutations. More importantly, since EMS mutations have been notoriously difficult to map to specific genes in the past, I briefly discuss mapping methods that allow rapid identification of the causative mutations.

  4. Small molecule screening identifies targetable zebrafish pigmentation pathways

    DEFF Research Database (Denmark)

    Colanesi, Sarah; Taylor, Kerrie L; Temperley, Nicholas D

    2012-01-01

    Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish and investig......Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish...... and investigate the effects of a few of these compounds in further detail. We identified and confirmed 57 compounds that altered pigment cell patterning, number, survival, or differentiation. Additional tissue targets and toxicity of small molecules are also discussed. Given that the majority of cell types...

  5. Mathematical Teaching Strategies: Pathways to Critical Thinking and Metacognition

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    Su, Hui Fang Huang; Ricci, Frederick A.; Mnatsakanian, Mamikon

    2016-01-01

    A teacher that emphasizes reasoning, logic and validity gives their students access to mathematics as an effective way of practicing critical thinking. All students have the ability to enhance and expand their critical thinking when learning mathematics. Students can develop this ability when confronting mathematical problems, identifying possible…

  6. Critical Radionuclide and Pathway Analysis for the Savannah River Site, 2016 Update

    Energy Technology Data Exchange (ETDEWEB)

    Jannik, Tim [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Hartman, Larry [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2016-09-08

    During the operational history of Savannah River Site, many different radionuclides have been released from site facilities. However, as shown in this analysis, only a relatively small number of the released radionuclides have been significant contributors to doses to the offsite public. This report is an update to the 2011 analysis, Critical Radionuclide and Pathway Analysis for the Savannah River Site. SRS-based Performance Assessments for E-Area, Saltstone, F-Tank Farm, H-Tank Farm, and a Comprehensive SRS Composite Analysis have been completed. The critical radionuclides and pathways identified in those extensive reports are also detailed and included in this analysis.

  7. Critical pathways of change in fruit export regions at desert margin (Chile)

    DEFF Research Database (Denmark)

    Frederiksen, Peter

    The purpose is to elucidate how critical pathways function in a fruit export region at the desert margin in Chile. The region was investigated at the system level as an open land system with managed fruit plantations in a geographically complex valley. Data collection procedures included total...... of barriers and the creation of possibilities were related to land tenure and water rights. Resulting pathways were physical, biological, societal and cultural. A clear differentiation of regional pathways was identified between plantation owners and smallholder farmers. Founder effects at different time...

  8. Comparative Transcriptomics to Identify Novel Genes and Pathways in Dinoflagellates

    Science.gov (United States)

    Ryan, D.

    2016-02-01

    The unarmored dinoflagellate Karenia brevis is among the most prominent harmful, bloom-forming phytoplankton species in the Gulf of Mexico. During blooms, the polyketides PbTx-1 and PbTx-2 (brevetoxins) are produced by K. brevis. Brevetoxins negatively impact human health and the Gulf shellfish harvest. However, the genes underlying brevetoxin synthesis are currently unknown. Because the K. brevis genome is extremely large ( 1 × 1011 base pairs long), and with a high proportion of repetitive, non-coding DNA, it has not been sequenced. In fact, large, repetitive genomes are common among the dinoflagellate group. High-throughput RNA sequencing technology enabled us to assemble Karenia transcriptomes de novo and investigate potential genes in the brevetoxin pathway through comparative transcriptomics. The brevetoxin profile varies among K. brevis clonal cultures. For example, well-documented Wilson-CCFWC268 typically produces 8-10 pg PbTx per cell, whereas SP1 produces polyketide synthases (PKSs), were only expressed by brevetoxin-producing K. brevis and K. papilionacea, not K. mikimotoi. Examination of gene expression between the typical- and low-toxin Wilson clones identified about 3,500 genes with significantly different expression levels, including 2 putative PKSs. One of the 2 PKSs was only found in the brevetoxin-producing Karenia species. These transcriptomes could not have been characterized without high-throughput RNA sequencing.

  9. Simple Model for Identifying Critical Regions in Atrial Fibrillation

    Science.gov (United States)

    Christensen, Kim; Manani, Kishan A.; Peters, Nicholas S.

    2015-01-01

    Atrial fibrillation (AF) is the most common abnormal heart rhythm and the single biggest cause of stroke. Ablation, destroying regions of the atria, is applied largely empirically and can be curative but with a disappointing clinical success rate. We design a simple model of activation wave front propagation on an anisotropic structure mimicking the branching network of heart muscle cells. This integration of phenomenological dynamics and pertinent structure shows how AF emerges spontaneously when the transverse cell-to-cell coupling decreases, as occurs with age, beyond a threshold value. We identify critical regions responsible for the initiation and maintenance of AF, the ablation of which terminates AF. The simplicity of the model allows us to calculate analytically the risk of arrhythmia and express the threshold value of transversal cell-to-cell coupling as a function of the model parameters. This threshold value decreases with increasing refractory period by reducing the number of critical regions which can initiate and sustain microreentrant circuits. These biologically testable predictions might inform ablation therapies and arrhythmic risk assessment.

  10. Identifying the Vulnerabilities of Working Coasts Supporting Critical Energy Infrastructure

    Directory of Open Access Journals (Sweden)

    David E. Dismukes

    2015-12-01

    Full Text Available The U.S. Gulf of Mexico (GOM is an excellent example of a working coast that supports a considerable degree of critical energy infrastructure across several sectors (crude oil, natural gas, electric power, petrochemicals and functionalities (production, processing/refining, transmission, distribution. The coastal communities of the GOM form a highly productive and complicated human, physical, and natural environment that interacts in ways that are unlike anywhere else around the globe. This paper formulates a Coastal Infrastructure Vulnerability Index (CIVI that characterizes interactions between energy assets and the physical and human aspects of GOM communities to identify and prioritize, using a multi-dimensional index, coastal vulnerability. The CIVI leads to results that are significantly different than traditional methods and serves as an alternative, and potentially more useful tool for coastal planning and policy, particularly in those areas characterized by very high infrastructure concentrations.

  11. Critical immunological pathways are downregulated in APECED patient dendritic cells.

    Science.gov (United States)

    Pöntynen, Nora; Strengell, Mari; Sillanpää, Niko; Saharinen, Juha; Ulmanen, Ismo; Julkunen, Ilkka; Peltonen, Leena

    2008-10-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE functions as a transcriptional regulator, and it has a central role in the development of immunological tolerance. AIRE regulates the expression of ectopic antigens in epithelial cells of the thymic medulla and has been shown to participate in the development of peripheral tolerance. However, the mechanism of action of AIRE has remained elusive. To further investigate the role of AIRE in host immune functions, we studied the properties and transcript profiles in in vitro monocyte-differentiated dendritic cells (moDCs) obtained from APECED patients and healthy controls. AIRE-deficient monocytes showed typical DC morphology and expressed DC marker proteins cluster of differentiation 86 and human leukocyte antigen class II. APECED patient-derived moDCs were functionally impaired: the transcriptional response of cytokine genes to pathogens was drastically reduced. Interestingly, some changes were observable already at the immature DC stage. Pathway analyses of transcript profiles revealed that the expression of the components of the host cell signaling pathways involved in cell-cell signalling, innate immune responses, and cytokine activity were reduced in APECED moDCs. Our observations support a role for AIRE in peripheral tolerance and are the first ones to show that AIRE has a critical role in DC responses to microbial stimuli in humans.

  12. Pathways-Driven Sparse Regression Identifies Pathways and Genes Associated with High-Density Lipoprotein Cholesterol in Two Asian Cohorts

    Science.gov (United States)

    Silver, Matt; Chen, Peng; Li, Ruoying; Cheng, Ching-Yu; Wong, Tien-Yin; Tai, E-Shyong; Teo, Yik-Ying; Montana, Giovanni

    2013-01-01

    Standard approaches to data analysis in genome-wide association studies (GWAS) ignore any potential functional relationships between gene variants. In contrast gene pathways analysis uses prior information on functional structure within the genome to identify pathways associated with a trait of interest. In a second step, important single nucleotide polymorphisms (SNPs) or genes may be identified within associated pathways. The pathways approach is motivated by the fact that genes do not act alone, but instead have effects that are likely to be mediated through their interaction in gene pathways. Where this is the case, pathways approaches may reveal aspects of a trait's genetic architecture that would otherwise be missed when considering SNPs in isolation. Most pathways methods begin by testing SNPs one at a time, and so fail to capitalise on the potential advantages inherent in a multi-SNP, joint modelling approach. Here, we describe a dual-level, sparse regression model for the simultaneous identification of pathways and genes associated with a quantitative trait. Our method takes account of various factors specific to the joint modelling of pathways with genome-wide data, including widespread correlation between genetic predictors, and the fact that variants may overlap multiple pathways. We use a resampling strategy that exploits finite sample variability to provide robust rankings for pathways and genes. We test our method through simulation, and use it to perform pathways-driven gene selection in a search for pathways and genes associated with variation in serum high-density lipoprotein cholesterol levels in two separate GWAS cohorts of Asian adults. By comparing results from both cohorts we identify a number of candidate pathways including those associated with cardiomyopathy, and T cell receptor and PPAR signalling. Highlighted genes include those associated with the L-type calcium channel, adenylate cyclase, integrin, laminin, MAPK signalling and immune

  13. A Novel Method to Identify Differential Pathways in Hippocampus Alzheimer's Disease.

    Science.gov (United States)

    Liu, Chun-Han; Liu, Lian

    2017-05-08

    BACKGROUND Alzheimer's disease (AD) is the most common type of dementia. The objective of this paper is to propose a novel method to identify differential pathways in hippocampus AD. MATERIAL AND METHODS We proposed a combined method by merging existed methods. Firstly, pathways were identified by four known methods (DAVID, the neaGUI package, the pathway-based co-expressed method, and the pathway network approach), and differential pathways were evaluated through setting weight thresholds. Subsequently, we combined all pathways by a rank-based algorithm and called the method the combined method. Finally, common differential pathways across two or more of five methods were selected. RESULTS Pathways obtained from different methods were also different. The combined method obtained 1639 pathways and 596 differential pathways, which included all pathways gained from the four existing methods; hence, the novel method solved the problem of inconsistent results. Besides, a total of 13 common pathways were identified, such as metabolism, immune system, and cell cycle. CONCLUSIONS We have proposed a novel method by combining four existing methods based on a rank product algorithm, and identified 13 significant differential pathways based on it. These differential pathways might provide insight into treatment and diagnosis of hippocampus AD.

  14. Identifying biological pathway interrupting toxins using multi-tree ensembles

    Directory of Open Access Journals (Sweden)

    Gergo Barta

    2016-08-01

    Full Text Available The pharmaceutical industry constantly seeks new ways to improve current methods that scientists use to evaluate environmental chemicals and develop new medicines. Various automated steps are involved in the process as testing hundreds of thousands of chemicals manually would be infeasible. Our research effort and the Toxicology in the 21st Century Data Challenge focused on cost-effective automation of toxicological testing, a chemical substance screening process looking for possible toxic effects caused by interrupting biological pathways. The computational models we propose in this paper successfully combine various publicly available substance fingerprinting tools with advanced machine learning techniques. In our paper, we explore the significance and utility of assorted feature selection methods as the structural analyzers generate a plethora of features for each substance. Machine learning models were carefully selected and evaluated based on their capability to cope with the high-dimensional high-variety data with multi-tree ensemble methods coming out on top. Techniques like Random forests and Extra trees combine numerous simple tree models and proved to produce reliable predictions on toxic activity while being nearly non-parametric and insensitive to dimensionality extremes. The Tox21 Data Challenge contest offered a great platform to compare a wide range of solutions in a controlled and orderly manner. The results clearly demonstrate that the generic approach presented in this paper is comparable to advanced deep learning and domain-specific solutions. Even surpassing the competition in some nuclear receptor signaling and stress pathway assays and achieving an accuracy of up to 94 percent.

  15. Pathway-based association analyses identified TRAIL pathway for osteoporotic fractures.

    Directory of Open Access Journals (Sweden)

    Yin-Ping Zhang

    Full Text Available Hip OF carries the highest morbidity and mortality. Previous studies revealed that individual genes/loci in the Tumor Necrosis Factor (TNF-Related Apoptosis-Inducing Ligand (TRAIL pathway were associated with bone metabolism. This study aims to verify the potential association between hip OF and TRAIL pathway.Using genome-wide genotype data from Affymetrix 500 K SNP arrays, we performed novel pathway-based association analyses for hip OF in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls.The TRAIL pathway achieved a significant p value (p = 0.01 for association with hip OF. Among the 38 genes in the TRAIL pathway, seven genes achieved nominally significant association with hip OF (p<0.05; the TNFSF10 (TRAIL gene obtained the most significant p value (p = 1.70×10(-4. SNPs (rs719126, rs6533015, rs9594738, rs1805034, rs11160706 from five genes (CFLAR, NFKB1, TNFSF11, TNFRSF11A, TRAF3 of the pathway had minor alleles that appear to be protective to hip OF. SNPs (rs6445063 and rs4259415 from two genes (TNFSF10 and TNFRSF10B of the pathway had minor alleles (A that are associated with an increased risk of hip OF, with the ORs (odds ratios of 16.51 (95%CI:3.83-71.24 and 1.37 (95%CI:1.08-1.74, respectively.Our study supports the potential role of the TRAIL pathway in the pathogenesis of hip OF in Chinese Han population. Further functional study of this pathway will be pursued to determine the mechanism by which it confers risk to hip OF.

  16. Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development.

    Science.gov (United States)

    Chen, Meng; Rothman, Nathaniel; Ye, Yuanqing; Gu, Jian; Scheet, Paul A; Huang, Maosheng; Chang, David W; Dinney, Colin P; Silverman, Debra T; Figueroa, Jonine D; Chanock, Stephen J; Wu, Xifeng

    2016-07-01

    Genome-wide association studies (GWAS) are designed to identify individual regions associated with cancer risk, but only explain a small fraction of the inherited variability. Alternative approach analyzing genetic variants within biological pathways has been proposed to discover networks of susceptibility genes with additional effects. The gene set enrichment analysis (GSEA) may complement and expand traditional GWAS analysis to identify novel genes and pathways associated with bladder cancer risk. We selected three GSEA methods: Gen-Gen, Aligator, and the SNP Ratio Test to evaluate cellular signaling pathways involved in bladder cancer susceptibility in a Texas GWAS population. The candidate genetic polymorphisms from the significant pathway selected by GSEA were validated in an independent NCI GWAS. We identified 18 novel pathways ( P CACNA1S, COL4A2, SRC , and CACNA1C were associated with bladder cancer risk. Two CCNE1 variants, rs8102137 and rs997669, from cell cycle pathways showed the strongest associations; the CCNE1 signal at 19q12 has already been reported in previous GWAS. These findings offer additional etiologic insights highlighting the specific genes and pathways associated with bladder cancer development. GSEA may be a complementary tool to GWAS to identify additional loci of cancer susceptibility.

  17. Renewable Fuel Pathways II Final Rule to Identify Additional Fuel Pathways under Renewable Fuel Standard Program

    Science.gov (United States)

    This final rule describes EPA’s evaluation of biofuels derived from biogas fuel pathways under the RFS program and other minor amendments related to survey requirements associated with ULSD program and misfueling mitigation regulations for E15.

  18. Competing endogenous RNA network analysis identifies critical genes among the different breast cancer subtypes.

    Science.gov (United States)

    Chen, Juan; Xu, Juan; Li, Yongsheng; Zhang, Jinwen; Chen, Hong; Lu, Jianping; Wang, Zishan; Zhao, Xueying; Xu, Kang; Li, Yixue; Li, Xia; Zhang, Yan

    2017-02-07

    Although competing endogenous RNAs (ceRNAs) have been implicated in many solid tumors, their roles in breast cancer subtypes are not well understood. We therefore generated a ceRNA network for each subtype based on the significance of both, positive co-expression and the shared miRNAs, in the corresponding subtype miRNA dys-regulatory network, which was constructed based on negative regulations between differentially expressed miRNAs and targets. All four subtype ceRNA networks exhibited scale-free architecture and showed that the common ceRNAs were at the core of the networks. Furthermore, the common ceRNA hubs had greater connectivity than the subtype-specific hubs. Functional analysis of the common subtype ceRNA hubs highlighted factors involved in proliferation, MAPK signaling pathways and tube morphogenesis. Subtype-specific ceRNA hubs highlighted unique subtype-specific pathways, like the estrogen response and inflammatory pathways in the luminal subtypes or the factors involved in the coagulation process that participates in the basal-like subtype. Ultimately, we identified 29 critical subtype-specific ceRNA hubs that characterized the different breast cancer subtypes. Our study thus provides new insight into the common and specific subtype ceRNA interactions that define the different categories of breast cancer and enhances our understanding of the pathology underlying the different breast cancer subtypes, which can have prognostic and therapeutic implications in the future.

  19. Other Shades of Diversity: Identifying Factors that Facilitate Critical Thought

    Science.gov (United States)

    2015-06-01

    strength and also eliminates the threat of damage to each member’s self - esteem from hearing his or her own judgments on vital issues criticized by...These include a need to fit in socially, a lack of self - esteem , and a lack of self -confidence. One factor contributing to these traits, especially...to determine whether it is possible to have diversity of thought among a group of people of the same race and/or gender , specifically Caucasian

  20. A probabilistic framework for identifying biosignatures using Pathway Complexity

    Science.gov (United States)

    Marshall, Stuart M.; Murray, Alastair R. G.; Cronin, Leroy

    2017-11-01

    One thing that discriminates living things from inanimate matter is their ability to generate similarly complex or non-random structures in a large abundance. From DNA sequences to folded protein structures, living cells, microbial communities and multicellular structures, the material configurations in biology can easily be distinguished from non-living material assemblies. Many complex artefacts, from ordinary bioproducts to human tools, though they are not living things, are ultimately produced by biological processes-whether those processes occur at the scale of cells or societies, they are the consequences of living systems. While these objects are not living, they cannot randomly form, as they are the product of a biological organism and hence are either technological or cultural biosignatures. A generalized approach that aims to evaluate complex objects as possible biosignatures could be useful to explore the cosmos for new life forms. However, it is not obvious how it might be possible to create such a self-contained approach. This would require us to prove rigorously that a given artefact is too complex to have formed by chance. In this paper, we present a new type of complexity measure, which we call `Pathway Complexity', that allows us not only to threshold the abiotic-biotic divide, but also to demonstrate a probabilistic approach based on object abundance and complexity which can be used to unambiguously assign complex objects as biosignatures. We hope that this approach will not only open up the search for biosignatures beyond the Earth, but also allow us to explore the Earth for new types of biology, and to determine when a complex chemical system discovered in the laboratory could be considered alive. This article is part of the themed issue 'Reconceptualizing the origins of life'.

  1. Identification of Pathways Critical to Quorum Sensing and Virulence Induction

    Energy Technology Data Exchange (ETDEWEB)

    Ognibene, Ted J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Young, N. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Holtz-Morris, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Daley, P. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2009-02-27

    Quorum sensing is a mode of intercellular communication between bacteria that allows them to collectively regulate behavior such as virulence, sporulation, motility and biofilm formation. It is mediated by bacterially synthesized, diffusible, signaling molecules (autoinducers) that increase in concentration as a bacterial population expands until a critical threshold concentration is reached. However, in most bacterial species that produce autoinducer molecules, the physiologic concentration of these molecules is unknown. Moreover, many bacterial species, including Y. pestis, produce an array of quorum sensing molecules and the physiologic concentration of each individual type of autoinducer molecule is not known. There is a need to accurately and precisely quantitate these molecules, as it may be that different types of autoinducer molecules have different effects on virulence in the bacterium. We focused our efforts on the construction of a platform to identify and quantitate autoinducer molecules using FTICR, 14C isotope labeling and accelerator mass spectrometry (AMS). Specifically, we focused on autoinducer-1 type molecules, acylhomoserine lactone (HSL), derived from S-adenosylmethionine (SAM).

  2. A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

    International Nuclear Information System (INIS)

    Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro; Uehara, Takeki; Kato, Yuki; Kono, Hiroshi; Bataller, Ramon; Rusyn, Ivan

    2016-01-01

    Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl 4 )-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl 4 (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl 4 . We observed that combined treatment with CCl 4 and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis

  3. Network Analysis Identifies Disease-Specific Pathways for Parkinson's Disease.

    Science.gov (United States)

    Monti, Chiara; Colugnat, Ilaria; Lopiano, Leonardo; Chiò, Adriano; Alberio, Tiziana

    2018-01-01

    Neurodegenerative diseases are characterized by the progressive loss of specific neurons in selected regions of the central nervous system. The main clinical manifestation (movement disorders, cognitive impairment, and/or psychiatric disturbances) depends on the neuron population being primarily affected. Parkinson's disease is a common movement disorder, whose etiology remains mostly unknown. Progressive loss of dopaminergic neurons in the substantia nigra causes an impairment of the motor control. Some of the pathogenetic mechanisms causing the progressive deterioration of these neurons are not specific for Parkinson's disease but are shared by other neurodegenerative diseases, like Alzheimer's disease and amyotrophic lateral sclerosis. Here, we performed a meta-analysis of the literature of all the quantitative proteomic investigations of neuronal alterations in different models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis to distinguish between general and Parkinson's disease-specific pattern of neurodegeneration. Then, we merged proteomics data with genetics information from the DisGeNET database. The comparison of gene and protein information allowed us to identify 25 proteins involved uniquely in Parkinson's disease and we verified the alteration of one of them, i.e., transaldolase 1 (TALDO1), in the substantia nigra of 5 patients. By using open-source bioinformatics tools, we identified the biological processes specifically affected in Parkinson's disease, i.e., proteolysis, mitochondrion organization, and mitophagy. Eventually, we highlighted four cellular component complexes mostly involved in the pathogenesis: the proteasome complex, the protein phosphatase 2A, the chaperonins CCT complex, and the complex III of the respiratory chain.

  4. Gene expression meta-analysis identifies metastatic pathways and transcription factors in breast cancer

    International Nuclear Information System (INIS)

    Thomassen, Mads; Tan, Qihua; Kruse, Torben A

    2008-01-01

    Metastasis is believed to progress in several steps including different pathways but the determination and understanding of these mechanisms is still fragmentary. Microarray analysis of gene expression patterns in breast tumors has been used to predict outcome in recent studies. Besides classification of outcome, these global expression patterns may reflect biological mechanisms involved in metastasis of breast cancer. Our purpose has been to investigate pathways and transcription factors involved in metastasis by use of gene expression data sets. We have analyzed 8 publicly available gene expression data sets. A global approach, 'gene set enrichment analysis' as well as an approach focusing on a subset of significantly differently regulated genes, GenMAPP, has been applied to rank pathway gene sets according to differential regulation in metastasizing tumors compared to non-metastasizing tumors. Meta-analysis has been used to determine overrepresentation of pathways and transcription factors targets, concordant deregulated in metastasizing breast tumors, in several data sets. The major findings are up-regulation of cell cycle pathways and a metabolic shift towards glucose metabolism reflected in several pathways in metastasizing tumors. Growth factor pathways seem to play dual roles; EGF and PDGF pathways are decreased, while VEGF and sex-hormone pathways are increased in tumors that metastasize. Furthermore, migration, proteasome, immune system, angiogenesis, DNA repair and several signal transduction pathways are associated to metastasis. Finally several transcription factors e.g. E2F, NFY, and YY1 are identified as being involved in metastasis. By pathway meta-analysis many biological mechanisms beyond major characteristics such as proliferation are identified. Transcription factor analysis identifies a number of key factors that support central pathways. Several previously proposed treatment targets are identified and several new pathways that may

  5. Facial assessments: identifying the suitable pathway to facial rejuvenation.

    Science.gov (United States)

    Weinkle, S

    2006-05-01

    There are now numerous ways in which a patient can rejuvenate their facial appearance, including various types of expensive, invasive, surgical procedures, and an ever increasing gamut of products that can be inserted or injected beneath the skin to restore a youthful look to the face. The importance of facial assessments in identifying the most suitable treatment option is discussed here. Before a patient commits to any one of these corrective options, it is the responsibility of the physician to conduct a thorough assessment of the patient's face. All of the facial characteristics should be examined closely: underlying bone and musculature, shape, proportion, and features including folds, wrinkles, fine lines, volume deficits and changes in pigmentation. The degree of ptosis in the facial tissues should be assessed by light palpation. Following assessment of the face, digital photographs should be taken of the patient's full face and profile, allowing the physician to indicate areas, on a visual display, that need correction and there are now computer programs which can 'morph' the features of a facial photograph, providing an approximation of the post-treatment result. Shape and proportion are neglected facets in the assessment of the face prior to corrective treatment. A treatment or technique which rejuvenates a 'thin' face may not work so successfully on a 'round' face and vice versa. Most importantly, the physician should aim to understand the patient's objective and subjective perceptions of their face and ascertain the results that are desired by the patient before evaluating what can be achieved. Appropriate corrective options can then be discussed in detail, highlighting the risks, side effects, costs, invasiveness, logistics and anticipated outcomes of each. A comprehensive assessment of the patient's face allows the physician to formulate a regimen of treatments that will reach or exceed the expectations of the patient.

  6. A Bayesian method for identifying missing enzymes in predicted metabolic pathway databases

    Directory of Open Access Journals (Sweden)

    Karp Peter D

    2004-06-01

    Full Text Available Abstract Background The PathoLogic program constructs Pathway/Genome databases by using a genome's annotation to predict the set of metabolic pathways present in an organism. PathoLogic determines the set of reactions composing those pathways from the enzymes annotated in the organism's genome. Most annotation efforts fail to assign function to 40–60% of sequences. In addition, large numbers of sequences may have non-specific annotations (e.g., thiolase family protein. Pathway holes occur when a genome appears to lack the enzymes needed to catalyze reactions in a pathway. If a protein has not been assigned a specific function during the annotation process, any reaction catalyzed by that protein will appear as a missing enzyme or pathway hole in a Pathway/Genome database. Results We have developed a method that efficiently combines homology and pathway-based evidence to identify candidates for filling pathway holes in Pathway/Genome databases. Our program not only identifies potential candidate sequences for pathway holes, but combines data from multiple, heterogeneous sources to assess the likelihood that a candidate has the required function. Our algorithm emulates the manual sequence annotation process, considering not only evidence from homology searches, but also considering evidence from genomic context (i.e., is the gene part of an operon? and functional context (e.g., are there functionally-related genes nearby in the genome? to determine the posterior belief that a candidate has the required function. The method can be applied across an entire metabolic pathway network and is generally applicable to any pathway database. The program uses a set of sequences encoding the required activity in other genomes to identify candidate proteins in the genome of interest, and then evaluates each candidate by using a simple Bayes classifier to determine the probability that the candidate has the desired function. We achieved 71% precision at a

  7. Metabolomic association between venous thromboembolism in critically ill trauma patients and kynurenine pathway of tryptophan metabolism.

    Science.gov (United States)

    Voils, Stacy A; Shahin, Mohamed H; Garrett, Timothy J; Frye, Reginald F

    2018-03-08

    Incidence of venous thromboembolism (VTE) in critically ill patients remains unacceptably high despite widespread use of thromboprophylaxis. A systems biology approach may be useful in understanding disease pathology and predicting response to treatment. Metabolite profile under specific environmental conditions provides the closest link to phenotype, but the relationship between metabolomics and risk of VTE in critically ill patients is unknown. In this study, metabolomics signatures are compared in patients with and without VTE. Multicenter case-control study using prospectively collected data from the Inflammation and Host Response to Injury program, with pathway and in silico gene expression analyses. Eight level 1 US trauma centers. Critically ill adults with blunt trauma who developed VTE within the first 28 days of hospitalization compared to patients without VTE (N-VTE). None. Patients included in the study (n = 20 VTE, n = 20 N-VTE) were mean age of 34 years, injury severity score of 35, and VTE diagnosed a median of 10.5 days after admission. Global metabolomics revealed two kynurenine metabolites, N-formylkynurenine (AUC = 0.77; 95% CI: 0.59-0.89) and 5-hydroxy-N-formylkynurenine (AUC = 0.80; 95% CI:0.63-0.90) significantly discriminated VTE and N-VTE; ratio between N-formylkynurenine/5-hydroxy-N-formylkynurenine improved predictive power (AUC = 0.87; 95% CI: 0.74-0.95). In the pathway analysis, tryptophan was the only significant metabolic pathway including N-formylkynurenine and 5-hydroxy-N-formylkynurenine (p < 0.001), and 8 proteins directly or indirectly interacted with these metabolites in the interaction network analysis. Of the 8 genes tested in the in silico gene expression analyses, KYNU (p < 0.001), CCBL1 (p < 0.001), and CCBL2 (p = 0.001) were significantly different between VTE and N-VTE, controlling for age and sex. Two novel kynurenine metabolites in the tryptophan pathway associated with

  8. Integrated systems approach identifies risk regulatory pathways and key regulators in coronary artery disease.

    Science.gov (United States)

    Zhang, Yan; Liu, Dianming; Wang, Lihong; Wang, Shuyuan; Yu, Xuexin; Dai, Enyu; Liu, Xinyi; Luo, Shanshun; Jiang, Wei

    2015-12-01

    Coronary artery disease (CAD) is the most common type of heart disease. However, the molecular mechanisms of CAD remain elusive. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, inferring risk regulatory pathways is an important step toward elucidating the mechanisms underlying CAD. With advances in high-throughput data, we developed an integrated systems approach to identify CAD risk regulatory pathways and key regulators. Firstly, a CAD-related core subnetwork was identified from a curated transcription factor (TF) and microRNA (miRNA) regulatory network based on a random walk algorithm. Secondly, candidate risk regulatory pathways were extracted from the subnetwork by applying a breadth-first search (BFS) algorithm. Then, risk regulatory pathways were prioritized based on multiple CAD-associated data sources. Finally, we also proposed a new measure to prioritize upstream regulators. We inferred that phosphatase and tensin homolog (PTEN) may be a key regulator in the dysregulation of risk regulatory pathways. This study takes a closer step than the identification of disease subnetworks or modules. From the risk regulatory pathways, we could understand the flow of regulatory information in the initiation and progression of the disease. Our approach helps to uncover its potential etiology. We developed an integrated systems approach to identify risk regulatory pathways. We proposed a new measure to prioritize the key regulators in CAD. PTEN may be a key regulator in dysregulation of the risk regulatory pathways.

  9. A sub-pathway based method to identify candidate agents for Ankylosing Spondylitis.

    Science.gov (United States)

    Chen, Kai; Zhao, Yingchuan; Chen, Yu; Wang, Chuanfeng; Chen, Ziqiang; Bai, Yushu; Zhu, Xiaodong; Li, Ming

    2012-10-22

    The need for new therapeutics for Ankylosing Spondylitis (AS) is highlighted by the general lack of efficacy for most agents currently available for this disease. Many recent studies have detailed molecular pathways in AS, and several molecule-targeting agents are undergoing evaluation. We aimed to explore the mechanism of AS and identify biologically active small molecules capable of targeting the sub-pathways which were disregulated in the development of AS. By using the GSE25101 microarray data accessible from the Gene Expression Omnibus database, we first identified the differentially expressed genes (DEGs) between AS samples and healthy controls, followed by the sub-pathway enrichment analysis of the DEGs. In addition, we propose the use of an approach based on targeting sub-pathways to identify potential agents for AS. A total of 3,280 genes were identified as being significantly different between patients and controls with p-values pathway and some immune-associated pathways may be involved in the development of AS. Besides, our bioinformatics analysis revealed a total of 15 small molecules which may play a role in perturbing the development of AS. Our study proposes the use of an approach based on targeting sub-pathways to identify potential agents for AS. Candidate agents identified by our approach may provide the groundwork for a combination therapy approach for AS.

  10. A Sub-Pathway Based Method to Identify Candidate Agents for Ankylosing Spondylitis

    Directory of Open Access Journals (Sweden)

    Ming Li

    2012-10-01

    Full Text Available The need for new therapeutics for Ankylosing Spondylitis (AS is highlighted by the general lack of efficacy for most agents currently available for this disease. Many recent studies have detailed molecular pathways in AS, and several molecule-targeting agents are undergoing evaluation. We aimed to explore the mechanism of AS and identify biologically active small molecules capable of targeting the sub-pathways which were disregulated in the development of AS. By using the GSE25101 microarray data accessible from the Gene Expression Omnibus database, we first identified the differentially expressed genes (DEGs between AS samples and healthy controls, followed by the sub-pathway enrichment analysis of the DEGs. In addition, we propose the use of an approach based on targeting sub-pathways to identify potential agents for AS. A total of 3,280 genes were identified as being significantly different between patients and controls with p-values < 0.1. Our study showed that neurotrophic signaling pathway and some immune-associated pathways may be involved in the development of AS. Besides, our bioinformatics analysis revealed a total of 15 small molecules which may play a role in perturbing the development of AS. Our study proposes the use of an approach based on targeting sub-pathways to identify potential agents for AS. Candidate agents identified by our approach may provide the groundwork for a combination therapy approach for AS.

  11. Memory deficits following neonatal critical illness: A common neurodevelopmental pathway

    NARCIS (Netherlands)

    R.M. Schiller (Raisa); H. IJsselstijn (Hanneke); A. Hoskote (Aparna); T.J.H. White (Tonya); F.C. Verhulst (Frank); A.F.J. van Heijst (Arno); D. Tibboel (Dick)

    2017-01-01

    textabstractSummary Over the last decade, knowledge has emerged that children growing up after neonatal critical illness, irrespective of underlying diagnosis, are at risk of memory impairment and school problems. Strikingly, these problems are manifest even when intelligence is normal. In this

  12. Identifying Barriers and Pathways to Success for Renewable Energy Development on American Indian Lands

    Energy Technology Data Exchange (ETDEWEB)

    Necefer, Len Edward [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Univ. of Arizona, Tucson, AZ (United States); Jones, Thomas Elisha [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Carnegie Mellon Univ., Pittsburgh, PA (United States)

    2016-11-01

    American Indian tribes possess lands rich with renewable energy (RE) resources. Tribes have great potential and need to develop these resources, yet face a host of barriers that continue to impede development. Understanding these challenges as well as the pathways that can be taken to overcome them may facilitate more economic development to meet community needs and better position tribes to play a role in securing a low-carbon energy future for the United States. This paper presents the results of an expert elicitation of 24 tribal energy experts from federal, tribal, academic, and private industry backgrounds to identify barriers and opportunities for federally recognized tribes in the lower 48 states. Experts identified a number of unique challenges facing tribes including financing and funding, infrastructure, tribal leadership and staff, state-level influence, and partnerships. Cultural factors were seen only to be of concern with large-scale development. Tribal sovereignty is a significant motivation for RE development and has yet to be fully realized. Cultural considerations are critical to the success of future projects; smaller residential and community-scale projects may be a better fit. Improving partnerships between tribes and the private sector can increase RE deployment and overcome historical distrust. States can have a double-ended influence on projects within tribal lands through taxation.

  13. The critical pathway for deceased donation : reportable uniformity in the approach to deceased donation

    NARCIS (Netherlands)

    Dominguez-Gil, Beatriz; Delmonico, Francis L.; Shaheen, Faissal A. M.; Matesanz, Rafael; O'Connor, Kevin; Minina, Marina; Muller, Elmi; Young, Kimberly; Manyalich, Marti; Chapman, Jeremy; Kirste, Guenter; Al-Mousawi, Mustafa; Coene, Leen; Garcia, Valter Duro; Gautier, Serguei; Hasegawa, Tomonori; Jha, Vivekanand; Kwek, Tong Kiat; Chen, Zhonghua Klaus; Loty, Bernard; Costa, Alessandro Nanni; Nathan, Howard M.; Ploeg, Rutger; Reznik, Oleg; Rosendale, John D.; Tibell, Annika; Tsoulfas, George; Vathsala, Anantharaman; Noel, Luc

    P>The critical pathway of deceased donation provides a systematic approach to the organ donation process, considering both donation after cardiac death than donation after brain death. The pathway provides a tool for assessing the potential of deceased donation and for the prospective identification

  14. Whole-Exome Sequencing to Identify Novel Biological Pathways Associated With Infertility After Pelvic Inflammatory Disease.

    Science.gov (United States)

    Taylor, Brandie D; Zheng, Xiaojing; Darville, Toni; Zhong, Wujuan; Konganti, Kranti; Abiodun-Ojo, Olayinka; Ness, Roberta B; O'Connell, Catherine M; Haggerty, Catherine L

    2017-01-01

    Ideal management of sexually transmitted infections (STI) may require risk markers for pathology or vaccine development. Previously, we identified common genetic variants associated with chlamydial pelvic inflammatory disease (PID) and reduced fecundity. As this explains only a proportion of the long-term morbidity risk, we used whole-exome sequencing to identify biological pathways that may be associated with STI-related infertility. We obtained stored DNA from 43 non-Hispanic black women with PID from the PID Evaluation and Clinical Health Study. Infertility was assessed at a mean of 84 months. Principal component analysis revealed no population stratification. Potential covariates did not significantly differ between groups. Sequencing kernel association test was used to examine associations between aggregates of variants on a single gene and infertility. The results from the sequencing kernel association test were used to choose "focus genes" (P < 0.01; n = 150) for subsequent Ingenuity Pathway Analysis to identify "gene sets" that are enriched in biologically relevant pathways. Pathway analysis revealed that focus genes were enriched in canonical pathways including, IL-1 signaling, P2Y purinergic receptor signaling, and bone morphogenic protein signaling. Focus genes were enriched in pathways that impact innate and adaptive immunity, protein kinase A activity, cellular growth, and DNA repair. These may alter host resistance or immunopathology after infection. Targeted sequencing of biological pathways identified in this study may provide insight into STI-related infertility.

  15. A search engine to identify pathway genes from expression data on multiple organisms

    Directory of Open Access Journals (Sweden)

    Zambon Alexander C

    2007-05-01

    Full Text Available Abstract Background The completion of several genome projects showed that most genes have not yet been characterized, especially in multicellular organisms. Although most genes have unknown functions, a large collection of data is available describing their transcriptional activities under many different experimental conditions. In many cases, the coregulatation of a set of genes across a set of conditions can be used to infer roles for genes of unknown function. Results We developed a search engine, the Multiple-Species Gene Recommender (MSGR, which scans gene expression datasets from multiple organisms to identify genes that participate in a genetic pathway. The MSGR takes a query consisting of a list of genes that function together in a genetic pathway from one of six organisms: Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, Arabidopsis thaliana, and Helicobacter pylori. Using a probabilistic method to merge searches, the MSGR identifies genes that are significantly coregulated with the query genes in one or more of those organisms. The MSGR achieves its highest accuracy for many human pathways when searches are combined across species. We describe specific examples in which new genes were identified to be involved in a neuromuscular signaling pathway and a cell-adhesion pathway. Conclusion The search engine can scan large collections of gene expression data for new genes that are significantly coregulated with a pathway of interest. By integrating searches across organisms, the MSGR can identify pathway members whose coregulation is either ancient or newly evolved.

  16. Ventral aspect of the visual form pathway is not critical for the perception of biological motion

    Science.gov (United States)

    Gilaie-Dotan, Sharon; Saygin, Ayse Pinar; Lorenzi, Lauren J.; Rees, Geraint; Behrmann, Marlene

    2015-01-01

    Identifying the movements of those around us is fundamental for many daily activities, such as recognizing actions, detecting predators, and interacting with others socially. A key question concerns the neurobiological substrates underlying biological motion perception. Although the ventral “form” visual cortex is standardly activated by biologically moving stimuli, whether these activations are functionally critical for biological motion perception or are epiphenomenal remains unknown. To address this question, we examined whether focal damage to regions of the ventral visual cortex, resulting in significant deficits in form perception, adversely affects biological motion perception. Six patients with damage to the ventral cortex were tested with sensitive point-light display paradigms. All patients were able to recognize unmasked point-light displays and their perceptual thresholds were not significantly different from those of three different control groups, one of which comprised brain-damaged patients with spared ventral cortex (n > 50). Importantly, these six patients performed significantly better than patients with damage to regions critical for biological motion perception. To assess the necessary contribution of different regions in the ventral pathway to biological motion perception, we complement the behavioral findings with a fine-grained comparison between the lesion location and extent, and the cortical regions standardly implicated in biological motion processing. This analysis revealed that the ventral aspects of the form pathway (e.g., fusiform regions, ventral extrastriate body area) are not critical for biological motion perception. We hypothesize that the role of these ventral regions is to provide enhanced multiview/posture representations of the moving person rather than to represent biological motion perception per se. PMID:25583504

  17. Can ambulance telephone triage using NHS Pathways accurately identify paediatric cardiac arrest?

    Science.gov (United States)

    Deakin, Charles D; England, Simon; Diffey, Debbie; Maconochie, Ian

    2017-07-01

    Most out-of-hospital paediatric cardiac arrests (CA) are not identified until a call is made to the emergency medical services. Accurate identification increases overall survival by enabling immediate ambulance dispatch and delivery of bystander CPR. European ambulance services use a variety of didactic telephone scripts to interrogate the caller and rapidly identify paediatric CA. The performance of these scripts has not been reported. This study aims to evaluate the diagnostic accuracy of the NHS Pathways as a telephone triage tool to identify patients less than 16 years age in cardiac arrest. All emergency calls to South Central Ambulance Service (SCAS) over a 12-month period screened by 'NHS Pathways' v9.04 were identified. All actual or presumed paediatric CAs (telephone triage system for identifying CA. Further work is required to refine telephone triage pathways for paediatric cardiac arrest. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance.

    Science.gov (United States)

    Lindsey, J C; Kawauchi, D; Schwalbe, E C; Solecki, D J; Selby, M P; McKinnon, P J; Olson, J M; Hayden, J T; Grundy, R G; Ellison, D W; Williamson, D; Bailey, S; Roussel, M F; Clifford, S C

    2015-09-03

    The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.

  19. The use of functional chemical-protein associations to identify multi-pathway renoprotectants.

    Directory of Open Access Journals (Sweden)

    Jia Xu

    Full Text Available Typically, most nephropathies can be categorized as complex human diseases in which the cumulative effect of multiple minor genes, combined with environmental and lifestyle factors, determines the disease phenotype. Thus, multi-target drugs would be more likely to facilitate comprehensive renoprotection than single-target agents. In this study, functional chemical-protein association analysis was performed to retrieve multi-target drugs of high pathway wideness from the STITCH 3.1 database. Pathway wideness of a drug evaluated the efficiency of regulation of Kyoto Encyclopedia of Genes and Genomes (KEGG pathways in quantity. We identified nine experimentally validated renoprotectants that exerted remarkable impact on KEGG pathways by targeting a limited number of proteins. We selected curcumin as an illustrative compound to display the advantage of multi-pathway drugs on renoprotection. We compared curcumin with hemin, an agonist of heme oxygenase-1 (HO-1, which significantly affects only one KEGG pathway, porphyrin and chlorophyll metabolism (adjusted p = 1.5×10-5. At the same concentration (10 µM, both curcumin and hemin equivalently mitigated oxidative stress in H2O2-treated glomerular mesangial cells. The benefit of using hemin was derived from its agonistic effect on HO-1, providing relief from oxidative stress. Selective inhibition of HO-1 completely blocked the action of hemin but not that of curcumin, suggesting simultaneous multi-pathway intervention by curcumin. Curcumin also increased cellular autophagy levels, enhancing its protective effect; however, hemin had no effects. Based on the fact that the dysregulation of multiple pathways is implicated in the etiology of complex diseases, we proposed a feasible method for identifying multi-pathway drugs from compounds with validated targets. Our efforts will help identify multi-pathway agents capable of providing comprehensive protection against renal injuries.

  20. Identifying and classifying indicators affected by performing clinical pathways in hospitals: a scoping review.

    Science.gov (United States)

    Shabaninejad, Hosein; Alidoost, Saeide; Delgoshaei, Bahram

    2018-03-01

    To analyse the evidence regarding indicators affected by clinical pathways (CPW) in hospitals and offer suggestions for conducting comprehensive systematic reviews. We conducted a systematic scoping review and searched the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, OVID, Science Direct, ProQuest, EMBASE and PubMed. We also reviewed the reference lists of included studies. The criteria for inclusion of studies included experimental and quasi-experimental studies, implementing CPW in secondary and tertiary hospitals and investigating at least one indicator. Quality of included studies was assessed by two authors independently using the Critical Appraisal Skills Program for clinical trials and cohort studies and the Joanna Briggs Institute Critical Appraisal Tool for Quasi-Experimental Studies. Forty-seven out of 2191 studies met the eligibility and inclusion criteria. The majority of included studies had pretest-posttest quasi-experimental design and had been done in developed countries, especially the United States. The investigation of evidence resulted in identifying 62 indicators which were classified into three categories: input indicators, process and output indicators and outcome indicators. Outcome indicators were more frequent than other indicators. Complication rate, hospital costs and length of hospital stay were dominant in their own category. Indicators such as quality of life and adherence to guidelines have been considered in studies that were done in recent years. Implementing CPW can affect different types of indicators such as input, process, output and outcome indicators, although outcome indicators capture more attention than other indicators. Patient-related indicators were dominant outcome indicators, whereas professional indicators and organizational factors were considered less extensively. WHAT IS KNOWN ABOUT THE TOPIC?: WHAT DOES THIS ARTICLE ADD?

  1. A Sub-Pathway Based Method to Identify Candidate Agents for Ankylosing Spondylitis

    OpenAIRE

    Chen, Kai; Zhao, Yingchuan; Chen, Yu; Wang, Chuanfeng; Chen, Ziqiang; Bai, Yushu; Zhu, Xiaodong; Li, Ming

    2012-01-01

    The need for new therapeutics for Ankylosing Spondylitis (AS) is highlighted by the general lack of efficacy for most agents currently available for this disease. Many recent studies have detailed molecular pathways in AS, and several molecule-targeting agents are undergoing evaluation. We aimed to explore the mechanism of AS and identify biologically active small molecules capable of targeting the sub-pathways which were disregulated in the development of AS. By using the GSE25101 microarray...

  2. Analysis of patient-dropouts from the critical pathways for gastric cancer.

    Science.gov (United States)

    Kim, Sungsoo; Yoo, Young Sun; Kim, Jin Ha; Min, Young Don

    2015-06-01

    This study was designed to determine the factors affecting completion of critical pathway for elective gastrectomy. Since 2008, a critical pathway has been applied for elective gastrectomy at Chosun University Hospital. We retrospectively analyzed 252 patients who underwent elective gastrectomies from January 2009 to April 2013. The completion rate was determined, and risk factors for patient dropout were examined. The completion rate of the critical pathway was 45.6% (115/252). Mean length of stay was 11.7 ± 8.6 days (8-59 days). Readmission rates were 4.4% (11/252). Causes of failure for clinical pathway were systemic complications (21/137, 15.3%), intra-abdominal complications (44/137, 32.8%), patient factors (41/137, 29.9%), and wound complications (30/137, 21.9%). There were no significant differences between the two groups in age, sex, American Society of Anesthesiologists (ASA) score, operation time, readmission, and underlying disease (P > 0.05). Body mass index (P = 0.008) and pathologic stage (P = 0.001) were significantly different between the two groups. In multivariate analysis, the conventional approach (odds ratio, 2.0), and total gastrectomy (odds ratio, 5.3) were determined to be independent risk factors to drop the critical pathway. But there were no significant differences between total and distal gastrectomy groups in age, gender, underlying diseases, ASA score, readmission, operation time, and cause of dropout (P > 0.05). We concluded that total gastrectomy may not be suitable for the critical pathway. We suggest that the critical pathway for elective distal gastrectomy is divided 2 subgroups, according to the surgical approach.

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

    Science.gov (United States)

    Darabos, Christian; Qiu, Jingya; Moore, Jason H

    2016-01-01

    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.

  4. Using Critical Thinking to Identify Bias in the News Media: The Art of Critical Analysis.

    Science.gov (United States)

    Paul, Richard W.; Adamson, Kenneth R.

    1990-01-01

    Urges social studies teachers to help students understand and identify sociocentric, national bias in the news media. Illustrates how the media fosters "us versus them" thinking and how word choice often reflects bias. Outlines activities to help students recognize bias. Provides weak and strong examples of students' analyses of bias in news…

  5. Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases.

    Science.gov (United States)

    Arakelyan, Arsen; Nersisyan, Lilit; Petrek, Martin; Löffler-Wirth, Henry; Binder, Hans

    2016-01-01

    Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent.

  6. Critical Thinking Skills among Elementary School Students: Comparing Identified Gifted and General Education Student Performance

    Science.gov (United States)

    Kettler, Todd

    2014-01-01

    Education reform efforts, including the current adoption of Common Core State Standards, have increased attention to teaching critical thinking skills to all students. This study investigated the critical thinking skills of fourth-grade students from a school district in Texas, including 45 identified gifted students and 163 general education…

  7. PAPA: a flexible tool for identifying pleiotropic pathways using genome-wide association study summaries.

    Science.gov (United States)

    Wen, Yan; Wang, Wenyu; Guo, Xiong; Zhang, Feng

    2016-03-15

    : Pleiotropy is common in the genetic architectures of complex diseases. To the best of our knowledge, no analysis tool has been developed for identifying pleiotropic pathways using multiple genome-wide association study (GWAS) summaries by now. Here, we present PAPA, a flexible tool for pleiotropic pathway analysis utilizing GWAS summary results. The performance of PAPA was validated using publicly available GWAS summaries of body mass index and waist-hip ratio of the GIANT datasets. PAPA identified a set of pleiotropic pathways, which have been demonstrated to be involved in the development of obesity. PAPA program, document and illustrative example are available at http://sourceforge.net/projects/papav1/files/ : fzhxjtu@mail.xjtu.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells.

    Science.gov (United States)

    Sato, Tatsuhiro; Higuchi, Yutaka; Shibagaki, Yoshio; Hattori, Seisuke

    2017-09-01

    Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  9. Identifying teens at risk: developmental pathways of online and offline sexual risk behavior

    NARCIS (Netherlands)

    Baumgartner, S.E.; Sumter, S.R.; Peter, J.; Valkenburg, P.M.

    2012-01-01

    OBJECTIVES: The aims of this study were (1) to investigate the prevalence and development of both online (OnSRB) and offline sexual risk behavior (OffSRB) in adolescence, (2) to establish whether OnSRBs and OffSRBs are related, and (3) to identify risk factors that determine problematic pathways of

  10. PathScore: a web tool for identifying altered pathways in cancer data.

    Science.gov (United States)

    Gaffney, Stephen G; Townsend, Jeffrey P

    2016-12-01

    PathScore quantifies the level of enrichment of somatic mutations within curated pathways, applying a novel approach that identifies pathways enriched across patients. The application provides several user-friendly, interactive graphic interfaces for data exploration, including tools for comparing pathway effect sizes, significance, gene-set overlap and enrichment differences between projects. Web application available at pathscore.publichealth.yale.edu. Site implemented in Python and MySQL, with all major browsers supported. Source code available at: github.com/sggaffney/pathscore with a GPLv3 license. stephen.gaffney@yale.edu. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Simulation platform developed to study and identify critical cases in a future smart grid

    DEFF Research Database (Denmark)

    Mihet-Popa, Lucian; Zong, Yi; You, Shi

    2016-01-01

    simulation and planning tools, with a particular objective on the challenges faced by the introduction of Smart Grid technologies. Another important issue of the paper is to identify critical load cases, as well as the voltage variations with the highest potential, able to implement the grid model......This paper proposes a simulation platform developed to study and identify critical cases in a Smart Grid. A distribution network with different Distributed Energy Resources (DER) components, connected along the feeders, is analyzed, having the objective to identify limitations of existing...

  12. Failure mode effects and criticality analysis: innovative risk assessment to identify critical areas for improvement in emergency department sepsis resuscitation.

    Science.gov (United States)

    Powell, Emilie S; O'Connor, Lanty M; Nannicelli, Anna P; Barker, Lisa T; Khare, Rahul K; Seivert, Nicholas P; Holl, Jane L; Vozenilek, John A

    2014-06-01

    Sepsis is an increasing problem in the practice of emergency medicine as the prevalence is increasing and optimal care to reduce mortality requires significant resources and time. Evidence-based septic shock resuscitation strategies exist, and rely on appropriate recognition and diagnosis, but variation in adherence to the recommendations and therefore outcomes remains. Our objective was to perform a multi-institutional prospective risk-assessment, using failure mode effects and criticality analysis (FMECA), to identify high-risk failures in ED sepsis resuscitation. We conducted a FMECA, which prospectively identifies critical areas for improvement in systems and processes of care, across three diverse hospitals. A multidisciplinary group of participants described the process of emergency department (ED) sepsis resuscitation to then create a comprehensive map and table listing all process steps and identified process failures. High-risk failures in sepsis resuscitation from each of the institutions were compiled to identify common high-risk failures. Common high-risk failures included limited availability of equipment to place the central venous catheter and conduct invasive monitoring, and cognitive overload leading to errors in decision-making. Additionally, we identified great variability in care processes across institutions. Several common high-risk failures in sepsis care exist: a disparity in resources available across hospitals, a lack of adherence to the invasive components of care, and cognitive barriers that affect expert clinicians' decision-making capabilities. Future work may concentrate on dissemination of non-invasive alternatives and overcoming cognitive barriers in diagnosis and knowledge translation.

  13. Identifying Drug Effects via Pathway Alterations using an Integer Linear Programming Optimization Formulation on Phosphoproteomic Data

    Science.gov (United States)

    Mitsos, Alexander; Melas, Ioannis N.; Siminelakis, Paraskeuas; Chairakaki, Aikaterini D.; Saez-Rodriguez, Julio; Alexopoulos, Leonidas G.

    2009-01-01

    Understanding the mechanisms of cell function and drug action is a major endeavor in the pharmaceutical industry. Drug effects are governed by the intrinsic properties of the drug (i.e., selectivity and potency) and the specific signaling transduction network of the host (i.e., normal vs. diseased cells). Here, we describe an unbiased, phosphoproteomic-based approach to identify drug effects by monitoring drug-induced topology alterations. With our proposed method, drug effects are investigated under diverse stimulations of the signaling network. Starting with a generic pathway made of logical gates, we build a cell-type specific map by constraining it to fit 13 key phopshoprotein signals under 55 experimental conditions. Fitting is performed via an Integer Linear Program (ILP) formulation and solution by standard ILP solvers; a procedure that drastically outperforms previous fitting schemes. Then, knowing the cell's topology, we monitor the same key phosphoprotein signals under the presence of drug and we re-optimize the specific map to reveal drug-induced topology alterations. To prove our case, we make a topology for the hepatocytic cell-line HepG2 and we evaluate the effects of 4 drugs: 3 selective inhibitors for the Epidermal Growth Factor Receptor (EGFR) and a non-selective drug. We confirm effects easily predictable from the drugs' main target (i.e., EGFR inhibitors blocks the EGFR pathway) but we also uncover unanticipated effects due to either drug promiscuity or the cell's specific topology. An interesting finding is that the selective EGFR inhibitor Gefitinib inhibits signaling downstream the Interleukin-1alpha (IL1α) pathway; an effect that cannot be extracted from binding affinity-based approaches. Our method represents an unbiased approach to identify drug effects on small to medium size pathways which is scalable to larger topologies with any type of signaling interventions (small molecules, RNAi, etc). The method can reveal drug effects on pathways

  14. A nuclear calcium-sensing pathway is critical for gene regulation and salt stress tolerance in Arabidopsis.

    Science.gov (United States)

    Guan, Qingmei; Wu, Jianmin; Yue, Xiule; Zhang, Yanyan; Zhu, Jianhua

    2013-08-01

    Salt stress is an important environmental factor that significantly limits crop productivity worldwide. Studies on responses of plants to salt stress in recent years have identified novel signaling pathways and have been at the forefront of plant stress biology and plant biology in general. Thus far, research on salt stress in plants has been focused on cytoplasmic signaling pathways. In this study, we discovered a nuclear calcium-sensing and signaling pathway that is critical for salt stress tolerance in the reference plant Arabidopsis. Through a forward genetic screen, we found a nuclear-localized calcium-binding protein, RSA1 (SHORT ROOT IN SALT MEDIUM 1), which is required for salt tolerance, and identified its interacting partner, RITF1, a bHLH transcription factor. We show that RSA1 and RITF1 regulate the transcription of several genes involved in the detoxification of reactive oxygen species generated by salt stress and that they also regulate the SOS1 gene that encodes a plasma membrane Na(+)/H(+) antiporter essential for salt tolerance. Together, our results suggest the existence of a novel nuclear calcium-sensing and -signaling pathway that is important for gene regulation and salt stress tolerance.

  15. A MicroRNA Screen Identifies the Wnt Signaling Pathway as a Regulator of the Interferon Response during Flavivirus Infection.

    Science.gov (United States)

    Smith, Jessica L; Jeng, Sophia; McWeeney, Shannon K; Hirsch, Alec J

    2017-04-15

    The impact of mosquito-borne flavivirus infections worldwide is significant, and many critical aspects of these viruses' biology, including virus-host interactions, host cell requirements for replication, and how virus-host interactions impact pathology, remain to be fully understood. The recent reemergence and spread of flaviviruses, including dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV), highlight the importance of performing basic research on this important group of pathogens. MicroRNAs (miRNAs) are small, noncoding RNAs that modulate gene expression posttranscriptionally and have been demonstrated to regulate a broad range of cellular processes. Our research is focused on identifying pro- and antiflaviviral miRNAs as a means of characterizing cellular pathways that support or limit viral replication. We have screened a library of known human miRNA mimics for their effect on the replication of three flaviviruses, DENV, WNV, and Japanese encephalitis virus (JEV), using a high-content immunofluorescence screen. Several families of miRNAs were identified as inhibiting multiple flaviviruses, including the miRNA miR-34, miR-15, and miR-517 families. Members of the miR-34 family, which have been extensively characterized for their ability to repress Wnt/β-catenin signaling, demonstrated strong antiflaviviral effects, and this inhibitory activity extended to other viruses, including ZIKV, alphaviruses, and herpesviruses. Previous research suggested a possible link between the Wnt and type I interferon (IFN) signaling pathways. Therefore, we investigated the role of type I IFN induction in the antiviral effects of the miR-34 family and confirmed that these miRNAs potentiate interferon regulatory factor 3 (IRF3) phosphorylation and translocation to the nucleus, the induction of IFN-responsive genes, and the release of type I IFN from transfected cells. We further demonstrate that the intersection between the Wnt and IFN signaling pathways occurs at

  16. Integrated genomics identifies convergence of ankylosing spondylitis with global immune mediated disease pathways.

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    Uddin, Mohammed; Codner, Dianne; Hasan, S M Mahmud; Scherer, Stephen W; O'Rielly, Darren D; Rahman, Proton

    2015-05-18

    Ankylosing spondylitis(AS), a highly heritable complex inflammatory arthritis. Although, a handful of non-HLA risk loci have been identified, capturing the unexplained genetic contribution to AS pathogenesis remains a challenge attributed to additive, pleiotropic and epistatic-interactions at the molecular level. Here, we developed multiple integrated genomic approaches to quantify molecular convergence of non-HLA loci with global immune mediated diseases. We show that non-HLA genes are significantly sensitive to deleterious mutation accumulation in the general population compared with tolerant genes. Human developmental proteomics (prenatal to adult) analysis revealed that proteins encoded by non-HLA AS risk loci are 2-fold more expressed in adult hematopoietic cells.Enrichment analysis revealed AS risk genes overlap with a significant number of immune related pathways (p pathways with other immune mediated diseases. This information will be pivotal to fully explain AS pathogenesis and identify new therapeutic targets.

  17. Quantitative phosphoproteomic analysis identifies activation of the RET and IGF-1R/IR signaling pathways in neuroblastoma.

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    Bradley D DeNardo

    Full Text Available Neuroblastoma is an embryonal tumor of childhood with a heterogenous clinical presentation that reflects differences in activation of complex biological signaling pathways. Protein phosphorylation is a key component of cellular signal transduction and plays a critical role in processes that control cancer cell growth and survival. We used shotgun LC/MS to compare phosphorylation between a human MYCN amplified neuroblastoma cell line (NB10, modeling a resistant tumor, and a human neural precursor cell line (NPC, modeling a normal baseline neural crest cell. 2181 unique phosphorylation sites representing 1171 proteins and 2598 phosphopeptides were found. Protein kinases accounted for 6% of the proteome, with a predominance of tyrosine kinases, supporting their prominent role in oncogenic signaling pathways. Highly abundant receptor tyrosine kinase (RTK phosphopeptides in the NB10 cell line relative to the NPC cell line included RET, insulin-like growth factor 1 receptor/insulin receptor (IGF-1R/IR, and fibroblast growth factor receptor 1 (FGFR1. Multiple phosphorylated peptides from downstream mediators of the PI3K/AKT/mTOR and RAS pathways were also highly abundant in NB10 relative to NPC. Our analysis highlights the importance of RET, IGF-1R/IR and FGFR1 as RTKs in neuroblastoma and suggests a methodology that can be used to identify potential novel biological therapeutic targets. Furthermore, application of this previously unexploited technology in the clinic opens the possibility of providing a new wide-scale molecular signature to assess disease progression and prognosis.

  18. Systematic enrichment analysis of gene expression profiling studies identifies consensus pathways implicated in colorectal cancer development

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    Jesús Lascorz

    2011-01-01

    Full Text Available Background: A large number of gene expression profiling (GEP studies on colorectal carcinogenesis have been performed but no reliable gene signature has been identified so far due to the lack of reproducibility in the reported genes. There is growing evidence that functionally related genes, rather than individual genes, contribute to the etiology of complex traits. We used, as a novel approach, pathway enrichment tools to define functionally related genes that are consistently up- or down-regulated in colorectal carcinogenesis. Materials and Methods: We started the analysis with 242 unique annotated genes that had been reported by any of three recent meta-analyses covering GEP studies on genes differentially expressed in carcinoma vs normal mucosa. Most of these genes (218, 91.9% had been reported in at least three GEP studies. These 242 genes were submitted to bioinformatic analysis using a total of nine tools to detect enrichment of Gene Ontology (GO categories or Kyoto Encyclopedia of Genes and Genomes (KEGG pathways. As a final consistency criterion the pathway categories had to be enriched by several tools to be taken into consideration. Results: Our pathway-based enrichment analysis identified the categories of ribosomal protein constituents, extracellular matrix receptor interaction, carbonic anhydrase isozymes, and a general category related to inflammation and cellular response as significantly and consistently overrepresented entities. Conclusions: We triaged the genes covered by the published GEP literature on colorectal carcinogenesis and subjected them to multiple enrichment tools in order to identify the consistently enriched gene categories. These turned out to have known functional relationships to cancer development and thus deserve further investigation.

  19. Clustering analysis of water distribution systems: identifying critical components and community impacts.

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    Diao, K; Farmani, R; Fu, G; Astaraie-Imani, M; Ward, S; Butler, D

    2014-01-01

    Large water distribution systems (WDSs) are networks with both topological and behavioural complexity. Thereby, it is usually difficult to identify the key features of the properties of the system, and subsequently all the critical components within the system for a given purpose of design or control. One way is, however, to more explicitly visualize the network structure and interactions between components by dividing a WDS into a number of clusters (subsystems). Accordingly, this paper introduces a clustering strategy that decomposes WDSs into clusters with stronger internal connections than external connections. The detected cluster layout is very similar to the community structure of the served urban area. As WDSs may expand along with urban development in a community-by-community manner, the correspondingly formed distribution clusters may reveal some crucial configurations of WDSs. For verification, the method is applied to identify all the critical links during firefighting for the vulnerability analysis of a real-world WDS. Moreover, both the most critical pipes and clusters are addressed, given the consequences of pipe failure. Compared with the enumeration method, the method used in this study identifies the same group of the most critical components, and provides similar criticality prioritizations of them in a more computationally efficient time.

  20. Portable penetrometer for agricultural soil: sensitivity test to identify critical compaction depth

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    João Carlos Medeiros

    2010-12-01

    Full Text Available To express the negative effects of soil compaction, some researchers use critical values for soil mechanical strength that severely impair plant growth. The aim of this study was to identify this critical compaction depth, to test the functionality of a new, portable penetrometer developed from a spring dynamometer, and compare it to an electronic penetrometer traditionally used in compaction studies of agricultural soils. Three soils with distinct texture were conventionally tilled using a disk plow, and cultivated with different plant species. The critical soil resistance defined to establish critical compaction depth was equal to 1.5 MPa. The results of the new equipment were similar to the electronic penetrometer, indicating its viability as a tool for assessing the soil physical conditions for plant growth.

  1. Gene expression profiling in whole blood identifies distinct biological pathways associated with obesity

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    Gorman Shelby A

    2010-12-01

    Full Text Available Abstract Background Obesity is reaching epidemic proportions and represents a significant risk factor for cardiovascular disease, diabetes, and cancer. Methods To explore the relationship between increased body mass and gene expression in blood, we conducted whole-genome expression profiling of whole blood from seventeen obese and seventeen well matched lean subjects. Gene expression data was analyzed at the individual gene and pathway level and a preliminary assessment of the predictive value of blood gene expression profiles in obesity was carried out. Results Principal components analysis of whole-blood gene expression data from obese and lean subjects led to efficient separation of the two cohorts. Pathway analysis by gene-set enrichment demonstrated increased transcript levels for genes belonging to the "ribosome", "apoptosis" and "oxidative phosphorylation" pathways in the obese cohort, consistent with an altered metabolic state including increased protein synthesis, enhanced cell death from proinflammatory or lipotoxic stimuli, and increased energy demands. A subset of pathway-specific genes acted as efficient predictors of obese or lean class membership when used in Naive Bayes or logistic regression based classifiers. Conclusion This study provides a comprehensive characterization of the whole blood transcriptome in obesity and demonstrates that the investigation of gene expression profiles from whole blood can inform and illustrate the biological processes related to regulation of body mass. Additionally, the ability of pathway-related gene expression to predict class membership suggests the feasibility of a similar approach for identifying clinically useful blood-based predictors of weight loss success following dietary or surgical interventions.

  2. Quantitative proteomics and integrative network analysis identified novel genes and pathways related to osteoporosis.

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    Zeng, Yong; Zhang, Lan; Zhu, Wei; Xu, Chao; He, Hao; Zhou, Yu; Liu, Yao-Zhong; Tian, Qing; Zhang, Ji-Gang; Deng, Fei-Yan; Hu, Hong-Gang; Zhang, Li-Shu; Deng, Hong-Wen

    2016-06-16

    Osteoporosis is mainly characterized by low bone mineral density (BMD), and can be attributed to excessive bone resorption by osteoclasts. Migration of circulating monocytes from blood to bone is important for subsequent osteoclast differentiation and bone resorption. Identification of those genes and pathways related to osteoclastogenesis and BMD will contribute to a better understanding of the pathophysiological mechanisms of osteoporosis. In this study, we applied the LC-nano-ESI-MS(E) (Liquid Chromatograph-nano-Electrospray Ionization-Mass Spectrometry) for quantitative proteomic profiling in 33 female Caucasians with discordant BMD levels, with 16 high vs. 17 low BMD subjects. Protein quantitation was accomplished by label-free measurement of total ion currents collected from MS(E) data. Comparison of protein expression in high vs. low BMD subjects showed that ITGA2B (p=0.0063) and GSN (p=0.019) were up-regulated in the high BMD group. Additionally, our protein-RNA integrative analysis showed that RHOA (p=0.00062) differentially expressed between high vs. low BMD groups. Network analysis based on multiple tools revealed two pathways: "regulation of actin cytoskeleton" (p=1.13E-5, FDR=3.34E-4) and "leukocyte transendothelial migration" (p=2.76E-4, FDR=4.71E-3) that are functionally relevant to osteoporosis. Consistently, ITGA2B, GSN and RHOA played crucial roles in these two pathways respectively. All together, our study strongly supported the contribution of the genes ITGA2B, GSN and RHOA and the two pathways to osteoporosis risk. Mass spectrometry based quantitative proteomics study integrated with network analysis identified novel genes and pathways related to osteoporosis. The results were further verified in multiple level studies including protein-RNA integrative analysis and genome wide association studies. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Quantifying nitrous oxide production pathways in wastewater treatment systems using isotope technology - A critical review.

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    Duan, Haoran; Ye, Liu; Erler, Dirk; Ni, Bing-Jie; Yuan, Zhiguo

    2017-10-01

    Nitrous oxide (N 2 O) is an important greenhouse gas and an ozone-depleting substance which can be emitted from wastewater treatment systems (WWTS) causing significant environmental impacts. Understanding the N 2 O production pathways and their contribution to total emissions is the key to effective mitigation. Isotope technology is a promising method that has been applied to WWTS for quantifying the N 2 O production pathways. Within the scope of WWTS, this article reviews the current status of different isotope approaches, including both natural abundance and labelled isotope approaches, to N 2 O production pathways quantification. It identifies the limitations and potential problems with these approaches, as well as improvement opportunities. We conclude that, while the capabilities of isotope technology have been largely recognized, the quantification of N 2 O production pathways with isotope technology in WWTS require further improvement, particularly in relation to its accuracy and reliability. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

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    Hidekazu Ishida

    2016-07-01

    Full Text Available A surface marker that distinctly identifies cardiac progenitors (CPs is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2, specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.

  5. A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity

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    Chen, Shih-Hsiang; Yang, Wenjian; Fan, Yiping; Stocco, Gabriele; Crews, Kristine R.; Yang, Jun J.; Paugh, Steven W.; Pui, Ching-Hon; Evans, William E.; Relling, Mary V.

    2011-01-01

    Asparaginase is an important component of treatment for childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we employed a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50% of growth (IC50). In CEU lines, we tested 2,390,203 SNP genotypes at the individual SNP (p ADSL and DARS genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (p = 5.5 × 10−5). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity. PMID:21072045

  6. Identifying critical issues in recreation planning and management: improving the management-research partnership

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    John H. Schomaker; David W. Lime

    1988-01-01

    The "nominal group" process is a proven technique to systematically arrive at a consensus about critical information needs in recreation planning and management. Using this process, 41 managers who attended a 1983 conference on river management identified 114 specific information needs grouped under 11 general questions. Clearly, some concerns of...

  7. Carbon and chlorine isotope analysis to identify abiotic degradation pathways of 1,1,1-trichloroethane.

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    Palau, Jordi; Shouakar-Stash, Orfan; Hunkeler, Daniel

    2014-12-16

    This study investigates dual C-Cl isotope fractionation during 1,1,1-TCA transformation by heat-activated persulfate (PS), hydrolysis/dehydrohalogenation (HY/DH) and Fe(0). Compound-specific chlorine isotope analysis of 1,1,1-TCA was performed for the first time, and transformation-associated isotope fractionation ε bulk C and ε bulk Cl values were -4.0 ± 0.2‰ and no chlorine isotope fractionation with PS, -1.6 ± 0.2‰ and -4.7 ± 0.1‰ for HY/DH, -7.8 ± 0.4‰ and -5.2 ± 0.2‰ with Fe(0). Distinctly different dual isotope slopes (Δδ13C/Δδ37Cl): ∞ with PS, 0.33 ± 0.04 for HY/DH and 1.5 ± 0.1 with Fe(0) highlight the potential of this approach to identify abiotic degradation pathways of 1,1,1-TCA in the field. The trend observed with PS agreed with a C-H bond oxidation mechanism in the first reaction step. For HY/DH and Fe(0) pathways, different slopes were obtained although both pathways involve cleavage of a C-Cl bond in their initial reaction step. In contrast to the expected larger primary carbon isotope effects relative to chlorine for C-Cl bond cleavage, ε bulk C isotope effects. Therefore, different magnitude of secondary chlorine isotope effects could at least be partly responsible for the distinct slopes between HY/DH and Fe(0) pathways. Following this dual isotope approach, abiotic transformation processes can unambiguously be identified and quantified.

  8. Mergeomics: a web server for identifying pathological pathways, networks, and key regulators via multidimensional data integration.

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    Arneson, Douglas; Bhattacharya, Anindya; Shu, Le; Mäkinen, Ville-Petteri; Yang, Xia

    2016-09-09

    Human diseases are commonly the result of multidimensional changes at molecular, cellular, and systemic levels. Recent advances in genomic technologies have enabled an outpour of omics datasets that capture these changes. However, separate analyses of these various data only provide fragmented understanding and do not capture the holistic view of disease mechanisms. To meet the urgent needs for tools that effectively integrate multiple types of omics data to derive biological insights, we have developed Mergeomics, a computational pipeline that integrates multidimensional disease association data with functional genomics and molecular networks to retrieve biological pathways, gene networks, and central regulators critical for disease development. To make the Mergeomics pipeline available to a wider research community, we have implemented an online, user-friendly web server ( http://mergeomics. idre.ucla.edu/ ). The web server features a modular implementation of the Mergeomics pipeline with detailed tutorials. Additionally, it provides curated genomic resources including tissue-specific expression quantitative trait loci, ENCODE functional annotations, biological pathways, and molecular networks, and offers interactive visualization of analytical results. Multiple computational tools including Marker Dependency Filtering (MDF), Marker Set Enrichment Analysis (MSEA), Meta-MSEA, and Weighted Key Driver Analysis (wKDA) can be used separately or in flexible combinations. User-defined summary-level genomic association datasets (e.g., genetic, transcriptomic, epigenomic) related to a particular disease or phenotype can be uploaded and computed real-time to yield biologically interpretable results, which can be viewed online and downloaded for later use. Our Mergeomics web server offers researchers flexible and user-friendly tools to facilitate integration of multidimensional data into holistic views of disease mechanisms in the form of tissue-specific key regulators

  9. Gene expression profiling identifies molecular pathways associated with collagen VI deficiency and provides novel therapeutic targets.

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    Sonia Paco

    Full Text Available Ullrich congenital muscular dystrophy (UCMD, caused by collagen VI deficiency, is a common congenital muscular dystrophy. At present, the role of collagen VI in muscle and the mechanism of disease are not fully understood. To address this we have applied microarrays to analyse the transcriptome of UCMD muscle and compare it to healthy muscle and other muscular dystrophies. We identified 389 genes which are differentially regulated in UCMD relative to controls. In addition, there were 718 genes differentially expressed between UCMD and dystrophin deficient muscle. In contrast, only 29 genes were altered relative to other congenital muscular dystrophies. Changes in gene expression were confirmed by real-time PCR. The set of regulated genes was analysed by Gene Ontology, KEGG pathways and Ingenuity Pathway analysis to reveal the molecular functions and gene networks associated with collagen VI defects. The most significantly regulated pathways were those involved in muscle regeneration, extracellular matrix remodelling and inflammation. We characterised the immune response in UCMD biopsies as being mainly mediated via M2 macrophages and the complement pathway indicating that anti-inflammatory treatment may be beneficial to UCMD as for other dystrophies. We studied the immunolocalisation of ECM components and found that biglycan, a collagen VI interacting proteoglycan, was reduced in the basal lamina of UCMD patients. We propose that biglycan reduction is secondary to collagen VI loss and that it may be contributing towards UCMD pathophysiology. Consequently, strategies aimed at over-expressing biglycan and restore the link between the muscle cell surface and the extracellular matrix should be considered.

  10. Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities.

    Science.gov (United States)

    Itakura, Haruka; Achrol, Achal S; Mitchell, Lex A; Loya, Joshua J; Liu, Tiffany; Westbroek, Erick M; Feroze, Abdullah H; Rodriguez, Scott; Echegaray, Sebastian; Azad, Tej D; Yeom, Kristen W; Napel, Sandy; Rubin, Daniel L; Chang, Steven D; Harsh, Griffith R; Gevaert, Olivier

    2015-09-02

    Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic "clusters" emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters--pre-multifocal, spherical, and rim-enhancing, names reflecting their image features--were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM. Copyright © 2015, American Association for the Advancement of Science.

  11. Life after the Liverpool Care Pathway (LCP): a qualitative study of critical care practitioners delivering end-of-life care.

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    Ramasamy Venkatasalu, Munikumar; Whiting, Dean; Cairnduff, Karen

    2015-09-01

    To explore the experiences, challenges and practices of critical care practitioners since the discontinuation of the Liverpool Care Pathway in critical care settings. The Liverpool Care Pathway was widely used with an aim to improve communication and care for dying individuals and their relatives. However, widespread media criticism prompted a review, which resulted in the discontinuation of the Liverpool Care Pathway across all UK clinical settings. A qualitative study. The study was carried out in two large acute hospitals in England. Semi-structured interviews were conducted with 14 critical care practitioners, 6 months after discontinuation of the Liverpool Care Pathway. Transcribed verbatim data were analysed using framework analysis. Three key themes emerged: 'lessons learned', 'uncertainties and ambivalences' and 'the future'. Critical care practitioners reported that life after the Liverpool Care Pathway in critical care settings often involved various clinical ambivalences, uncertainties and inconsistencies in the delivery of end-of-life care, especially for less experienced practitioners. Critical care practitioners had 'become accustomed' to the components of the Liverpool Care Pathway, which still guide them in principle to ensure quality end-of-life care. The Liverpool Care Pathway's structured format was perceived to be a useful clinical tool, but was also criticized as a 'tick-box exercise' and for lacking in family involvement. This study posits two key conclusions. Despite experienced critical care practitioners being able to deliver quality end-of-life care without using the Liverpool Care Pathway, junior nursing and medical staff need clear guidelines and support from experienced mentors in practice. Evidence-based guidelines related to family involvement in end-of-life care planning in critical care settings are also needed to avoid future controversies. © 2015 John Wiley & Sons Ltd.

  12. Serum metabolomic profiling in acute alcoholic hepatitis identifies multiple dysregulated pathways.

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    Rachakonda, Vikrant; Gabbert, Charles; Raina, Amit; Bell, Lauren N; Cooper, Sara; Malik, Shahid; Behari, Jaideep

    2014-01-01

    While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Severe AAH is characterized by a distinct metabolic phenotype spanning

  13. Identifying work setting profile factors from the Career Pathway Evaluation Program.

    Science.gov (United States)

    Schommer, Jon C; Sogol, Elliott M; Brown, Lawrence M

    2013-11-12

    To describe the work factors associated with 28 different career areas as reported by pharmacists who responded to the American Pharmacists Association (APhA) Career Pathway Evaluation Program for Pharmacy Professionals, 2012 Pharmacist Profile Survey. Data from the 1,119 completed survey instruments from the 2012 Pharmacist Profile Survey were analyzed. Exploratory factor analysis was used to identify the underlying factors that best represented respondents' work setting profiles. Eleven underlying factors were identified for the respondents' work setting profiles: patient care, application of clinical knowledge, innovation, stress, research, managerial responsibility, work schedule flexibility, job position flexibility, self-actualization, geographic location, and continuity of coworker relationships. Findings revealed variation for these underlying factors among career categories. Variation among pharmacist career types exists. The profiles constructed in this study describe the characteristics of various career paths and can be helpful for decisions regarding educational, experiential, residency, and certification training in pharmacist careers.

  14. Identifying Work Setting Profile Factors From the Career Pathway Evaluation Program

    Science.gov (United States)

    Sogol, Elliott M.; Brown, Lawrence M.

    2013-01-01

    Objectives. To describe the work factors associated with 28 different career areas as reported by pharmacists who responded to the American Pharmacists Association (APhA) Career Pathway Evaluation Program for Pharmacy Professionals, 2012 Pharmacist Profile Survey Methods. Data from the 1,119 completed survey instruments from the 2012 Pharmacist Profile Survey were analyzed. Exploratory factor analysis was used to identify the underlying factors that best represented respondents’ work setting profiles. Results. Eleven underlying factors were identified for the respondents’ work setting profiles: patient care, application of clinical knowledge, innovation, stress, research, managerial responsibility, work schedule flexibility, job position flexibility, self-actualization, geographic location, and continuity of coworker relationships. Findings revealed variation for these underlying factors among career categories. Conclusion. Variation among pharmacist career types exists. The profiles constructed in this study describe the characteristics of various career paths and can be helpful for decisions regarding educational, experiential, residency, and certification training in pharmacist careers. PMID:24249856

  15. Simulated Annealing Based Algorithm for Identifying Mutated Driver Pathways in Cancer

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    Hai-Tao Li

    2014-01-01

    Full Text Available With the development of next-generation DNA sequencing technologies, large-scale cancer genomics projects can be implemented to help researchers to identify driver genes, driver mutations, and driver pathways, which promote cancer proliferation in large numbers of cancer patients. Hence, one of the remaining challenges is to distinguish functional mutations vital for cancer development, and filter out the unfunctional and random “passenger mutations.” In this study, we introduce a modified method to solve the so-called maximum weight submatrix problem which is used to identify mutated driver pathways in cancer. The problem is based on two combinatorial properties, that is, coverage and exclusivity. Particularly, we enhance an integrative model which combines gene mutation and expression data. The experimental results on simulated data show that, compared with the other methods, our method is more efficient. Finally, we apply the proposed method on two real biological datasets. The results show that our proposed method is also applicable in real practice.

  16. Curiosity and critical thinking: identifying child abuse before it is too late.

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    Jackson, Allison M; Deye, Katherine P; Halley, Tina; Hinds, Tanya; Rosenthal, Eric; Shalaby-Rana, Eglal; Goldman, Ellen F

    2015-01-01

    We reviewed medical records to identify factors contributing to not recognizing child abuse in cases where it was subsequently identified. Eighteen cases of delayed diagnosis of physical abuse were reviewed for qualitative themes. Missed abuse was defined by prior medical encounters that revealed findings concerning for physical abuse that were not recognized. Clinical limitations contributing to a delay in diagnosis included inattention to skin and subconjunctival findings, acceptance of inadequate explanations for injuries, no history obtained from verbal children, insufficient exploration of signs and symptoms, nonadherence to the maltreatment pathway, and incorrect diagnoses from radiologic examinations. System-based limitations included limited medical record access or completeness and admission to less-than-optimal settings. Having a greater index of suspicion for abuse may mitigate missed opportunities. With variability of medical training in child abuse, the factors we identified can be used as learning objectives for continuing medical education. © The Author(s) 2014.

  17. Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human.

    Science.gov (United States)

    Zanotto-Filho, Alfeu; Dashnamoorthy, Ravi; Loranc, Eva; de Souza, Luis H T; Moreira, José C F; Suresh, Uthra; Chen, Yidong; Bishop, Alexander J R

    2016-01-01

    Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray) prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair), DNA-mRNA-protein metabolism (transcription/translation) and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH)-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress)/Unfolded Protein Responses (UPR) in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival.

  18. Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human.

    Directory of Open Access Journals (Sweden)

    Alfeu Zanotto-Filho

    Full Text Available Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair, DNA-mRNA-protein metabolism (transcription/translation and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress/Unfolded Protein Responses (UPR in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival.

  19. Identifying the Critical Links in Road Transportation Networks: Centrality-based approach utilizing structural properties

    Energy Technology Data Exchange (ETDEWEB)

    Chinthavali, Supriya [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2016-04-01

    Surface transportation road networks share structural properties similar to other complex networks (e.g., social networks, information networks, biological networks, and so on). This research investigates the structural properties of road networks for any possible correlation with the traffic characteristics such as link flows those determined independently. Additionally, we define a criticality index for the links of the road network that identifies the relative importance in the network. We tested our hypotheses with two sample road networks. Results show that, correlation exists between the link flows and centrality measures of a link of the road (dual graph approach is followed) and the criticality index is found to be effective for one test network to identify the vulnerable nodes.

  20. Use of a deformable atlas to identify cryptic critical structures in the treatment of glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    David C Weksberg

    Full Text Available Dose constraints for traditional neural critical structures (e.g. optic chiasm, brain stem are a standard component of planning radiation therapy to the central nervous system. Increasingly, investigators are becoming interested in accounting for the dose delivered to other non-target neural structures (e.g. hippocampi, which are not easily identified on axial imaging. In this pilot study, a commercially available digital atlas was used to identify cryptic neural structures (hippocampus, optic radiations, and visual cortices in 6 patients who received intensity modulated radiation therapy (IMRT as part of multimodal management of glioblastoma multiforme (GBM. The patient's original IMRT plans were re-optimized, with avoidance parameters for the newly identified critical structures. Re-optimization was able to reduce both mean and maximum dose to the volumes of interest, with a more pronounced effect for contralateral structures. Mean dose was reduced by 11% and 3% to contralateral and ipsilateral structures, respectively, with comparable reduction in maximum dose of 10% and 2%, respectively. Importantly, target coverage was not compromised, with an average change in coverage of 0.2%. Overall, our results demonstrate the feasibility of incorporating tools for cryptic critical structure identification into the treatment planning process for GBM.

  1. Elongation factor P mediates a novel post-transcriptional regulatory pathway critical for bacterial virulence

    DEFF Research Database (Denmark)

    Zou, S Betty; Roy, Hervé; Ibba, Michael

    2012-01-01

    of the pathogen to respond to external cues are typically attenuating. Here we discuss our recent discovery of a novel post-transcriptional regulatory pathway critical for Salmonella virulence and stress resistance. The enzymes PoxA and YjeK coordinately attach a unique beta-amino acid onto a highly conserved......Bacterial pathogens detect and integrate multiple environmental signals to coordinate appropriate changes in gene expression including the selective expression of virulence factors, changes to metabolism and the activation of stress response systems. Mutations that abolish the ability...... changes in the translation machinery during stress adaptation, indicating that the role of these factors in physiology may be broadly conserved....

  2. Elongation factor P mediates a novel post-transcriptional regulatory pathway critical for bacterial virulence

    DEFF Research Database (Denmark)

    Zou, S Betty; Roy, Hervé; Ibba, Michael

    2012-01-01

    Bacterial pathogens detect and integrate multiple environmental signals to coordinate appropriate changes in gene expression including the selective expression of virulence factors, changes to metabolism and the activation of stress response systems. Mutations that abolish the ability...... of the pathogen to respond to external cues are typically attenuating. Here we discuss our recent discovery of a novel post-transcriptional regulatory pathway critical for Salmonella virulence and stress resistance. The enzymes PoxA and YjeK coordinately attach a unique beta-amino acid onto a highly conserved...

  3. Applicability of the Critical pathway analysis usually used for nuclear installations, to the control marine environment pollution by heavy metals

    International Nuclear Information System (INIS)

    Franca, E.P.; Pfeiffer, W.C.; Fiszman, M.; Lacerda, L.D. de

    1984-01-01

    The methodology of the controlling radionuclide releases from nuclear facilities by the critical pathway criteria, is given. The use of this methodology for the environmental impact studies for an industry that causes pollution is discussed. (M.A.) [pt

  4. A quantitative metric to identify critical elements within seafood supply networks.

    Science.gov (United States)

    Plagányi, Éva E; van Putten, Ingrid; Thébaud, Olivier; Hobday, Alistair J; Innes, James; Lim-Camacho, Lilly; Norman-López, Ana; Bustamante, Rodrigo H; Farmery, Anna; Fleming, Aysha; Frusher, Stewart; Green, Bridget; Hoshino, Eriko; Jennings, Sarah; Pecl, Gretta; Pascoe, Sean; Schrobback, Peggy; Thomas, Linda

    2014-01-01

    A theoretical basis is required for comparing key features and critical elements in wild fisheries and aquaculture supply chains under a changing climate. Here we develop a new quantitative metric that is analogous to indices used to analyse food-webs and identify key species. The Supply Chain Index (SCI) identifies critical elements as those elements with large throughput rates, as well as greater connectivity. The sum of the scores for a supply chain provides a single metric that roughly captures both the resilience and connectedness of a supply chain. Standardised scores can facilitate cross-comparisons both under current conditions as well as under a changing climate. Identification of key elements along the supply chain may assist in informing adaptation strategies to reduce anticipated future risks posed by climate change. The SCI also provides information on the relative stability of different supply chains based on whether there is a fairly even spread in the individual scores of the top few key elements, compared with a more critical dependence on a few key individual supply chain elements. We use as a case study the Australian southern rock lobster Jasus edwardsii fishery, which is challenged by a number of climate change drivers such as impacts on recruitment and growth due to changes in large-scale and local oceanographic features. The SCI identifies airports, processors and Chinese consumers as the key elements in the lobster supply chain that merit attention to enhance stability and potentially enable growth. We also apply the index to an additional four real-world Australian commercial fishery and two aquaculture industry supply chains to highlight the utility of a systematic method for describing supply chains. Overall, our simple methodological approach to empirically-based supply chain research provides an objective method for comparing the resilience of supply chains and highlighting components that may be critical.

  5. A quantitative metric to identify critical elements within seafood supply networks.

    Directory of Open Access Journals (Sweden)

    Éva E Plagányi

    Full Text Available A theoretical basis is required for comparing key features and critical elements in wild fisheries and aquaculture supply chains under a changing climate. Here we develop a new quantitative metric that is analogous to indices used to analyse food-webs and identify key species. The Supply Chain Index (SCI identifies critical elements as those elements with large throughput rates, as well as greater connectivity. The sum of the scores for a supply chain provides a single metric that roughly captures both the resilience and connectedness of a supply chain. Standardised scores can facilitate cross-comparisons both under current conditions as well as under a changing climate. Identification of key elements along the supply chain may assist in informing adaptation strategies to reduce anticipated future risks posed by climate change. The SCI also provides information on the relative stability of different supply chains based on whether there is a fairly even spread in the individual scores of the top few key elements, compared with a more critical dependence on a few key individual supply chain elements. We use as a case study the Australian southern rock lobster Jasus edwardsii fishery, which is challenged by a number of climate change drivers such as impacts on recruitment and growth due to changes in large-scale and local oceanographic features. The SCI identifies airports, processors and Chinese consumers as the key elements in the lobster supply chain that merit attention to enhance stability and potentially enable growth. We also apply the index to an additional four real-world Australian commercial fishery and two aquaculture industry supply chains to highlight the utility of a systematic method for describing supply chains. Overall, our simple methodological approach to empirically-based supply chain research provides an objective method for comparing the resilience of supply chains and highlighting components that may be critical.

  6. Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate.

    Directory of Open Access Journals (Sweden)

    Galen W Heyne

    Full Text Available The Hedgehog (Hh signaling pathway mediates multiple spatiotemporally-specific aspects of brain and face development. Genetic and chemical disruptions of the pathway are known to result in an array of structural malformations, including holoprosencephaly (HPE, clefts of the lip with or without cleft palate (CL/P, and clefts of the secondary palate only (CPO. Here, we examined patterns of dysmorphology caused by acute, stage-specific Hh signaling inhibition. Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the potent pathway antagonist vismodegib at discrete time points between gestational day (GD 7.0 and 10.0, an interval approximately corresponding to the 15th to 24th days of human gestation. The resultant pattern of facial and brain dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. Unilateral clefts of the lip extending into the primary palate were also observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 and GD10.0 resulted in CPO and forelimb abnormalities. We have previously demonstrated that Hh antagonist-induced cleft lip results from deficiency of the medial nasal process and show here that CPO is associated with reduced growth of the maxillary-derived palatal shelves. By defining the critical periods for the induction of HPE, CL/P, and CPO with fine temporal resolution, these results provide a mechanism by which Hh pathway disruption can result in "non-syndromic" orofacial clefting, or HPE with or without co-occurring clefts. This study also establishes a novel and tractable mouse model of human craniofacial malformations using a single dose of a commercially available and pathway-specific drug.

  7. Use of critical pathway models and log-normal frequency distributions for siting nuclear facilities

    International Nuclear Information System (INIS)

    Waite, D.A.; Denham, D.H.

    1975-01-01

    The advantages and disadvantages of potential sites for nuclear facilities are evaluated through the use of environmental pathway and log-normal distribution analysis. Environmental considerations of nuclear facility siting are necessarily geared to the identification of media believed to be sifnificant in terms of dose to man or to be potential centres for long-term accumulation of contaminants. To aid in meeting the scope and purpose of this identification, an exposure pathway diagram must be developed. This type of diagram helps to locate pertinent environmental media, points of expected long-term contaminant accumulation, and points of population/contaminant interface for both radioactive and non-radioactive contaminants. Confirmation of facility siting conclusions drawn from pathway considerations must usually be derived from an investigatory environmental surveillance programme. Battelle's experience with environmental surveillance data interpretation using log-normal techniques indicates that this distribution has much to offer in the planning, execution and analysis phases of such a programme. How these basic principles apply to the actual siting of a nuclear facility is demonstrated for a centrifuge-type uranium enrichment facility as an example. A model facility is examined to the extent of available data in terms of potential contaminants and facility general environmental needs. A critical exposure pathway diagram is developed to the point of prescribing the characteristics of an optimum site for such a facility. Possible necessary deviations from climatic constraints are reviewed and reconciled with conclusions drawn from the exposure pathway analysis. Details of log-normal distribution analysis techniques are presented, with examples of environmental surveillance data to illustrate data manipulation techniques and interpretation procedures as they affect the investigatory environmental surveillance programme. Appropriate consideration is given these

  8. Signature pathways identified from gene expression profiles in the human uterine cervix before and after spontaneous term parturition

    Science.gov (United States)

    HASSAN, Sonia S.; ROMERO, Roberto; TARCA, Adi L.; DRAGHICI, Sorin; PINELES, Beth; BUGRIM, Andrej; KHALEK, Nahla; CAMACHO, Natalia; MITTAL, Pooja; YOON, Bo Hyun; ESPINOZA, Jimmy; KIM, Chong Jai; SOROKIN, Yoram; MALONE, John

    2008-01-01

    Objective This study aimed to discover ‘signature pathways’ characterizing biological processes based on genes differentially expressed in the uterine cervix before and after spontaneous labor. Study Design The cervical transcriptome was previously characterized from biopsies taken before and after term labor. Pathway analysis was used to study the differentially expressed genes based on two gene-to-pathway annotation databases (KEGG and Metacore™). Over-represented and highly impacted pathways and connectivity nodes were identified. Results Fifty-two pathways in the Metacore™ database were significantly enriched in differentially expressed genes. Three of the top 5 pathways were known to be involved in cervical remodeling.Two novel pathways were: plasmin signaling and plasminogen activator urokinase (PLAU) signaling. The same analysis in the KEGG database identified 4 significant pathways, of which impact analysis confirmed. Multiple nodes providing connectivity within the plasmin and PLAU signaling pathways were identified.. Conclusions Three strategies for pathway analysis were consistent in their identification of novel, unexpected as well as expected networks, suggesting that this approach is both valid and effective for the elucidation of biological mechanisms involved in cervical dilation and remodeling. PMID:17826407

  9. An integrative framework for Bayesian variable selection with informative priors for identifying genes and pathways.

    Science.gov (United States)

    Peng, Bin; Zhu, Dianwen; Ander, Bradley P; Zhang, Xiaoshuai; Xue, Fuzhong; Sharp, Frank R; Yang, Xiaowei

    2013-01-01

    The discovery of genetic or genomic markers plays a central role in the development of personalized medicine. A notable challenge exists when dealing with the high dimensionality of the data sets, as thousands of genes or millions of genetic variants are collected on a relatively small number of subjects. Traditional gene-wise selection methods using univariate analyses face difficulty to incorporate correlational, structural, or functional structures amongst the molecular measures. For microarray gene expression data, we first summarize solutions in dealing with 'large p, small n' problems, and then propose an integrative Bayesian variable selection (iBVS) framework for simultaneously identifying causal or marker genes and regulatory pathways. A novel partial least squares (PLS) g-prior for iBVS is developed to allow the incorporation of prior knowledge on gene-gene interactions or functional relationships. From the point view of systems biology, iBVS enables user to directly target the joint effects of multiple genes and pathways in a hierarchical modeling diagram to predict disease status or phenotype. The estimated posterior selection probabilities offer probabilitic and biological interpretations. Both simulated data and a set of microarray data in predicting stroke status are used in validating the performance of iBVS in a Probit model with binary outcomes. iBVS offers a general framework for effective discovery of various molecular biomarkers by combining data-based statistics and knowledge-based priors. Guidelines on making posterior inferences, determining Bayesian significance levels, and improving computational efficiencies are also discussed.

  10. Soldier, civilian, criminal: identifying pathways to offending of ex-armed forces personnel in prison

    Science.gov (United States)

    Wainwright, Verity; McDonnell, Sharon; Lennox, Charlotte; Shaw, Jenny; Senior, Jane

    2016-01-01

    ABSTRACT Little is known about why some ex-armed forces personnel become involved in the criminal justice system, however, they represent the largest known occupational group in prison. In-depth interviews were employed to explore possible pathways to offending. Twenty ex-armed forces personnel in prison were recruited from five prisons in England. Data were analysed using a combination of thematic analysis and constant comparison methods rooted in grounded theory. Four predominant themes were identified: experiences of trauma and adversity; belonging; impulsivity and creating a soldier. Participants had experienced a number of traumatic incidents and adversity in their lives, encompassing pre, during and post-service but felt a sense of belonging in the armed forces. Participants demonstrated impulsivity in a number of areas with links to both their service in the armed forces and offending behaviour. The creation of the identity of ‘soldier’ was perceived to impact participants’ lives in a number of ways, including their offending, alcohol use and coping with trauma. The interplay of these themes and their potential impact on participants’ pathways to offending are discussed. PMID:27570440

  11. Soldier, civilian, criminal: identifying pathways to offending of ex-armed forces personnel in prison.

    Science.gov (United States)

    Wainwright, Verity; McDonnell, Sharon; Lennox, Charlotte; Shaw, Jenny; Senior, Jane

    2016-09-13

    Little is known about why some ex-armed forces personnel become involved in the criminal justice system, however, they represent the largest known occupational group in prison. In-depth interviews were employed to explore possible pathways to offending. Twenty ex-armed forces personnel in prison were recruited from five prisons in England. Data were analysed using a combination of thematic analysis and constant comparison methods rooted in grounded theory. Four predominant themes were identified: experiences of trauma and adversity; belonging; impulsivity and creating a soldier . Participants had experienced a number of traumatic incidents and adversity in their lives, encompassing pre, during and post-service but felt a sense of belonging in the armed forces. Participants demonstrated impulsivity in a number of areas with links to both their service in the armed forces and offending behaviour. The creation of the identity of 'soldier' was perceived to impact participants' lives in a number of ways, including their offending, alcohol use and coping with trauma. The interplay of these themes and their potential impact on participants' pathways to offending are discussed.

  12. A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

    Science.gov (United States)

    Giotopoulos, George; van der Weyden, Louise; Osaki, Hikari; Rust, Alistair G.; Gallipoli, Paolo; Meduri, Eshwar; Horton, Sarah J.; Chan, Wai-In; Foster, Donna; Prinjha, Rab K.; Pimanda, John E.; Tenen, Daniel G.; Vassiliou, George S.; Koschmieder, Steffen; Adams, David J.

    2015-01-01

    The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease. PMID:26304963

  13. msiDBN: A Method of Identifying Critical Proteins in Dynamic PPI Networks

    Directory of Open Access Journals (Sweden)

    Yuan Zhang

    2014-01-01

    Full Text Available Dynamics of protein-protein interactions (PPIs reveals the recondite principles of biological processes inside a cell. Shown in a wealth of study, just a small group of proteins, rather than the majority, play more essential roles at crucial points of biological processes. This present work focuses on identifying these critical proteins exhibiting dramatic structural changes in dynamic PPI networks. First, a comprehensive way of modeling the dynamic PPIs is presented which simultaneously analyzes the activity of proteins and assembles the dynamic coregulation correlation between proteins at each time point. Second, a novel method is proposed, named msiDBN, which models a common representation of multiple PPI networks using a deep belief network framework and analyzes the reconstruction errors and the variabilities across the time courses in the biological process. Experiments were implemented on data of yeast cell cycles. We evaluated our network construction method by comparing the functional representations of the derived networks with two other traditional construction methods. The ranking results of critical proteins in msiDBN were compared with the results from the baseline methods. The results of comparison showed that msiDBN had better reconstruction rate and identified more proteins of critical value to yeast cell cycle process.

  14. Implementing critical pathways and a multidisciplinary team approach to cardiovascular disease management.

    Science.gov (United States)

    Peterson, Eric D; Albert, Nancy M; Amin, Alpesh; Patterson, J Herbert; Fonarow, Gregg C

    2008-09-08

    According to several medical registries, there is a need to improve the care of post-myocardial infarction (MI) patients, especially those with left ventricular dysfunction (LVD) and heart failure. This can potentially be achieved by implementing disease management programs, which include critical pathways, patient education, and multidisciplinary hospital teams. Currently, algorithms for critical pathways, including discharge processes, are lacking for post-MI LVD patients. Such schemes can increase the use of evidence-based medicines proved to reduce mortality. Educational programs are aimed at increasing patients' awareness of their condition, promoting medication compliance, and encouraging the adoption of healthy behaviors; such programs have been shown to be effective in improving outcomes of post-MI LVD patients. Reductions in all-cause hospitalizations and medical costs as well as improved survival rates have been observed when a multidisciplinary team (a nurse, a pharmacist, and a hospitalist) is engaged in patient care. In addition, the use of the "pay for performance" method, which can be advantageous for patients, physicians, and hospitals, may potentially improve the care of post-MI patients with LVD.

  15. Identifying hotspots and management of critical ecosystem services in rapidly urbanizing Yangtze River Delta Region, China.

    Science.gov (United States)

    Cai, Wenbo; Gibbs, David; Zhang, Lang; Ferrier, Graham; Cai, Yongli

    2017-04-15

    Rapid urbanization has altered many ecosystems, causing a decline in many ecosystem services, generating serious ecological crisis. To cope with these challenges, we presented a comprehensive framework comprising five core steps for identifying and managing hotspots of critical ecosystem services in a rapid urbanizing region. This framework was applied in the case study of the Yangtze River Delta (YRD) Region. The study showed that there was large spatial heterogeneity in the hotspots of ecosystem services in the region, hotspots of supporting services and regulating services aggregately distributing in the southwest mountainous areas while hotspots of provisioning services mainly in the northeast plain, and hotspots of cultural services widespread in the waterbodies and southwest mountainous areas. The regionalization of the critical ecosystem services was made through the hotspot analysis. This study provided valuable information for environmental planning and management in a rapid urbanizing region and helped improve China's ecological redlines policy at regional scale. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Genome-Wide Chromatin Landscape Transitions Identify Novel Pathways in Early Commitment to Osteoblast Differentiation.

    Science.gov (United States)

    Thompson, Bethtrice; Varticovski, Lyuba; Baek, Songjoon; Hager, Gordon L

    2016-01-01

    Bone continuously undergoes remodeling by a tightly regulated process that involves osteoblast differentiation from Mesenchymal Stem Cells (MSC). However, commitment of MSC to osteoblastic lineage is a poorly understood process. Chromatin organization functions as a molecular gatekeeper of DNA functions. Detection of sites that are hypersensitive to Dnase I has been used for detailed examination of changes in response to hormones and differentiation cues. To investigate the early steps in commitment of MSC to osteoblasts, we used a model human temperature-sensitive cell line, hFOB. When shifted to non-permissive temperature, these cells undergo "spontaneous" differentiation that takes several weeks, a process that is greatly accelerated by osteogenic induction media. We performed Dnase I hypersensitivity assays combined with deep sequencing to identify genome-wide potential regulatory events in cells undergoing early steps of commitment to osteoblasts. Massive reorganization of chromatin occurred within hours of differentiation. Whereas ~30% of unique DHS sites were located in the promoters, the majority was outside of the promoters, designated as enhancers. Many of them were at novel genomic sites and need to be confirmed experimentally. We developed a novel method for identification of cellular networks based solely on DHS enhancers signature correlated to gene expression. The analysis of enhancers that were unique to differentiating cells led to identification of bone developmental program encompassing 147 genes that directly or indirectly participate in osteogenesis. Identification of these pathways provided an unprecedented view of genomic regulation during early steps of differentiation and changes related to WNT, AP-1 and other pathways may have therapeutic implications.

  17. Genome-Wide Chromatin Landscape Transitions Identify Novel Pathways in Early Commitment to Osteoblast Differentiation.

    Directory of Open Access Journals (Sweden)

    Bethtrice Thompson

    Full Text Available Bone continuously undergoes remodeling by a tightly regulated process that involves osteoblast differentiation from Mesenchymal Stem Cells (MSC. However, commitment of MSC to osteoblastic lineage is a poorly understood process. Chromatin organization functions as a molecular gatekeeper of DNA functions. Detection of sites that are hypersensitive to Dnase I has been used for detailed examination of changes in response to hormones and differentiation cues. To investigate the early steps in commitment of MSC to osteoblasts, we used a model human temperature-sensitive cell line, hFOB. When shifted to non-permissive temperature, these cells undergo "spontaneous" differentiation that takes several weeks, a process that is greatly accelerated by osteogenic induction media. We performed Dnase I hypersensitivity assays combined with deep sequencing to identify genome-wide potential regulatory events in cells undergoing early steps of commitment to osteoblasts. Massive reorganization of chromatin occurred within hours of differentiation. Whereas ~30% of unique DHS sites were located in the promoters, the majority was outside of the promoters, designated as enhancers. Many of them were at novel genomic sites and need to be confirmed experimentally. We developed a novel method for identification of cellular networks based solely on DHS enhancers signature correlated to gene expression. The analysis of enhancers that were unique to differentiating cells led to identification of bone developmental program encompassing 147 genes that directly or indirectly participate in osteogenesis. Identification of these pathways provided an unprecedented view of genomic regulation during early steps of differentiation and changes related to WNT, AP-1 and other pathways may have therapeutic implications.

  18. An integrative framework for Bayesian variable selection with informative priors for identifying genes and pathways.

    Directory of Open Access Journals (Sweden)

    Bin Peng

    Full Text Available The discovery of genetic or genomic markers plays a central role in the development of personalized medicine. A notable challenge exists when dealing with the high dimensionality of the data sets, as thousands of genes or millions of genetic variants are collected on a relatively small number of subjects. Traditional gene-wise selection methods using univariate analyses face difficulty to incorporate correlational, structural, or functional structures amongst the molecular measures. For microarray gene expression data, we first summarize solutions in dealing with 'large p, small n' problems, and then propose an integrative Bayesian variable selection (iBVS framework for simultaneously identifying causal or marker genes and regulatory pathways. A novel partial least squares (PLS g-prior for iBVS is developed to allow the incorporation of prior knowledge on gene-gene interactions or functional relationships. From the point view of systems biology, iBVS enables user to directly target the joint effects of multiple genes and pathways in a hierarchical modeling diagram to predict disease status or phenotype. The estimated posterior selection probabilities offer probabilitic and biological interpretations. Both simulated data and a set of microarray data in predicting stroke status are used in validating the performance of iBVS in a Probit model with binary outcomes. iBVS offers a general framework for effective discovery of various molecular biomarkers by combining data-based statistics and knowledge-based priors. Guidelines on making posterior inferences, determining Bayesian significance levels, and improving computational efficiencies are also discussed.

  19. The use of arithmetic average method in identifying critical success criteria for Homestay Programmes

    Science.gov (United States)

    Daud, Shahidah Md; Ramli, Razamin; Kasim, Maznah Mat; Kayat, Kalsom; Razak, Rafidah Abd

    2015-12-01

    Malaysian Homestay is very unique. It is classified as Community Based Tourism (CBT). Homestay Programme which is a community events where a tourist stays together with a host family for a period of time and enjoying cultural exchange besides having new experiences. Homestay programme has booming the tourism industry since there is over 100 Homestay Programme currently being registered with the Ministry of Culture and Tourism Malaysia. However, only few Homestay Programme enjoying the benefits of success Homestay Programme. Hence, this article seeks to identify the critical success factors for a Homestay Programme in Malaysia. An Arithmetic Average method is utilized to further evaluate the identified success factors in a more meaningful way. The findings will help Homestay Programme function as a community development tool that manages tourism resources. Thus, help the community in improving local economy and creating job opportunities.

  20. Structural identifiability of systems biology models: a critical comparison of methods.

    Directory of Open Access Journals (Sweden)

    Oana-Teodora Chis

    Full Text Available Analysing the properties of a biological system through in silico experimentation requires a satisfactory mathematical representation of the system including accurate values of the model parameters. Fortunately, modern experimental techniques allow obtaining time-series data of appropriate quality which may then be used to estimate unknown parameters. However, in many cases, a subset of those parameters may not be uniquely estimated, independently of the experimental data available or the numerical techniques used for estimation. This lack of identifiability is related to the structure of the model, i.e. the system dynamics plus the observation function. Despite the interest in knowing a priori whether there is any chance of uniquely estimating all model unknown parameters, the structural identifiability analysis for general non-linear dynamic models is still an open question. There is no method amenable to every model, thus at some point we have to face the selection of one of the possibilities. This work presents a critical comparison of the currently available techniques. To this end, we perform the structural identifiability analysis of a collection of biological models. The results reveal that the generating series approach, in combination with identifiability tableaus, offers the most advantageous compromise among range of applicability, computational complexity and information provided.

  1. A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency

    Science.gov (United States)

    Artyomov, Maxim; Meissner, Alex; Chakraborty, Arup

    2010-03-01

    Most cells in an organism have the same DNA. Yet, different cell types express different proteins and carry out different functions. This is because of epigenetic differences; i.e., DNA in different cell types is packaged distinctly, making it hard to express certain genes while facilitating the expression of others. During development, upon receipt of appropriate cues, pluripotent embryonic stem cells differentiate into diverse cell types that make up the organism (e.g., a human). There has long been an effort to make this process go backward -- i.e., reprogram a differentiated cell (e.g., a skin cell) to pluripotent status. Recently, this has been achieved by transfecting certain transcription factors into differentiated cells. This method does not use embryonic material and promises the development of patient-specific regenerative medicine, but it is inefficient. The mechanisms that make reprogramming rare, or even possible, are poorly understood. We have developed the first computational model of transcription factor-induced reprogramming. Results obtained from the model are consistent with diverse observations, and identify the rare pathways that allow reprogramming to occur. If validated, our model could be further developed to design optimal strategies for reprogramming and shed light on basic questions in biology.

  2. Pathways to obesity: identifying local, modifiable determinants of physical activity and diet.

    Science.gov (United States)

    Stafford, Mai; Cummins, Steven; Ellaway, Anne; Sacker, Amanda; Wiggins, Richard D; Macintyre, Sally

    2007-11-01

    Many studies document small area inequalities in morbidity and mortality and show associations between area deprivation and health. However, few studies unpack the "black box" of area deprivation to show which specific local social and physical environmental characteristics impact upon health, and might be amenable to modification. We theorised a model of the potential causal pathways to obesity and employed path analysis using a rich data set from national studies in England and Scotland to test the model empirically. Significant associations between obesity and neighbourhood disorder and access to local high street facilities (local shops, financial services and health-related stores found in a typical small UK town) were found. There was a tendency for lower levels of obesity in areas with more swimming pools and supermarkets. In turn, policing levels, physical dereliction and recorded violent crime were associated with neighbourhood disorder. The analysis identifies several factors that are associated with (and are probably determinants of) obesity and which are outside the standard remit of the healthcare sector. They highlight the role that public and private sector organisations have in promoting the nation's health. Public health professionals should seek to work alongside or within these organisations to capitalise on opportunities to improve health.

  3. A new approach to hazardous materials transportation risk analysis: decision modeling to identify critical variables.

    Science.gov (United States)

    Clark, Renee M; Besterfield-Sacre, Mary E

    2009-03-01

    We take a novel approach to analyzing hazardous materials transportation risk in this research. Previous studies analyzed this risk from an operations research (OR) or quantitative risk assessment (QRA) perspective by minimizing or calculating risk along a transport route. Further, even though the majority of incidents occur when containers are unloaded, the research has not focused on transportation-related activities, including container loading and unloading. In this work, we developed a decision model of a hazardous materials release during unloading using actual data and an exploratory data modeling approach. Previous studies have had a theoretical perspective in terms of identifying and advancing the key variables related to this risk, and there has not been a focus on probability and statistics-based approaches for doing this. Our decision model empirically identifies the critical variables using an exploratory methodology for a large, highly categorical database involving latent class analysis (LCA), loglinear modeling, and Bayesian networking. Our model identified the most influential variables and countermeasures for two consequences of a hazmat incident, dollar loss and release quantity, and is one of the first models to do this. The most influential variables were found to be related to the failure of the container. In addition to analyzing hazmat risk, our methodology can be used to develop data-driven models for strategic decision making in other domains involving risk.

  4. Betweenness-Based Method to Identify Critical Transmission Sectors for Supply Chain Environmental Pressure Mitigation.

    Science.gov (United States)

    Liang, Sai; Qu, Shen; Xu, Ming

    2016-02-02

    To develop industry-specific policies for mitigating environmental pressures, previous studies primarily focus on identifying sectors that directly generate large amounts of environmental pressures (a.k.a. production-based method) or indirectly drive large amounts of environmental pressures through supply chains (e.g., consumption-based method). In addition to those sectors as important environmental pressure producers or drivers, there exist sectors that are also important to environmental pressure mitigation as transmission centers. Economy-wide environmental pressure mitigation might be achieved by improving production efficiency of these key transmission sectors, that is, using less upstream inputs to produce unitary output. We develop a betweenness-based method to measure the importance of transmission sectors, borrowing the betweenness concept from network analysis. We quantify the betweenness of sectors by examining supply chain paths extracted from structural path analysis that pass through a particular sector. We take China as an example and find that those critical transmission sectors identified by betweenness-based method are not always identifiable by existing methods. This indicates that betweenness-based method can provide additional insights that cannot be obtained with existing methods on the roles individual sectors play in generating economy-wide environmental pressures. Betweenness-based method proposed here can therefore complement existing methods for guiding sector-level environmental pressure mitigation strategies.

  5. Identifying critical success factors (CSFs) of implementing building information modeling (BIM) in Malaysian construction industry

    Science.gov (United States)

    Yaakob, Mazri; Ali, Wan Nur Athirah Wan; Radzuan, Kamaruddin

    2016-08-01

    Building Information Modeling (BIM) is defined as existing from the earliest concept to demolition and it involves creating and using an intelligent 3D model to inform and communicate project decisions. This research aims to identify the critical success factors (CSFs) of BIM implementation in Malaysian construction industry. A literature review was done to explore previous BIM studies on definitions and history of BIM, construction issues, application of BIM in construction projects as well as benefits of BIM. A series of interviews with multidisciplinary Malaysian construction experts will be conducted purposely for data collection process guided by the research design and methodology approach of this study. The analysis of qualitative data from the process will be combined with criteria identified in the literature review in order to identify the CSFs. Finally, the CSFs of BIM implementation will be validated by further Malaysian industrialists during a workshop. The validated CSFs can be used as a term of reference for both Malaysian practitioners and academics towards measuring BIM effectiveness level in their organizations.

  6. Identifying Critical Factors in the Eco-Efficiency of Remanufacturing Based on the Fuzzy DEMATEL Method

    Directory of Open Access Journals (Sweden)

    Qianwang Deng

    2015-11-01

    Full Text Available Remanufacturing can bring considerable economic and environmental benefits such as cost saving, conservation of energy and resources, and reduction of emissions. With the increasing awareness of sustainable manufacturing, remanufacturing gradually becomes the research priority. Most studies concentrate on the analysis of influencing factors, or the evaluation of the economic and environmental performance in remanufacturing, while little effort has been devoted to investigating the critical factors influencing the eco-efficiency of remanufacturing. Considering the current development of the remanufacturing industry in China, this paper proposes a set of factors influencing the eco-efficiency of remanufacturing and then utilizes a fuzzy Decision Making Trial and Evaluation Laboratory (DEMATEL method to establish relation matrixes reflecting the interdependent relationships among these factors. Finally, the contributions of each factor to eco-efficiency and mutual influence values among them are obtained, and critical factors in eco-efficiency of remanufacturing are identified. The results of the present work can provide theoretical supports for the government to make appropriate policies to improve the eco-efficiency of remanufacturing.

  7. Identifying driving gene clusters in complex diseases through critical transition theory

    Science.gov (United States)

    Wolanyk, Nathaniel; Wang, Xujing; Hessner, Martin; Gao, Shouguo; Chen, Ye; Jia, Shuang

    A novel approach of looking at the human body using critical transition theory has yielded positive results: clusters of genes that act in tandem to drive complex disease progression. This cluster of genes can be thought of as the first part of a large genetic force that pushes the body from a curable, but sick, point to an incurable diseased point through a catastrophic bifurcation. The data analyzed is time course microarray blood assay data of 7 high risk individuals for Type 1 Diabetes who progressed into a clinical onset, with an additional larger study requested to be presented at the conference. The normalized data is 25,000 genes strong, which were narrowed down based on statistical metrics, and finally a machine learning algorithm using critical transition metrics found the driving network. This approach was created to be repeatable across multiple complex diseases with only progression time course data needed so that it would be applicable to identifying when an individual is at risk of developing a complex disease. Thusly, preventative measures can be enacted, and in the longer term, offers a possible solution to prevent all Type 1 Diabetes.

  8. An integrated care pathway to save the critically ischaemic diabetic foot.

    Science.gov (United States)

    El Sakka, K; Fassiadis, N; Gambhir, R P S; Halawa, M; Zayed, H; Doxford, M; Greensitt, C; Edmonds, M; Rashid, H

    2006-06-01

    This prospective study describes and evaluates the efficacy of an integrated care pathway for the management of the critically ischaemic diabetic foot patients by a multidisciplinary team. A weekly joint diabetes/vascular/podiatry ward round and outpatient clinic was established where patients were assessed within 7 days of referral by clinical examination, ankle-brachial-index-pressures, duplex angiogram and transcutaneous oxygen pressures. An angiogram +/- angioplasty or alternatively a magnetic resonance angiography prior to surgical revascularisation was performed in patients deemed not suitable for angioplasty based on the above vascular assessment. Between January 2002 and June 2003(18 months), 128 diabetic patients with lower limb ischaemia were seen. Thirty-four (26.6%) patients received medical treatment alone, and 18 (14.1%) were deemed 'palliative' due to their significant co-morbidities. The remaining 76 (59.4%) patients underwent either angioplasty (n = 56), surgical reconstruction (n = 18), primary major amputation (n = 2) or secondary amputation after surgical revascularisation (n = 1). Minor toe amputations were required in 35 patients. The mortality in the intervention group was 14% (11/76). This integrated multidisciplinary approach offers a consistent and equitable service to diabetic patients with critically ischaemic feet and appears to have a beneficial major/minor amputation ratio.

  9. An exploratory study to identify critical factors of innovation culture in organizations

    Directory of Open Access Journals (Sweden)

    Hamed Asgari

    2013-07-01

    Full Text Available During the past two decades, there has been a growing trend on knowledge-based organizations. Innovation, on the other hand, plays essential role on building competitive business units. In this paper, we present an exploratory study to identify critical factors of innovation culture in organizations. We detect important factors influencing innovation culture in construction industry based on the implementation of factor analysis. The proposed study designs a questionnaire and distributes it among 400 experts who are involved in construction industry. Cronbach alpha has been calculated as 0.779, which validates the overall questionnaire. The results of factor analysis have indicated that six factors of building cultural infrastructures, education, organizational vision, established culture, strategic culture and flexible culture are the most important items influencing innovation culture.

  10. Stakeholder Engagement to Identify Priorities for Improving the Quality and Value of Critical Care.

    Directory of Open Access Journals (Sweden)

    Henry T Stelfox

    Full Text Available Large amounts of scientific evidence are generated, but not implemented into patient care (the 'knowledge-to-care' gap. We identified and prioritized knowledge-to-care gaps in critical care as opportunities to improve the quality and value of healthcare.We used a multi-method community-based participatory research approach to engage a Network of all adult (n = 14 and pediatric (n = 2 medical-surgical intensive care units (ICUs in a fully integrated geographically defined healthcare system serving 4 million residents. Participants included Network oversight committee members (n = 38 and frontline providers (n = 1,790. Network committee members used a modified RAND/University of California Appropriateness Methodology, to serially propose, rate (validated 9 point scale and revise potential knowledge-to-care gaps as priorities for improvement. The priorities were sent to frontline providers for evaluation. Results were relayed back to all frontline providers for feedback.Initially, 68 knowledge-to-care gaps were proposed, rated and revised by the committee (n = 32 participants over 3 rounds of review and resulted in 13 proposed priorities for improvement. Then, 1,103 providers (62% response rate evaluated the priorities, and rated 9 as 'necessary' (median score 7-9. Several factors were associated with rating priorities as necessary in multivariable logistic regression, related to the provider (experience, teaching status of ICU and topic (strength of supporting evidence, potential to benefit the patient, potential to improve patient/family experience, potential to decrease costs.A community-based participatory research approach engaged a diverse group of stakeholders to identify 9 priorities for improving the quality and value of critical care. The approach was time and cost efficient and could serve as a model to prioritize areas for research quality improvement across other settings.

  11. Stakeholder Engagement to Identify Priorities for Improving the Quality and Value of Critical Care.

    Science.gov (United States)

    Stelfox, Henry T; Niven, Daniel J; Clement, Fiona M; Bagshaw, Sean M; Cook, Deborah J; McKenzie, Emily; Potestio, Melissa L; Doig, Christopher J; O'Neill, Barbara; Zygun, David

    2015-01-01

    Large amounts of scientific evidence are generated, but not implemented into patient care (the 'knowledge-to-care' gap). We identified and prioritized knowledge-to-care gaps in critical care as opportunities to improve the quality and value of healthcare. We used a multi-method community-based participatory research approach to engage a Network of all adult (n = 14) and pediatric (n = 2) medical-surgical intensive care units (ICUs) in a fully integrated geographically defined healthcare system serving 4 million residents. Participants included Network oversight committee members (n = 38) and frontline providers (n = 1,790). Network committee members used a modified RAND/University of California Appropriateness Methodology, to serially propose, rate (validated 9 point scale) and revise potential knowledge-to-care gaps as priorities for improvement. The priorities were sent to frontline providers for evaluation. Results were relayed back to all frontline providers for feedback. Initially, 68 knowledge-to-care gaps were proposed, rated and revised by the committee (n = 32 participants) over 3 rounds of review and resulted in 13 proposed priorities for improvement. Then, 1,103 providers (62% response rate) evaluated the priorities, and rated 9 as 'necessary' (median score 7-9). Several factors were associated with rating priorities as necessary in multivariable logistic regression, related to the provider (experience, teaching status of ICU) and topic (strength of supporting evidence, potential to benefit the patient, potential to improve patient/family experience, potential to decrease costs). A community-based participatory research approach engaged a diverse group of stakeholders to identify 9 priorities for improving the quality and value of critical care. The approach was time and cost efficient and could serve as a model to prioritize areas for research quality improvement across other settings.

  12. Identification of cell proliferation, immune response and cell migration as critical pathways in a prognostic signature for HER2+:ERα- breast cancer.

    Directory of Open Access Journals (Sweden)

    Jeffrey C Liu

    Full Text Available Multi-gene prognostic signatures derived from primary tumor biopsies can guide clinicians in designing an appropriate course of treatment. Identifying genes and pathways most essential to a signature performance may facilitate clinical application, provide insights into cancer progression, and uncover potentially new therapeutic targets. We previously developed a 17-gene prognostic signature (HTICS for HER2+:ERα- breast cancer patients, using genes that are differentially expressed in tumor initiating cells (TICs versus non-TICs from MMTV-Her2/neu mammary tumors. Here we probed the pathways and genes that underlie the prognostic power of HTICS.We used Leave-One Out, Data Combination Test, Gene Set Enrichment Analysis (GSEA, Correlation and Substitution analyses together with Receiver Operating Characteristic (ROC and Kaplan-Meier survival analysis to identify critical biological pathways within HTICS. Publically available cohorts with gene expression and clinical outcome were used to assess prognosis. NanoString technology was used to detect gene expression in formalin-fixed paraffin embedded (FFPE tissues.We show that three major biological pathways: cell proliferation, immune response, and cell migration, drive the prognostic power of HTICS, which is further tuned by Homeostatic and Glycan metabolic signalling. A 6-gene minimal Core that retained a significant prognostic power, albeit less than HTICS, also comprised the proliferation/immune/migration pathways. Finally, we developed NanoString probes that could detect expression of HTICS genes and their substitutions in FFPE samples.Our results demonstrate that the prognostic power of a signature is driven by the biological processes it monitors, identify cell proliferation, immune response and cell migration as critical pathways for HER2+:ERα- cancer progression, and defines substitutes and Core genes that should facilitate clinical application of HTICS.

  13. Identify fracture-critical regions inside the proximal femur using statistical parametric mapping

    Science.gov (United States)

    Li, Wenjun; Kornak, John; Harris, Tamara; Keyak, Joyce; Li, Caixia; Lu, Ying; Cheng, Xiaoguang; Lang, Thomas

    2009-01-01

    We identified regions inside the proximal femur that are most strongly associated with hip fracture. Bone densitometry based on such fracture-critical regions showed improved power in discriminating fracture patients from controls. Introduction Hip fractures typically occur in lateral falls, with focal mechanical failure of the sub-volumes of tissue in which the applied stress exceeds the strength. In this study, we describe a new methodology to identify proximal femoral tissue elements with highest association with hip fracture. We hypothesize that bone mineral density (BMD) measured in such sub-volumes discriminates hip fracture risk better than BMD in standard anatomic regions such as the femoral neck and trochanter. Materials and Methods We employed inter-subject registration to transform hip QCT images of 37 patients with hip fractures and 38 age-matched controls into a voxel-based statistical atlas. Within voxels, we performed t-tests between the two groups to identify the regions which differed most. We then randomly divided the 75 scans into a training set and a test set. From the training set, we derived a fracture-driven region of interest (ROI) based on association with fracture. In the test set, we measured BMD in this ROI to determine fracture discrimination efficacy using ROC analysis. Additionally, we compared the BMD distribution differences between the 29 patients with neck fractures and the 8 patients with trochanteric fractures. Results By evaluating fracture discrimination power based on ROC analysis, the fracture-driven ROI had an AUC (area under curve) of 0.92, while anatomic ROIs (including the entire proximal femur, the femoral neck, trochanter and their cortical and trabecular compartments) had AUC values between 0.78 and 0.87. We also observed that the neck fracture patients had lower BMD (p=0.014) in a small region near the femoral neck and the femoral head, and patients with trochanteric fractures had lower BMD in trochanteric regions

  14. Pilot Critical Incident Reports as a Means to Identify Human Factors of Remotely Piloted Aircraft

    Science.gov (United States)

    Hobbs, Alan; Cardoza, Colleen; Null, Cynthia

    2016-01-01

    It has been estimated that aviation accidents are typically preceded by numerous minor incidents arising from the same causal factors that ultimately produced the accident. Accident databases provide in-depth information on a relatively small number of occurrences, however incident databases have the potential to provide insights into the human factors of Remotely Piloted Aircraft System (RPAS) operations based on a larger volume of less-detailed reports. Currently, there is a lack of incident data dealing with the human factors of unmanned aircraft systems. An exploratory study is being conducted to examine the feasibility of collecting voluntary critical incident reports from RPAS pilots. Twenty-three experienced RPAS pilots volunteered to participate in focus groups in which they described critical incidents from their own experience. Participants were asked to recall (1) incidents that revealed a system flaw, or (2) highlighted a case where the human operator contributed to system resilience or mission success. Participants were asked to only report incidents that could be included in a public document. During each focus group session, a note taker produced a de-identified written record of the incident narratives. At the end of the session, participants reviewed each written incident report, and made edits and corrections as necessary. The incidents were later analyzed to identify contributing factors, with a focus on design issues that either hindered or assisted the pilot during the events. A total of 90 incidents were reported. Human factor issues included the impact of reduced sensory cues, traffic separation in the absence of an out-the-window view, control latencies, vigilance during monotonous and ultra-long endurance flights, control station design considerations, transfer of control between control stations, the management of lost link procedures, and decision-making during emergencies. Pilots participated willingly and enthusiastically in the study

  15. Critical differences between elective and emergency surgery: identifying domains for quality improvement in emergency general surgery.

    Science.gov (United States)

    Columbus, Alexandra B; Morris, Megan A; Lilley, Elizabeth J; Harlow, Alyssa F; Haider, Adil H; Salim, Ali; Havens, Joaquim M

    2018-04-01

    The objective of our study was to characterize providers' impressions of factors contributing to disproportionate rates of morbidity and mortality in emergency general surgery to identify targets for care quality improvement. Emergency general surgery is characterized by a high-cost burden and disproportionate morbidity and mortality. Factors contributing to these observed disparities are not comprehensively understood and targets for quality improvement have not been formally developed. Using a grounded theory approach, emergency general surgery providers were recruited through purposive-criterion-based sampling to participate in semi-structured interviews and focus groups. Participants were asked to identify contributors to emergency general surgery outcomes, to define effective care for EGS patients, and to describe operating room team structure. Interviews were performed to thematic saturation. Transcripts were iteratively coded and analyzed within and across cases to identify emergent themes. Member checking was performed to establish credibility of the findings. A total of 40 participants from 5 academic hospitals participated in either individual interviews (n = 25 [9 anesthesia, 12 surgery, 4 nursing]) or focus groups (n = 2 [15 nursing]). Emergency general surgery was characterized by an exceptionally high level of variability, which can be subcategorized as patient-variability (acute physiology and comorbidities) and system-variability (operating room resources and workforce). Multidisciplinary communication is identified as a modifier to variability in emergency general surgery; however, nursing is often left out of early communication exchanges. Critical variability in emergency general surgery may impact outcomes. Patient-variability and system-variability, with focus on multidisciplinary communication, represent potential domains for quality improvement in this field. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Identifying effective pathways in a successful continuous quality improvement programme: the GEDAPS study.

    Science.gov (United States)

    Bodicoat, Danielle H; Mundet, Xavier; Gray, Laura J; Cos, Xavier; Davies, Melanie J; Khunti, Kamlesh; Cano, Juan-Franciso

    2014-12-01

    Continuous quality improvement programmes often target several aspects of care, some of which may be more effective meaning that resources could be focussed on these. The objective was to identify the effective and ineffective aspects of a successful continuous quality improvement programme for individuals with type 2 diabetes in primary care. Data were from a series of cross-sectional studies (GEDAPS) in primary care, Catalonia, Spain, in 55 centres (2239 participants) in 1993, and 92 centres (5819 participants) in 2002. A structural equation modelling approach was used. The intervention was associated with improved microvascular outcomes through microalbuminuria and funduscopy screening, which had a direct effect on microvascular outcomes, and through attending 2-4 nurse visits and having ≥1 blood pressure measurement, which acted through reducing systolic blood pressure. The intervention was associated with improved macrovascular outcomes through blood pressure measurement and attending 2-4 nurse visits (through systolic blood pressure) and having ≥3 education topics, ≥1 HbA1c measurement and adequate medication (through HbA1c). Cholesterol measurement, weight measurement and foot examination did not contribute towards the effectiveness of the intervention. The pathways through which a continuous quality improvement programme appeared to act to reduce microvascular and macrovascular complications were driven by reductions in systolic blood pressure and HbA1c, which were attained through changes in nurse and education visits, measurement and medication. This suggests that these factors are potential areas on which future quality improvement programmes should focus. © 2014 John Wiley & Sons, Ltd.

  17. Identifying critical recruitment bottlenecks limiting seedling establishment in a degraded seagrass ecosystem.

    Science.gov (United States)

    Statton, John; Montoya, Leonardo R; Orth, Robert J; Dixon, Kingsley W; Kendrick, Gary A

    2017-11-01

    Identifying early life-stage transitions limiting seagrass recruitment could improve our ability to target demographic processes most responsive to management. Here we determine the magnitude of life-stage transitions along gradients in physical disturbance limiting seedling establishment for the marine angiosperm, Posidonia australis. Transition matrix models and sensitivity analyses were used to identify which transitions were critical for successful seedling establishment during the first year of seed recruitment and projection models were used to predict the most appropriate environments and seeding densities. Total survival probability of seedlings was low (0.001), however, transition probabilities between life-stages differed across the environmental gradients; seedling recruitment was affected by grazing and bioturbation prevailing during the first life-stage transition (1 month), and 4-6 months later during the third life-stage transition when establishing seedlings are physically removed by winter storms. Models projecting population growth from different starting seed densities showed that seeds could replace other more labour intensive and costly methods, such as transplanting adult shoots, if disturbances are moderated sufficiently and if large numbers of seed can be collected in sufficient quantity and delivered to restoration sites efficiently. These outcomes suggest that by improving management of early demographic processes, we could increase recruitment in restoration programs.

  18. An Integrative data mining approach to identifying Adverse Outcome Pathway (AOP) Signatures

    Science.gov (United States)

    The Adverse Outcome Pathway (AOP) framework is a tool for making biological connections and summarizing key information across different levels of biological organization to connect biological perturbations at the molecular level to adverse outcomes for an individual or populatio...

  19. Identifying alternate pathways for climate change to impact inland recreational fishers

    Science.gov (United States)

    Hunt, Len M.; Fenichel, Eli P.; Fulton, David C.; Mendelsohn, Robert; Smith, Jordan W.; Tunney, Tyler D.; Lynch, Abigail J.; Paukert, Craig P.; Whitney, James E.

    2016-01-01

    Fisheries and human dimensions literature suggests that climate change influences inland recreational fishers in North America through three major pathways. The most widely recognized pathway suggests that climate change impacts habitat and fish populations (e.g., water temperature impacting fish survival) and cascades to impact fishers. Climate change also impacts recreational fishers by influencing environmental conditions that directly affect fishers (e.g., increased temperatures in northern climates resulting in extended open water fishing seasons and increased fishing effort). The final pathway occurs from climate change mitigation and adaptation efforts (e.g., refined energy policies result in higher fuel costs, making distant trips more expensive). To address limitations of past research (e.g., assessing climate change impacts for only one pathway at a time and not accounting for climate variability, extreme weather events, or heterogeneity among fishers), we encourage researchers to refocus their efforts to understand and document climate change impacts to inland fishers.

  20. Gene expression meta-analysis identifies metastatic pathways and transcription factors in breast cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Tan, Qihua; Kruse, Torben

    2008-01-01

    studies. Besides classification of outcome, these global expression patterns may reflect biological mechanisms involved in metastasis of breast cancer. Our purpose has been to investigate pathways and transcription factors involved in metastasis by use of gene expression data sets. METHODS: We have......ABSTRACT: BACKGROUND: Metastasis is believed to progress in several steps including different pathways but the determination and understanding of these mechanisms is still fragmentary. Microarray analysis of gene expression patterns in breast tumors has been used to predict outcome in recent...... tumors compared to non-metastasizing tumors. Meta-analysis has been used to determine overrepresentation of pathways and transcription factors targets, concordant deregulated in metastasizing breast tumors, in several data sets. RESULTS: The major findings are upregulation of cell cycle pathways...

  1. Critical assessment of human metabolic pathway databases: a stepping stone for future integration

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    Stobbe Miranda D

    2011-10-01

    Full Text Available Abstract Background Multiple pathway databases are available that describe the human metabolic network and have proven their usefulness in many applications, ranging from the analysis and interpretation of high-throughput data to their use as a reference repository. However, so far the various human metabolic networks described by these databases have not been systematically compared and contrasted, nor has the extent to which they differ been quantified. For a researcher using these databases for particular analyses of human metabolism, it is crucial to know the extent of the differences in content and their underlying causes. Moreover, the outcomes of such a comparison are important for ongoing integration efforts. Results We compared the genes, EC numbers and reactions of five frequently used human metabolic pathway databases. The overlap is surprisingly low, especially on reaction level, where the databases agree on 3% of the 6968 reactions they have combined. Even for the well-established tricarboxylic acid cycle the databases agree on only 5 out of the 30 reactions in total. We identified the main causes for the lack of overlap. Importantly, the databases are partly complementary. Other explanations include the number of steps a conversion is described in and the number of possible alternative substrates listed. Missing metabolite identifiers and ambiguous names for metabolites also affect the comparison. Conclusions Our results show that each of the five networks compared provides us with a valuable piece of the puzzle of the complete reconstruction of the human metabolic network. To enable integration of the networks, next to a need for standardizing the metabolite names and identifiers, the conceptual differences between the databases should be resolved. Considerable manual intervention is required to reach the ultimate goal of a unified and biologically accurate model for studying the systems biology of human metabolism. Our comparison

  2. Identifying the critical factors that influence intraocular pressure using an automated regression tree

    Directory of Open Access Journals (Sweden)

    Nishanee Rampersad

    2017-02-01

    Full Text Available Background: Assessment of intraocular pressure (IOP is an important test in glaucoma. In addition, anterior segment variables may be useful in screening for glaucoma risk. Studies have investigated the associations between IOP and anterior segment variables using traditional statistical methods. The classification and regression tree (CART method provides another dimension to detect important variables in a relationship automatically. Aim: To identify the critical factors that influence IOP using a regression tree. Methods: A quantitative cross-sectional research design was used. Anterior segment variables were measured in 700 participants using the iVue100 optical coherence tomographer, Oculus Keratograph and Nidek US-500 ultrasonographer. A Goldmann applanation tonometer was used to measure IOP. Data from only the right eyes were analysed because of high levels of interocular symmetry. A regression tree model was generated with the CART method and Pearson’s correlation coefficients were used to assess the relationships between the ocular variables. Results: The mean IOP for the entire sample was 14.63 mmHg ± 2.40 mmHg. The CART method selected three anterior segment variables in the regression tree model. Central corneal thickness was the most important variable with a cut-off value of 527 µm. The other important variables included average paracentral corneal thickness and axial anterior chamber depth. Corneal thickness measurements increased towards the periphery and were significantly correlated with IOP (r ≥ 0.50, p ≤ 0.001. Conclusion: The CART method identified the anterior segment variables that influenced IOP. Understanding the relationship between IOP and anterior segment variables may help to clinically identify patients with ocular risk factors associated with elevated IOPs.

  3. Nano hydroxyapatite-blasted titanium surface affects pre-osteoblast morphology by modulating critical intracellular pathways.

    Science.gov (United States)

    Bezerra, Fábio; Ferreira, Marcel R; Fontes, Giselle N; da Costa Fernandes, Célio Jr; Andia, Denise C; Cruz, Nilson C; da Silva, Rodrigo A; Zambuzzi, Willian F

    2017-08-01

    Although, intracellular signaling pathways are proposed to predict the quality of cell-surface relationship, this study addressed pre-osteoblast behavior in response to nano hydroxyapatite (HA)-blasted titanium (Ti) surface by exploring critical intracellular pathways and pre-osteoblast morphological change. Physicochemical properties were evaluated by atomic force microscopy (AFM) and wettability considering water contact angle of three differently texturized Ti surfaces: Machined (Mac), Dual acid-etching (DAE), and nano hydroxyapatite-blasted (nHA). The results revealed critical differences in surface topography, impacting the water contact angle and later the osteoblast performance. In order to evaluate the effect of those topographical characteristics on biological responses, we have seeded pre-osteoblast cells on the Ti discs for up to 4 h and subjected the cultures to biological analysis. First, we have observed pre-osteoblasts morphological changes resulting from the interaction with the Ti texturized surfaces whereas the cells cultured on nHA presented a more advanced spreading process when compared with the cells cultured on the other surfaces. These results argued us for analyzing the molecular machinery and thus, we have shown that nHA promoted a lower Bax/Bcl2 ratio, suggesting an interesting anti-apoptotic effect, maybe explained by the fact that HA is a natural element present in bone composition. Thereafter, we investigated the potential effect of those surfaces on promoting pre-osteoblast adhesion and survival signaling by performing crystal violet and immunoblotting approaches, respectively. Our results showed that nHA promoted a higher pre-osteoblast adhesion supported by up-modulating FAK and Src activations, both signaling transducers involved during eukaryotic cell adhesion. Also, we have shown Ras-Erk stimulation by the all evaluated surfaces. Finally, we showed that all Ti-texturing surfaces were able to promote osteoblast differentiation

  4. Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer.

    Science.gov (United States)

    Lee, Dae-Won; Han, Sae-Won; Cha, Yongjun; Bae, Jeong Mo; Kim, Hwang-Phill; Lyu, Jaemyun; Han, Hyojun; Kim, Hyoki; Jang, Hoon; Bang, Duhee; Huh, Iksoo; Park, Taesung; Won, Jae-Kyung; Jeong, Seung-Yong; Park, Kyu Joo; Kang, Gyeong Hoon; Kim, Tae-You

    2017-09-15

    Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor β [TGF-β]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-β pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK

  5. A Drosophila Model Identifies a Critical Role for Zinc in Mineralization for Kidney Stone Disease

    Science.gov (United States)

    Lang, Sven; Bose, Neelanjan; Kahn, Arnold; Flechner, Lawrence; Blaschko, Sarah D.; Zee, Tiffany; Muteliefu, Gulinuer; Bond, Nichole; Kolipinski, Marysia; Fakra, Sirine C.; Mandel, Neil; Miller, Joe; Ramanathan, Arvind; Killilea, David W.; Brückner, Katja; Kapahi, Pankaj; Stoller, Marshall L.

    2015-01-01

    Ectopic calcification is a driving force for a variety of diseases, including kidney stones and atherosclerosis, but initiating factors remain largely unknown. Given its importance in seemingly divergent disease processes, identifying fundamental principal actors for ectopic calcification may have broad translational significance. Here we establish a Drosophila melanogaster model for ectopic calcification by inhibiting xanthine dehydrogenase whose deficiency leads to kidney stones in humans and dogs. Micro X-ray absorption near edge spectroscopy (μXANES) synchrotron analyses revealed high enrichment of zinc in the Drosophila equivalent of kidney stones, which was also observed in human kidney stones and Randall’s plaques (early calcifications seen in human kidneys thought to be the precursor for renal stones). To further test the role of zinc in driving mineralization, we inhibited zinc transporter genes in the ZnT family and observed suppression of Drosophila stone formation. Taken together, genetic, dietary, and pharmacologic interventions to lower zinc confirm a critical role for zinc in driving the process of heterogeneous nucleation that eventually leads to stone formation. Our findings open a novel perspective on the etiology of urinary stones and related diseases, which may lead to the identification of new preventive and therapeutic approaches. PMID:25970330

  6. Targeting Policy for Obesity Prevention: Identifying the Critical Age for Weight Gain in Women

    Directory of Open Access Journals (Sweden)

    Trevor J. B. Dummer

    2012-01-01

    Full Text Available The obesity epidemic requires the development of prevention policy targeting individuals most likely to benefit. We used self-reported prepregnancy body weight of all women giving birth in Nova Scotia between 1988 and 2006 to define obesity and evaluated socioeconomic, demographic, and temporal trends in obesity using linear regression. There were 172,373 deliveries in this cohort of 110,743 women. Maternal body weight increased significantly by 0.5 kg per year from 1988, and lower income and rural residence were both associated significantly with increasing obesity. We estimated an additional 82,000 overweight or obese women in Nova Scotia in 2010, compared to the number that would be expected from obesity rates of just two decades ago. The critical age for weight gain was identified as being between 20 and 24 years. This age group is an important transition age between adolescence and adulthood when individuals first begin to accept responsibility for food planning, purchasing, and preparation. Policy and public health interventions must target those most at risk, namely, younger women and the socially deprived, whilst tackling the marketing of low-cost energy-dense foods at the expense of healthier options.

  7. A Fluorescent Probe for Detecting Mycobacterium tuberculosis and Identifying Genes Critical for Cell Entry

    Science.gov (United States)

    Yang, Dong; Ding, Feng; Mitachi, Katsuhiko; Kurosu, Michio; Lee, Richard E.; Kong, Ying

    2016-01-01

    The conventional method for quantitating Mycobacterium tuberculosis (Mtb) in vitro and in vivo relies on bacterial colony forming unit (CFU) enumeration on agar plates. Due to the slow growth rate of Mtb, it takes 3–6 weeks to observe visible colonies on agar plates. Imaging technologies that are capable of quickly quantitating both active and dormant tubercle bacilli in vitro and in vivo would accelerate research toward the development of anti-TB chemotherapies and vaccines. We have developed a fluorescent probe that can directly label the Mtb cell wall components. The fluorescent probe, designated as DLF-1, has a strong affinity to the D-Ala-D-Ala unit of the late peptidoglycan intermediates in the bacterial cell wall. We demonstrate that DLF-1 is capable of detecting Mtb in both the actively replicating and dormant states in vitro at 100 nM without inhibiting bacterial growth. The DLF-1 fluorescence signal correlated well with CFU of the labeled bacteria (R2 = 1 and 0.99 for actively replicating and dormant Mtb, respectively). DLF-1 can also quantitate labeled Mtb inside of cells. The utility of DLF-1 probe to quantitate Mtb was successfully applied to identify genes critical for cell invasion. In conclusion, this novel near infrared imaging probe provides a powerful new tool for enumerating Mtb with potential future use in bacterial virulence study. PMID:28066347

  8. A Fluorescent Probe for Detecting Mycobacterium tuberculosis and Identifying Genes Critical for Cell Entry

    Directory of Open Access Journals (Sweden)

    Dong Yang

    2016-12-01

    Full Text Available ABSTRACTThe conventional method for quantitating Mycobacterium tuberculosis (Mtb in vitro and in vivo relies on bacterial colony forming unit (CFU enumeration on agar plates. Due to the slow growth rate of Mtb, it takes 3-6 weeks to observe visible colonies on agar plates. Imaging technologies that are capable of quickly quantitating both active and dormant tubercle bacilli in vitro and in vivo would accelerate research towards the development of anti-TB chemotherapies and vaccines. We have developed a fluorescent probe that can directly label the Mtb cell wall components. The fluorescent probe, designated as DLF-1, has a strong affinity to the D-Ala-D-Ala unit of the late peptidoglycan intermediates in the bacterial cell wall. We demonstrate that DLF-1 is capable of detecting Mtb in both the active replicating and dormant states in vitro at 100 nM without inhibiting bacterial growth. The DLF-1 fluorescence signal correlated well with CFU of the labeled bacteria (R2=1 and 0.99 for active replicating and dormant Mtb, respectively. DLF-1 can also quantitate labeled Mtb inside of cells. The utility of DLF-1 probe to quantitate Mtb was also successfully applied to identify genes critical for cell invasion. In conclusion, this novel near infrared imaging probe provides a powerful new tool for enumerating Mtb with potential future use in bacterial virulence study.

  9. Trophic transfer of microplastics in aquatic ecosystems: Identifying critical research needs.

    Science.gov (United States)

    Au, Sarah Y; Lee, Cindy M; Weinstein, John E; van den Hurk, Peter; Klaine, Stephen J

    2017-05-01

    To evaluate the process of trophic transfer of microplastics, it is important to consider various abiotic and biotic factors involved in their ingestion, egestion, bioaccumulation, and biomagnification. Toward this end, a review of the literature on microplastics has been conducted to identify factors influencing their uptake and absorption; their residence times in organisms and bioaccumulation; the physical effects of their aggregation in gastrointestinal tracts; and their potential to act as vectors for the transfer of other contaminants. Limited field evidence from higher trophic level organisms in a variety of habitats suggests that trophic transfer of microplastics may be a common phenomenon and occurs concurrently with direct ingestion. Critical research needs include standardizing methods of field characterization of microplastics, quantifying uptake and depuration rates in organisms at different trophic levels, quantifying the influence that microplastics have on the uptake and/or depuration of environmental contaminants among different trophic levels, and investigating the potential for biomagnification of microplastic-associated chemicals. More integrated approaches involving computational modeling are required to fully assess trophic transfer of microplastics. Integr Environ Assess Manag 2017;13:505-509. © 2017 SETAC. © 2017 SETAC.

  10. Science education as a pathway to teaching language literacy: a critical book review

    Science.gov (United States)

    Tolbert, Sara

    2011-03-01

    In this paper, I present a critical review of the recent book, Science Education as a Pathway to Teaching Language Literacy, edited by Alberto J. Rodriguez. This volume is a timely collection of essays in which the authors bring to attention both the successes and challenges of integrating science instruction with literacy instruction (and vice versa). Although several themes in the book merit further attention, a central unifying issue throughout all of the chapters is the task of designing instruction which (1) gives students access to the dominant Discourses in science and literacy, (2) builds on students' lived experiences, and (3) connects new material to socially and culturally relevant contexts in both science and literacy instruction— all within the high stakes testing realities of teachers and students in public schools. In this review, I illustrate how the authors of these essays effectively address this formidable challenge through research that `ascends to the concrete'. I also discuss where we could build on the work of the authors to integrate literacy and science instruction with the purpose of `humanizing and democratizing' science education in K-12 classrooms.

  11. French Medico-Administrative Data to Identify the Care Pathways of Women With Breast Cancer.

    Science.gov (United States)

    Lefeuvre, Delphine; Le Bihan-Benjamin, Christine; Pauporté, Iris; Medioni, Jacques; Bousquet, Philippe-Jean

    2017-07-01

    Study of the care pathways is an important topic for care planning, as well as to observe guidelines application. This study aimed to describe care pathways and the period of time between treatments of women with breast cancer (BC), at a population level. Women with in situ, local and regional BC who were hospitalized and newly treated in 2012 were included and followed for 1 year. Care pathways were described, focusing on surgery (partial mastectomy [PM], total mastectomy [TM]), chemotherapy, and radiotherapy. The periods of time between treatments were measured and compared with the guidelines. The study involved 52,128 women. The most common care pathways among the 2845 women with in situ BC were PM-radiotherapy (46.7%) and TM (28.5%). Among the 41,470 women with local BC, they were: PM-radiotherapy (44.8%) or PM-chemotherapy-radiotherapy (16.0%). The 7813 women with regional BC had similar care pathways, although chemotherapy was given more frequently (73%). The periods of time between surgery and chemotherapy were in accordance with the guidelines for 98% of the women; those between surgery and radiotherapy were affected by adjuvant chemotherapy. Finally, the time between chemotherapy and radiotherapy was longer than recommended for 40% of the women. The French medicoadministrative databases allow the study, at a national population level, of the care pathways and periods of time between treatments of women with BC according to the stage of the disease. They were close to the guidelines, although an improvement is highly necessary. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats

    Science.gov (United States)

    This study was performed to characterize the gene expression profile and to identify the major carcinogenic pathways involved in rat peritoneal mesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Oligo a...

  13. Identifying parasitic current pathways in CIGS solar cells by modelling dark JV response

    NARCIS (Netherlands)

    Williams, B.L.; Smit, S.; Kniknie, B.J.; Bakkers, N.J.; Kessels, W.M.M.; Schropp, R.E.I.; Creatore, M.

    2014-01-01

    The presence of undetermined shunt pathways in CIGS solar cells can be severely limiting to the reproducibility of individual cell efficiency, both at lab-scale, and particularly in a roll-to-roll process. Here, a general model that describes the dark J-V characteristics of CIGS devices, accounting

  14. Identifying genetic variants for heart rate variability in the acetylcholine pathway

    NARCIS (Netherlands)

    Riese, Harriëtte; Muñoz Venegas, Loretto; Hartman, Catharina A; Ding, Xiuhua; Su, Shaoyong; Oldehinkel, Albertine J; van Roon, Arie M; van der Most, Peter J; Lefrandt, Joop; Gansevoort, Ronald; van der Harst, Pim; Verweij, Niek; Licht, Carmilla M M; Boomsma, Dorret I; Hottenga, Jouke-Jan; Willemsen, Gonneke; Penninx, Brenda W J H; Nolte, Ilja M; de Geus, Eco J C; Wang, Xiaoling; Snieder, Harold

    2014-01-01

    Heart rate variability is an important risk factor for cardiovascular disease and all-causemortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3,

  15. High-throughput screening identifies novel agents eliciting hypersensitivity in Fanconi pathway-deficient cancer cells

    Czech Academy of Sciences Publication Activity Database

    Gallmeier, E.; Hucl, T.; Brody, J.R.; Dezentje, D.A.; Tahir, K.; Kašpárková, Jana; Brabec, Viktor; Bachman, K.E.; Kern, S.E.

    2007-01-01

    Roč. 67, č. 5 (2007), s. 2169-2177 ISSN 0008-5472 R&D Projects: GA ČR(CZ) GA305/05/2030; GA MZd(CZ) NR8562 Institutional research plan: CEZ:AV0Z50040702 Keywords : cancer * Fanconi anemia pathway * p53 Subject RIV: BO - Biophysics Impact factor: 7.672, year: 2007

  16. Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism

    Directory of Open Access Journals (Sweden)

    Lars Stechemesser

    2017-01-01

    Conclusions: Our data suggest that high serum ferritin concentrations are linked to impaired glucose homeostasis in subjects with the MetS. Iron excess is associated to distinct changes in the serum concentrations of phosphatidylcholine subsets. A pathway involving sarcosine and citrulline also may be involved in iron-induced impairment of glucose metabolism.

  17. Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets.

    Science.gov (United States)

    Boadas-Vaello, P; Castany, S; Homs, J; Álvarez-Pérez, B; Deulofeu, M; Verdú, E

    2016-05-01

    This is a narrative review of the literature. This review aims to be useful in identifying therapeutic targets. It focuses on the molecular and biochemical neuroplasticity changes that occur in the somatosensory system, including ascending and descending pathways, during the development of neuropathic pain. Furthermore, it highlights the latest experimental strategies, based on the changes reported in the damaged nociceptive neurons during neuropathic pain states. This study was conducted in Girona, Catalonia, Spain. A MEDLINE search was performed using the following terms: descending pain pathways; ascending pain pathways; central sensitization; molecular pain; and neuropathic pain pharmacological treatment. Neuropathic pain triggered by traumatic lesions leads to sensitization and hyperexcitability of nociceptors and projection neurons of the dorsal horn, a strengthening in the descendent excitatory pathway and an inhibition of the descending inhibitory pathway of pain. These functional events are associated with molecular plastic changes such as overexpression of voltage-gated ion channels, algogen-sensitive receptors and synthesis of several neurotransmitters. Molecular studies on the plastic changes in the nociceptive somatosensory system enable the development of new pharmacological treatments against neuropathic pain, with higher specificity and effectiveness than classical drug treatments. Although research efforts have already focused on these aspects, additional research may be necessary to further explore the potential therapeutic targets in neuropathic pain involved in the neuroplasticity changes of neuropathological pathways from the injured somatosensory system.

  18. Several Critical Cell Types, Tissues, and Pathways Are Implicated in Genome-Wide Association Studies for Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Lu Liu

    2016-06-01

    Full Text Available We aimed to elucidate the cell types, tissues, and pathways influenced by common variants in systemic lupus erythematosus (SLE. We applied a nonparameter enrichment statistical approach, termed SNPsea, in 181 single nucleotide polymorphisms (SNPs that have been identified to be associated with the risk of SLE through genome-wide association studies (GWAS in Eastern Asian and Caucasian populations, to manipulate the critical cell types, tissues, and pathways. In the two most significant cells’ findings (B lymphocytes and CD14+ monocytes, we subjected the GWAS association evidence in the Han Chinese population to an enrichment test of expression quantitative trait locus (QTL sites and DNase I hypersensitivity, respectively. In both Eastern Asian and Caucasian populations, we observed that the expression level of SLE GWAS implicated genes was significantly elevated in xeroderma pigentosum B cells (P ≤ 1.00 × 10−6, CD14+ monocytes (P ≤ 2.74 × 10−4 and CD19+ B cells (P ≤ 2.00 × 10−6, and plasmacytoid dendritic cells (pDCs (P ≤ 9.00 × 10−6. We revealed that the SLE GWAS-associated variants were more likely to reside in expression QTL in B lymphocytes (q1/q0 = 2.15, P = 1.23 × 10−44 and DNase I hypersensitivity sites (DHSs in CD14+ monocytes (q1/q0 = 1.41, P = 0.08. We observed the common variants affected the risk of SLE mostly through by regulating multiple immune system processes and immune response signaling. This study sheds light on several immune cells and responses, as well as the regulatory effect of common variants in the pathogenesis of SLE.

  19. Identifying and Overcoming Critical Barriers to Widespread Second Use of PEV Batteries

    Energy Technology Data Exchange (ETDEWEB)

    Neubauer, J. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Smith, K. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Wood, E. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Pesaran, A. [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2015-02-01

    Both the market penetration of plug-in electric vehicles (PEVs) and deployment of grid-connected energy storage systems are presently restricted by the high cost of batteries. Battery second use (B2U) strategies--in which a single battery first serves an automotive application, then is redeployed into a secondary market--could help address both issues by reducing battery costs to the primary (automotive) and secondary (electricity grid) users. This study investigates the feasibility of and major barriers to the second use of lithium-ion PEV batteries by posing and answering the following critical B2U questions: 1. When will used automotive batteries become available, and how healthy will they be? 2. What is required to repurpose used automotive batteries, and how much will it cost? 3. How will repurposed automotive batteries be used, how long will they last, and what is their value? Advanced analysis techniques are employed that consider the electrical, thermal, and degradation response of batteries in both the primary (automotive) and secondary service periods. Second use applications are treated in detail, addressing operational requirements, economic value, and market potential. The study concludes that B2U is viable and could provide considerable societal benefits due to the large possible supply of repurposed automotive batteries and substantial remaining battery life following automotive service. However, the only identified secondary market large enough to consume the supply of these batteries (utility peaker plant replacement) is expected to be a low margin market, and thus B2U is not expected to affect the upfront cost of PEVs.

  20. Beta atomic contacts: identifying critical specific contacts in protein binding interfaces.

    Science.gov (United States)

    Liu, Qian; Kwoh, Chee Keong; Hoi, Steven C H

    2013-01-01

    Specific binding between proteins plays a crucial role in molecular functions and biological processes. Protein binding interfaces and their atomic contacts are typically defined by simple criteria, such as distance-based definitions that only use some threshold of spatial distance in previous studies. These definitions neglect the nearby atomic organization of contact atoms, and thus detect predominant contacts which are interrupted by other atoms. It is questionable whether such kinds of interrupted contacts are as important as other contacts in protein binding. To tackle this challenge, we propose a new definition called beta (β) atomic contacts. Our definition, founded on the β-skeletons in computational geometry, requires that there is no other atom in the contact spheres defined by two contact atoms; this sphere is similar to the van der Waals spheres of atoms. The statistical analysis on a large dataset shows that β contacts are only a small fraction of conventional distance-based contacts. To empirically quantify the importance of β contacts, we design βACV, an SVM classifier with β contacts as input, to classify homodimers from crystal packing. We found that our βACV is able to achieve the state-of-the-art classification performance superior to SVM classifiers with distance-based contacts as input. Our βACV also outperforms several existing methods when being evaluated on several datasets in previous works. The promising empirical performance suggests that β contacts can truly identify critical specific contacts in protein binding interfaces. β contacts thus provide a new model for more precise description of atomic organization in protein quaternary structures than distance-based contacts.

  1. Transcriptomic analysis identifies genes and pathways related to myrmecophagy in the Malayan pangolin (Manis javanica

    Directory of Open Access Journals (Sweden)

    Jing-E Ma

    2017-12-01

    Full Text Available The Malayan pangolin (Manis javanica is an unusual, scale-covered, toothless mammal that specializes in myrmecophagy. Due to their threatened status and continuing decline in the wild, concerted efforts have been made to conserve and rescue this species in captivity in China. Maintaining this species in captivity is a significant challenge, partly because little is known of the molecular mechanisms of its digestive system. Here, the first large-scale sequencing analyses of the salivary gland, liver and small intestine transcriptomes of an adult M. javanica genome were performed, and the results were compared with published liver transcriptome profiles for a pregnant M. javanica female. A total of 24,452 transcripts were obtained, among which 22,538 were annotated on the basis of seven databases. In addition, 3,373 new genes were predicted, of which 1,459 were annotated. Several pathways were found to be involved in myrmecophagy, including olfactory transduction, amino sugar and nucleotide sugar metabolism, lipid metabolism, and terpenoid and polyketide metabolism pathways. Many of the annotated transcripts were involved in digestive functions: 997 transcripts were related to sensory perception, 129 were related to digestive enzyme gene families, and 199 were related to molecular transporters. One transcript for an acidic mammalian chitinase was found in the annotated data, and this might be closely related to the unique digestive function of pangolins. These pathways and transcripts are involved in specialization processes related to myrmecophagy (a form of insectivory and carbohydrate, protein and lipid digestive pathways, probably reflecting adaptations to myrmecophagy. Our study is the first to investigate the molecular mechanisms underlying myrmecophagy in M. javanica, and we hope that our results may play a role in the conservation of this species.

  2. Identifying biological pathways in the MRI findings of people with low back pain

    DEFF Research Database (Denmark)

    Jensen, Rikke Krüger; Jensen, Tue Secher; Kjaer, Per

    on intervertebral disc height and signal intensity, disc protrusions, high intensity zones, size and type of vertebral endplate signal changes, vertebral endplate irregularities and defects, osteophytes, and spondylolisthesis. Latent class analysis (probabilistic data mining) was used to distinguish the best...... into a model of five different biological pathways of degeneration. Future research will test the association between these clusters and clinically important characteristics such as pain and activity limitation....

  3. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.

    Science.gov (United States)

    Bonilla, Ximena; Parmentier, Laurent; King, Bryan; Bezrukov, Fedor; Kaya, Gürkan; Zoete, Vincent; Seplyarskiy, Vladimir B; Sharpe, Hayley J; McKee, Thomas; Letourneau, Audrey; Ribaux, Pascale G; Popadin, Konstantin; Basset-Seguin, Nicole; Ben Chaabene, Rouaa; Santoni, Federico A; Andrianova, Maria A; Guipponi, Michel; Garieri, Marco; Verdan, Carole; Grosdemange, Kerstin; Sumara, Olga; Eilers, Martin; Aifantis, Iannis; Michielin, Olivier; de Sauvage, Frederic J; Antonarakis, Stylianos E; Nikolaev, Sergey I

    2016-04-01

    Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.

  4. Critical pathways for the management of preeclampsia and severe preeclampsia in institutionalised health care settings

    Directory of Open Access Journals (Sweden)

    Daftari Ashi

    2003-10-01

    Full Text Available Abstract Background Preeclampsia is a complex disease in which several providers should interact continuously and in a coordinated manner to provide proper health care. However, standardizing criteria to treat patients with preeclampsia is problematical and severe flaws have been observed in the management of the disease. This paper describes a set of critical pathways (CPs designed to provide uniform criteria for clinical decision-making at different levels of care of pregnant patients with preeclampsia or severe preeclampsia. Methods Clinicians and researchers from different countries participated in the construction of the CPs. The CPs were developed using the following steps: a Definition of the conceptual framework; b Identification of potential users: primary care physicians and maternal and child health nurses in ambulatory settings; ob/gyn and intensive care physicians in secondary and tertiary care levels. c Structural development. Results The CPs address the following care processes: 1. Screening for preeclampsia, risk assessment and classification according to the level of risk. 2. Management of preeclampsia at primary care clinics. 3. Evaluation and management of preeclampsia at secondary and tertiary care hospitals: 4. Criteria for clinical decision-making between conservative management and expedited delivery of patients with severe preeclampsia. Conclusion Since preeclampsia continues to be one of the primary causes of maternal deaths and morbidity worldwide, the expected impact of these CPs is the contribution to improving health care quality in both developed and developing countries. The CPs are designed to be applied in a complex health care system, where different physicians and health providers at different levels of care should interact continuously and in a coordinated manner to provide care to all preeclamptic women. Although the CPs were developed using evidence-based criteria, they could require careful evaluation and

  5. Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets

    Science.gov (United States)

    Karube, K; Enjuanes, A; Dlouhy, I; Jares, P; Martin-Garcia, D; Nadeu, F; Ordóñez, G R; Rovira, J; Clot, G; Royo, C; Navarro, A; Gonzalez-Farre, B; Vaghefi, A; Castellano, G; Rubio-Perez, C; Tamborero, D; Briones, J; Salar, A; Sancho, J M; Mercadal, S; Gonzalez-Barca, E; Escoda, L; Miyoshi, H; Ohshima, K; Miyawaki, K; Kato, K; Akashi, K; Mozos, A; Colomo, L; Alcoceba, M; Valera, A; Carrió, A; Costa, D; Lopez-Bigas, N; Schmitz, R; Staudt, L M; Salaverria, I; López-Guillermo, A; Campo, E

    2018-01-01

    Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies. PMID:28804123

  6. Expression Profiling of Differentiating Emerin-Null Myogenic Progenitor Identifies Molecular Pathways Implicated in Their Impaired Differentiation

    Directory of Open Access Journals (Sweden)

    Ashvin Iyer

    2017-10-01

    Full Text Available Mutations in the gene encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD, a disorder causing progressive skeletal muscle wasting, irregular heart rhythms and contractures of major tendons. RNA sequencing was performed on differentiating wildtype and emerin-null myogenic progenitors to identify molecular pathways implicated in EDMD, 340 genes were uniquely differentially expressed during the transition from day 0 to day 1 in wildtype cells. 1605 genes were uniquely expressed in emerin-null cells; 1706 genes were shared among both wildtype and emerin-null cells. One thousand and forty-seven transcripts showed differential expression during the transition from day 1 to day 2. Four hundred and thirty-one transcripts showed altered expression in both wildtype and emerin-null cells. Two hundred and ninety-five transcripts were differentially expressed only in emerin-null cells and 321 transcripts were differentially expressed only in wildtype cells. DAVID, STRING and Ingenuity Pathway Analysis identified pathways implicated in impaired emerin-null differentiation, including cell signaling, cell cycle checkpoints, integrin signaling, YAP/TAZ signaling, stem cell differentiation, and multiple muscle development and myogenic differentiation pathways. Functional enrichment analysis showed biological functions associated with the growth of muscle tissue and myogenesis of skeletal muscle were inhibited. The large number of differentially expressed transcripts upon differentiation induction suggests emerin functions during transcriptional reprograming of progenitors to committed myoblasts.

  7. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    International Nuclear Information System (INIS)

    Kleinstreuer, N.C.; Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R.; Weir-Hauptman, A.M.; Palmer, J.A.; Knudsen, T.B.; Dix, D.J.; Donley, E.L.R.; Cezar, G.G.

    2011-01-01

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox® model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: ► We tested 11 environmental compounds in a hESC metabolomics platform. ► Significant changes in secreted small molecule metabolites were observed. ► Perturbed mass features map to pathways critical for normal development and pregnancy. ► Arginine, proline, nicotinate, nicotinamide and glutathione pathways were affected.

  8. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    Energy Technology Data Exchange (ETDEWEB)

    Kleinstreuer, N.C., E-mail: kleinstreuer.nicole@epa.gov [NCCT, US EPA, RTP, NC 27711 (United States); Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Weir-Hauptman, A.M. [Covance, Inc., Madison, WI 53704 (United States); Palmer, J.A. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Knudsen, T.B.; Dix, D.J. [NCCT, US EPA, RTP, NC 27711 (United States); Donley, E.L.R. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Cezar, G.G. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); University of Wisconsin-Madison, Madison, WI 53706 (United States)

    2011-11-15

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast Trade-Mark-Sign chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox Registered-Sign model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: Black-Right-Pointing-Pointer We tested 11 environmental compounds in a hESC metabolomics platform. Black-Right-Pointing-Pointer Significant changes in secreted small molecule metabolites were observed. Black-Right-Pointing-Pointer Perturbed mass features map to pathways critical for normal

  9. Rigorous selection of random forest models for identifying compounds that activate toxicity-related pathways

    Directory of Open Access Journals (Sweden)

    Yoshihiro eUesawa

    2016-02-01

    Full Text Available Random forest (RF is a machine-learning ensemble method with high predictive performance. Majority voting in RF uses the discrimination results in numerous decision trees produced from bootstrapping data. For the same dataset, the bootstrapping process yields different predictive capacities in each generation. As participants in the Toxicology in the 21st Century (Tox21 DATA Challenge 2014, we produced numerous RF models for predicting the structures of compounds that can activate each toxicity-related pathway, and then selected the model with the highest predictive ability. Half of the compounds in the training dataset supplied by the competition organizer were allocated to the validation dataset. The remaining compounds were used in model construction. The charged and uncharged forms of each molecule were calculated using the molecular operating environment (MOE software. Subsequently, the descriptors were computed using MOE, MarvinView, and Dragon. These combined methods yielded over 4,071 descriptors for model construction. Using these descriptors, pattern recognition analyses were performed by RF implemented in JMP Pro (a statistical software package. A hundred to two hundred RF models were generated for each pathway. The predictive performance of each model was tested against the validation dataset, and the best-performing model was selected. In the competition, the latter model selected a best-performing model from the 50% test set that best predicted the structures of compounds that activate the estrogen receptor ligand-binding domain (ER-LBD.

  10. DMPD: Toll like receptors and autoimmunity: a critical appraisal. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17959357 Toll like receptors and autoimmunity: a critical appraisal. Papadimitraki ...ml) Show Toll like receptors and autoimmunity: a critical appraisal. PubmedID 17959357 Title Toll like receptors and auto

  11. DMPD: IRAK1: a critical signaling mediator of innate immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17890055 IRAK1: a critical signaling mediator of innate immunity. Gottipati S, Rao ...NL, Fung-Leung WP. Cell Signal. 2008 Feb;20(2):269-76. Epub 2007 Aug 23. (.png) (.svg) (.html) (.csml) Show IRAK1: a critical sign...aling mediator of innate immunity. PubmedID 17890055 Title IRAK1: a critical signaling

  12. A systematic, critical review of manual palpation for identifying myofascial trigger points

    DEFF Research Database (Denmark)

    Myburgh, Corrie; Larsen, Anders Holsgaard; Hartvigsen, Jan

    2008-01-01

    To determine the reproducibility of manual palpation in identifying trigger points based on a systematic review of available literature.......To determine the reproducibility of manual palpation in identifying trigger points based on a systematic review of available literature....

  13. A microcomputer-based model for identifying urban and suburban roadways with critical large truck accident rates

    International Nuclear Information System (INIS)

    Brogan, J.D.; Cashwell, J.W.

    1992-01-01

    This paper presents an overview of techniques for merging highway accident record and roadway inventory files and employing the combined data set to identify spots or sections on highway facilities in urban and suburban areas with unusually high large truck accident rates. A statistical technique, the rate/quality control method, is used to calculate a critical rate for each location of interest. This critical rate may then be compared to the location's actual accident rate to identify locations for further study. Model enhancements and modifications are described to enable the technique to be employed in the evaluation of routing alternatives for the transport of radioactive material

  14. Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans

    NARCIS (Netherlands)

    Smeekens, Sanne P.; Ng, Aylwin; Kumar, Vinod; Johnson, Melissa D.; Plantinga, Theo S.; van Diemen, Cleo; Arts, Peer; Verwiel, Eugene T. P.; Gresnigt, Mark S.; Fransen, Karin; van Sommeren, Suzanne; Oosting, Marije; Cheng, Shih-Chin; Joosten, Leo A. B.; Hoischen, Alexander; Kullberg, Bart-Jan; Scott, William K.; Perfect, John R.; van der Meer, Jos W. M.; Wijmenga, Cisca; Netea, Mihai G.; Xavier, Ramnik J.

    Candida albicans is the most common human fungal pathogen causing mucosal and systemic infections. However, human antifungal immunity remains poorly defined. Here by integrating transcriptional analysis and functional genomics, we identified Candida-specific host defence mechanisms in humans.

  15. STUDY OF THE EFFECTS OF THE EDUCATIONAL HOSPITALIZATION FOR DIABETES IMPLEMENTING CRITICAL PATHWAY ON LONG-TERM GLYCEMIC CONTROL

    OpenAIRE

    Kaga, Midori; Narita, Takuma; Yamada, Yuichiro

    2013-01-01

    We evaluated the effect of diabetes educational hospitalization utilizing the critical pathway (CP) on long-term glycemic control after discharge in type 2 diabetic patients by comparing changes in HbA1c in 18 patients admitted before CP introduction with those in 18 patients admitted after CP introduction. We also investigated the factors related to worsening of glycemic control after discharge from diabetes educational hospitalization. In the patients admitted before CP introduction, HbA1c ...

  16. Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats

    International Nuclear Information System (INIS)

    Kim, Yongbaek; Thai-Vu Ton; De Angelo, Anthony B.; Morgan, Kevin; Devereux, Theodora R.; Anna, Colleen; Collins, Jennifer B.; Paules, Richard S.; Crosby, Lynn M.; Sills, Robert C.

    2006-01-01

    This study was performed to characterize the gene expression profile and to identify the major carcinogenic pathways involved in rat peritoneal mesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Oligo arrays, with over 20,000 target genes, were used to evaluate o-NT- and BCA-induced RPMs, when compared to a non-transformed mesothelial cell line (Fred-PE). Analysis using Ingenuity Pathway Analysis software revealed 169 cancer-related genes that were categorized into binding activity, growth and proliferation, cell cycle progression, apoptosis, and invasion and metastasis. The microarray data were validated by positive correlation with quantitative real-time RT-PCR on 16 selected genes including igf1, tgfb3 and nov. Important carcinogenic pathways involved in RPM formation included insulin-like growth factor 1 (IGF-1), p38 MAPkinase, Wnt/β-catenin and integrin signaling pathways. This study demonstrated that mesotheliomas in rats exposed to o-NT- and BCA were similar to mesotheliomas in humans, at least at the cellular and molecular level

  17. Genomic characterization of a new endophytic Streptomyces kebangsaanensis identifies biosynthetic pathway gene clusters for novel phenazine antibiotic production

    Directory of Open Access Journals (Sweden)

    Juwairiah Remali

    2017-11-01

    Full Text Available Background Streptomyces are well known for their capability to produce many bioactive secondary metabolites with medical and industrial importance. Here we report a novel bioactive phenazine compound, 6-((2-hydroxy-4-methoxyphenoxy carbonyl phenazine-1-carboxylic acid (HCPCA extracted from Streptomyces kebangsaanensis, an endophyte isolated from the ethnomedicinal Portulaca oleracea. Methods The HCPCA chemical structure was determined using nuclear magnetic resonance spectroscopy. We conducted whole genome sequencing for the identification of the gene cluster(s believed to be responsible for phenazine biosynthesis in order to map its corresponding pathway, in addition to bioinformatics analysis to assess the potential of S. kebangsaanensis in producing other useful secondary metabolites. Results The S. kebangsaanensis genome comprises an 8,328,719 bp linear chromosome with high GC content (71.35% consisting of 12 rRNA operons, 81 tRNA, and 7,558 protein coding genes. We identified 24 gene clusters involved in polyketide, nonribosomal peptide, terpene, bacteriocin, and siderophore biosynthesis, as well as a gene cluster predicted to be responsible for phenazine biosynthesis. Discussion The HCPCA phenazine structure was hypothesized to derive from the combination of two biosynthetic pathways, phenazine-1,6-dicarboxylic acid and 4-methoxybenzene-1,2-diol, originated from the shikimic acid pathway. The identification of a biosynthesis pathway gene cluster for phenazine antibiotics might facilitate future genetic engineering design of new synthetic phenazine antibiotics. Additionally, these findings confirm the potential of S. kebangsaanensis for producing various antibiotics and secondary metabolites.

  18. Survey to identify depth of penetration of critical incident reporting systems in Austrian healthcare facilities.

    Science.gov (United States)

    Sendlhofer, Gerald; Eder, Harald; Leitgeb, Karina; Gorges, Roland; Jakse, Heidelinde; Raiger, Marianne; Türk, Silvia; Petschnig, Walter; Pregartner, Gudrun; Kamolz, Lars-Peter; Brunner, Gernot

    2018-01-01

    Incident reporting systems or so-called critical incident reporting systems (CIRS) were first recommended for use in health care more than 15 years ago. The uses of these CIRS are highly variable among countries, ranging from being used to report critical incidents, falls, or sentinel events resulting in death. In Austria, CIRS have only been introduced to the health care sector relatively recently. The goal of this work, therefore, was to determine whether and specifically how CIRS are used in Austria. A working group from the Austrian Society for Quality and Safety in Healthcare (ASQS) developed a survey on the topic of CIRS to collect information on penetration of CIRS in general and on how CIRS reports are used to increase patient safety. Three hundred seventy-one health care professionals from 274 health care facilities were contacted via e-mail. Seventy-eight respondents (21.0%) completed the online survey, thereof 66 from hospitals and 12 from other facilities (outpatient clinics, nursing homes). In all, 64.1% of the respondents indicated that CIRS were used in the entire health care facility; 20.6% had not yet introduced CIRS and 15.4% used CIRS only in particular areas. Most often, critical incidents without any harm to patients were reported (76.9%); however, some health care facilities also use their CIRS to report patient falls (16.7%), needle stick injuries (17.9%), technical problems (51.3%), or critical incidents involving health care professionals. CIRS are not yet extensively or homogeneously used in Austria. Inconsistencies exist with respect to which events are reported as well as how they are followed up and reported to health care professionals. Further recommendations for general use are needed to support the dissemination in Austrian health care environments.

  19. Workshop to identify critical windows of exposure for children's health: neurobehavioral work group summary.

    OpenAIRE

    Adams, J; Barone, S; LaMantia, A; Philen, R; Rice, D C; Spear, L; Susser, E

    2000-01-01

    This paper summarizes the deliberations of a work group charged with addressing specific questions relevant to risk estimation in developmental neurotoxicology. We focused on eight questions. a) Does it make sense to think about discrete windows of vulnerability in the development of the nervous system? If it does, which time periods are of greatest importance? b) Are there cascades of developmental disorders in the nervous system? For example, are there critical points that determine the cou...

  20. Proteome and Acetylome Analysis Identifies Novel Pathways and Targets Regulated by Perifosine in Neuroblastoma

    Science.gov (United States)

    Gu, Xiao; Hua, Zhongyan; Dong, Yudi; Zhan, Yue; Zhang, Xiaowen; Tian, Wei; Liu, Zhihui; Thiele, Carol J.; Li, Zhijie

    2017-01-01

    Perifosine, an Akt inhibitor, has been shown to be effective in controlling neuroblastoma tumor growth. However, studies indicate that in addition to the ability to inhibit Akt, other mechanisms contribute to perifosine’s anti-tumor activity. To gain insight into perifosine anti-tumor activity in neuroblastoma we have studied changes in the proteome and acetylome after perifosine treatment in SK-N-AS neuroblastoma cells using SILAC labeling, affinity enrichment, high-resolution and LC-MS/MS analysis. Bioinformatic analysis indicates that, a total of 5,880 proteins and 3,415 lysine acetylation sites were quantified in SK-N-AS cells and 216 differentially expressed proteins and 115 differentially expressed lysine acetylation sites were obtained. These differentially expressed proteins and lysine acetylated proteins were involved in a number of different biological functions, metabolic pathways and pathophysiological processes. This study details the impact of perifosine on proteome and lysine acetylome in SK-N-AS cells and expands our understanding of the mechanisms of perifosine action in neuroblastoma. PMID:28165023

  1. Genetic approach identifies distinct asthma pathways in overweight vs normal weight children.

    Science.gov (United States)

    Butsch Kovacic, M; Martin, L J; Biagini Myers, J M; He, H; Lindsey, M; Mersha, T B; Khurana Hershey, G K

    2015-08-01

    The pathogenesis of asthma in the context of excess body weight may be distinct from asthma that develops in normal weight children. The study's objective was to explore the biology of asthma in the context of obesity and normal weight status using genetic methodologies. Associations between asthma and SNPs in 49 genes were assessed, as well as, interactions between SNPs and overweight status in child participants of the Greater Cincinnati Pediatric Clinic Repository. Asthma was significantly associated with weight (OR = 1.38; P = 0.037). The number of genes and the magnitude of their associations with asthma were notably greater when considering overweight children alone vs normal weight and overweight children together. When considering weight, distinct sets of asthma-associated genes were observed, many times with opposing effects. We demonstrated that the underlying heterogeneity of asthma is likely due in part to distinct pathogenetic pathways that depend on preceding/comorbid overweight and/or allergy. It is therefore important to consider both obesity and asthma when conducting studies of asthma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Adolescents can know best: using concept mapping to identify factors and pathways driving adolescent sexuality in Lima, Peru.

    Science.gov (United States)

    Bayer, Angela M; Cabrera, Lilia Z; Gilman, Robert H; Hindin, Michelle J; Tsui, Amy O

    2010-06-01

    The primary objective of this study was to identify and describe individual- and environmental-level factors that Peruvian adolescents perceive to be related to adolescent sexuality. A series of concept mapping sessions were carried out from January-March 2006 with 63 15-17 year olds from a low-income community near Lima in order for adolescents to: (1) brainstorm items that they thought were related to sexuality, (2) sort, group and rate items to score their importance for sexuality-related outcomes, and (3) create pathways from the groups of items to engaging in sex. Brainstorming resulted in 61 items, which participants grouped into 11 clusters. The highest rated clusters were personal values, respect and confidence in partner relationships, future achievements and parent-child communication. The pathway of decision-making about having sex primarily contained items rated as only moderately important. This study identified important understudied factors, new perspectives on previously-recognized factors, and possible pathways to sexual behavior. These interesting and provocative findings underscore the importance of directly integrating adolescent voices into future sexual and reproductive health research, policies and programs that target this population. Copyright 2010 Elsevier Ltd. All rights reserved.

  3. Transcriptome profiling identifies genes/pathways associated with experimental resistance to paromomycin in Leishmania donovani

    Directory of Open Access Journals (Sweden)

    Aditya Verma

    2017-12-01

    Full Text Available Widespread resistance towards antimony and reports of relapses following miltefosine treatment has severely affected the management of visceral leishmaniasis (VL in the Indian subcontinent. Paromomycin (PMM, an aminoglycoside antibiotic, has been licensed for VL treatment in India in 2007. Although its use is still restricted in the field, unraveling the molecular mechanism of resistance towards PMM is the key to preserve the drug. In this study, PMM resistant lines were selected up to 100 μM of PMM in three distinct field isolates of Leishmania donovani at promastigote stage. The resistance induced at promastigote level was also evident in amastigotes which showed 6 fold decreases in PMM susceptibility. Comparative transcriptome profiling of PMM resistant (PMM-R and the corresponding PMM sensitive (PMM-S parasites revealed modulated expression of 500 genes (1.5 fold cut off in PMM-R parasites. Selected genes were validated for their modulated expression by quantitative real-time PCR. Functional classification and pathway analysis of modulated genes indicated probable adaptations in drug resistant lines which included a reduced oxidative phosphorylation; b increased glycosomal succinate fermentation and substrate level phosphorylation; c dependency on lipids and amino acids for energy generation; d reduced DNA synthesis and increased DNA damage repair and e decreased protein synthesis and degradation. Interestingly, PMM-R parasites showed a marked increase in PMM susceptibility in presence of verapamil and amlodipine, antagonists of Ca2+ channel that are also modulators of ABC transporters. Moreover, infection of macrophages by PMM-R parasites led to modulated nitric oxide (NO levels while reactive oxygen species (ROS level remained unaltered. The present study highlights the putative mechanisms of PMM resistance in Leishmania. Keywords: Leishmania donovani, Drug resistance, Paromomycin, Transcriptome, ABC transporters, Nitric oxide

  4. Use of a bovine genome array to identify new biological pathways for beef marbling in Hanwoo (Korean Cattle

    Directory of Open Access Journals (Sweden)

    Lim Da-jeong

    2010-11-01

    Full Text Available Abstract Background Marbling (intramuscular fat is a valuable trait that impacts on meat quality and an important factor determining price of beef in the Korean beef market. Animals that are destined for this high marbling market are fed a high concentrate ration for approximately 30 months in the Korean finishing farms. However, this feeding strategy leads to inefficiencies and excessive fat production. This study aimed to identify candidate genes and pathways associated with intramuscular fat deposition on highly divergent marbling phenotypes in adult Hanwoo cattle. Results Bovine genome array analysis was conducted to detect differentially expressed genes (DEGs in m. longissimus with divergent marbling phenotype (marbling score 2 to 7. Three data-processing methods (MAS5.0, GCRMA and RMA were used to test for differential expression (DE. Statistical analysis identified 21 significant transcripts from at least two data-processing methods (P . All 21 differentially expressed genes were validated by real-time PCR. Results showed a high concordance in the gene expression fold change between the microarrays and the real time PCR data. Gene Ontology (GO and pathway analysis demonstrated that some genes (ADAMTS4, CYP51A and SQLE over expressed in high marbled animals are involved in a protein catabolic process and a cholesterol biosynthesis process. In addition, pathway analysis also revealed that ADAMTS4 is activated by three regulators (IL-17A, TNFα and TGFβ1. QRT-PCR was used to investigate gene expression of these regulators in muscle with divergent intramuscular fat contents. The results demonstrate that ADAMTS4 and TGFβ1 are associated with increasing marbling fat. An ADAMTS4/TGFβ1 pathway seems to be associated with the phenotypic differences between high and low marbled groups. Conclusions Marbling differences are possibly a function of complex signaling pathway interactions between muscle and fat. These results suggest that ADAMTS4

  5. Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis

    Science.gov (United States)

    2014-01-01

    Background Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis. Methods We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS. Results GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72). Conclusions Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases. PMID:25085501

  6. Identifying Critical Success Factors for TQM and Employee Performance in Malaysian Automotive Industry: A Literature Review

    Science.gov (United States)

    Nadia Dedy, Aimie; Zakuan, Norhayati; Zaidi Bahari, Ahamad; Ariff, Mohd Shoki Md; Chin, Thoo Ai; Zameri Mat Saman, Muhamad

    2016-05-01

    TQM is a management philosophy embracing all activities through which the needs and expectations of the customer and the community and the goals of the companies are satisfied in the most efficient and cost effective way by maximizing the potential of all workers in a continuing drive for total quality improvement. TQM is very important to the company especially in automotive industry in order for them to survive in the competitive global market. The main objective of this study is to review a relationship between TQM and employee performance. Authors review updated literature on TQM study with two main targets: (a) evolution of TQM considering as a set of practice, (b) and its impacts to employee performance. Therefore, two research questions are proposed in order to review TQM constructs and employee performance measure: (a) Is the set of critical success factors associated with TQM valid as a whole? (b) What is the critical success factors should be considered to measure employee performance in automotive industry?

  7. Enhanced Sequential Search Methodology for Identifying Cost-Optimal Building Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Horowitz, S.; Christensen, C.; Brandemuehl, M.; Krarti, M.

    2008-06-01

    The BEopt software is a building energy optimization tool that generates a cost-optimal path of building designs from a reference building up to zero-net energy. It employs a sequential search methodology to account for complex energy interactions between building efficiency measures. Enhancement strategies to this search methodology are developed to increase accuracy (ability to identify the true cost-optimal curve) and speed (number of required energy simulations). A test suite of optimizations is used to gauge the effectiveness of each strategy. Combinations of strategies are assembled into packages, ranging from conservative to aggressive, with so up to 71% fewer required simulations are required.

  8. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.

    Directory of Open Access Journals (Sweden)

    Marcel Kool

    Full Text Available BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. METHODS AND FINDINGS: To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases, SHH signaling (B; 15 cases, expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively or photoreceptor genes (D and E; both 11 cases. Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E

  9. A CRISPR screen identifies a pathway required for paraquat-induced cell death.

    Science.gov (United States)

    Reczek, Colleen R; Birsoy, Kıvanç; Kong, Hyewon; Martínez-Reyes, Inmaculada; Wang, Tim; Gao, Peng; Sabatini, David M; Chandel, Navdeep S

    2017-12-01

    Paraquat, a herbicide linked to Parkinson's disease, generates reactive oxygen species (ROS), which causes cell death. Because the source of paraquat-induced ROS production remains unknown, we conducted a CRISPR-based positive-selection screen to identify metabolic genes essential for paraquat-induced cell death. Our screen uncovered three genes, POR (cytochrome P450 oxidoreductase), ATP7A (copper transporter), and SLC45A4 (sucrose transporter), required for paraquat-induced cell death. Furthermore, our results revealed POR as the source of paraquat-induced ROS production. Thus, our study highlights the use of functional genomic screens for uncovering redox biology.

  10. Single Molecule Cluster Analysis Identifies Signature Dynamic Conformations along the Splicing Pathway

    Science.gov (United States)

    Blanco, Mario R.; Martin, Joshua S.; Kahlscheuer, Matthew L.; Krishnan, Ramya; Abelson, John; Laederach, Alain; Walter, Nils G.

    2016-01-01

    The spliceosome is the dynamic RNA-protein machine responsible for faithfully splicing introns from precursor messenger RNAs (pre-mRNAs). Many of the dynamic processes required for the proper assembly, catalytic activation, and disassembly of the spliceosome as it acts on its pre-mRNA substrate remain poorly understood, a challenge that persists for many biomolecular machines. Here, we developed a fluorescence-based Single Molecule Cluster Analysis (SiMCAn) tool to dissect the manifold conformational dynamics of a pre-mRNA through the splicing cycle. By clustering common dynamic behaviors derived from selectively blocked splicing reactions, SiMCAn was able to identify signature conformations and dynamic behaviors of multiple ATP-dependent intermediates. In addition, it identified a conformation adopted late in splicing by a 3′ splice site mutant, invoking a mechanism for substrate proofreading. SiMCAn presents a novel framework for interpreting complex single molecule behaviors that should prove widely useful for the comprehensive analysis of a plethora of dynamic cellular machines. PMID:26414013

  11. Identifying Key Proteins in Hg Methylation Pathways of Desulfovibrio by Global Proteomics, Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Summers, Anne O. [Univ. of Georgia, Athens, GA (United States). Dept. of Microbiology; Miller, Susan M. [Univ. of California, San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry; Wall, Judy [Univ. of Missouri, Columbia, MO (United States). Dept. of Biochemistry; Lipton, Mary [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2016-06-18

    Elemental mercury, Hg(0) is a contaminant at many DOE sites, especially at Oak Ridge National Laboratory (ORNL) where the spread of spilled Hg and its effects on microbial populations have been monitored for decades. To explore the microbial interactions with Hg, we have devised a global proteomic approach capable of directly detecting Hg-adducts of proteins. This technique developed in the facultative anaerobe, Escherichia coli, allows us to identify the proteins most vulnerable to acute exposure to organomercurials phenyl- and ethyl-mercury (as surrogates for the highly neurotoxic methyl-Hg) (Polacco, et al, 2011). We have found >300 such proteins in all metabolic functional groups and cellular compartments; most are highly conserved and can serve as markers for acute Hg exposure (Zink, et al. 2016, in preparation). We have also discovered that acute Hg exposure severely disrupts thiol, iron and redox homeostases, and electrolyte balance (LaVoie, et al., 2015) Thus, we proposed to bring these techniques to bear on the central problem of identifying the cellular proteins involved in bacterial uptake and methylation of mercury and its release from the cell.

  12. Perinatal bisphenol A exposure and adult glucose homeostasis: identifying critical windows of exposure.

    Directory of Open Access Journals (Sweden)

    Jingli Liu

    Full Text Available Bisphenol A (BPA is a widespread endocrine-disrupting chemical used as the building block for polycarbonate plastics. Epidemiological evidence has correlated BPA exposure with higher risk of heart disease and type 2 diabetes. However, it remains unknown whether there are critical windows of susceptibility to BPA exposure on the development of dysglycemia. This study was an attempt to investigate the critical windows and the long-term consequences of perinatal exposure to BPA on glucose homeostasis. Pregnant mice were given either vehicle or BPA (100 µg/kg/day at different time of perinatal stage: 1 on days 1-6 of pregnancy (P1-P6, preimplantation exposure; 2 from day 6 of pregnancy until postnatal day (PND 0 (P6-PND0, fetal exposure; 3 from lactation until weaning (PND0-PND21, neonatal exposure; and 4 from day 6 of gestation until weaning (P6-PND21, fetal and neonatal exposure. At 3, 6 and 8 months of age, offspring in each group were challenged with glucose and insulin tolerance tests. Then islet morphometry and β-cell function were measured. The glucose homeostasis was impaired in P6-PND0 mice from 3 to 6 months of age, and this continued to 8 months in males, but not females. While in PND0-PND21 and P6-PND21 BPA-treated groups, only the 3-month-old male offspring developed glucose intolerance. Moreover, at the age of 3 months, perinatal exposure to BPA resulted in the increase of β-cell mass mainly due to the coordinate changes in cell replication, neogenesis, and apoptosis. The alterations of insulin secretion and insulin sensitivity, rather than β-cell mass, were consistent with the development of glucose intolerance. Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and the effects of BPA were dose, sex, and time-dependent. Fetal development stage may be the critical window of susceptibility to BPA exposure.

  13. An empirical study on identifying critical success factors on chaos management

    Directory of Open Access Journals (Sweden)

    Naser Azad

    2012-08-01

    Full Text Available Chaos management is one of the most necessary efforts on managing business units. Many organizations fail to cope with undesirable circumstances, which may happen without any prior notice and as a result, they may face with significant financial losses. In this paper, we present an empirical study to determine critical success factors, which could help handle any possible chaos in organizations. The proposed study of this paper is implemented for a set of travel agencies located in Tehran, Iran. Chronbach alpha is calculated as 0.821, which is well above the minimum desirable level. In addition, we have also performed factor analysis, which yields a KMO value of 0.576 with the level of significance of 0.000. The results indicate that there are six important factors including effective management strategy, internal environmental factors, creative and innovative attitudes, external environmental factors and top level management thoughts.

  14. MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development.

    Science.gov (United States)

    Harati, Sahar; Cooper, Lee A D; Moran, Josue D; Giuste, Felipe O; Du, Yuhong; Ivanov, Andrei A; Johns, Margaret A; Khuri, Fadlo R; Fu, Haian; Moreno, Carlos S

    2017-01-01

    Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology. Here we introduce a computational method (MEDICI) to predict PPI essentiality by combining gene knockdown studies with network models of protein interaction pathways in an analytic framework. Our method uses network topology to model how gene silencing can disrupt PPIs, relating the unknown essentialities of individual PPIs to experimentally observed protein essentialities. This model is then deconvolved to recover the unknown essentialities of individual PPIs. We demonstrate the validity of our approach via prediction of sensitivities to compounds based on PPI essentiality and differences in essentiality based on genetic mutations. We further show that lung cancer patients have improved overall survival when specific PPIs are no longer present, suggesting that these PPIs may be potentially new targets for therapeutic development. Software is freely available at https://github.com/cooperlab/MEDICI. Datasets are available at https://ctd2.nci.nih.gov/dataPortal.

  15. Evolution of a Pathogen: A Comparative Genomics Analysis Identifies a Genetic Pathway to Pathogenesis in Acinetobacter

    Science.gov (United States)

    Sahl, Jason W.; Gillece, John D.; Schupp, James M.; Waddell, Victor G.; Driebe, Elizabeth M.; Engelthaler, David M.; Keim, Paul

    2013-01-01

    Acinetobacter baumannii is an emergent and global nosocomial pathogen. In addition to A. baumannii, other Acinetobacter species, especially those in the Acinetobacter calcoaceticus-baumannii (Acb) complex, have also been associated with serious human infection. Although mechanisms of attachment, persistence on abiotic surfaces, and pathogenesis in A. baumannii have been identified, the genetic mechanisms that explain the emergence of A. baumannii as the most widespread and virulent Acinetobacter species are not fully understood. Recent whole genome sequencing has provided insight into the phylogenetic structure of the genus Acinetobacter. However, a global comparison of genomic features between Acinetobacter spp. has not been described in the literature. In this study, 136 Acinetobacter genomes, including 67 sequenced in this study, were compared to identify the acquisition and loss of genes in the expansion of the Acinetobacter genus. A whole genome phylogeny confirmed that A. baumannii is a monophyletic clade and that the larger Acb complex is also a well-supported monophyletic group. The whole genome phylogeny provided the framework for a global genomic comparison based on a blast score ratio (BSR) analysis. The BSR analysis demonstrated that specific genes have been both lost and acquired in the evolution of A. baumannii. In addition, several genes associated with A. baumannii pathogenesis were found to be more conserved in the Acb complex, and especially in A. baumannii, than in other Acinetobacter genomes; until recently, a global analysis of the distribution and conservation of virulence factors across the genus was not possible. The results demonstrate that the acquisition of specific virulence factors has likely contributed to the widespread persistence and virulence of A. baumannii. The identification of novel features associated with transcriptional regulation and acquired by clades in the Acb complex presents targets for better understanding the

  16. Evolution of a pathogen: a comparative genomics analysis identifies a genetic pathway to pathogenesis in Acinetobacter.

    Directory of Open Access Journals (Sweden)

    Jason W Sahl

    Full Text Available Acinetobacter baumannii is an emergent and global nosocomial pathogen. In addition to A. baumannii, other Acinetobacter species, especially those in the Acinetobacter calcoaceticus-baumannii (Acb complex, have also been associated with serious human infection. Although mechanisms of attachment, persistence on abiotic surfaces, and pathogenesis in A. baumannii have been identified, the genetic mechanisms that explain the emergence of A. baumannii as the most widespread and virulent Acinetobacter species are not fully understood. Recent whole genome sequencing has provided insight into the phylogenetic structure of the genus Acinetobacter. However, a global comparison of genomic features between Acinetobacter spp. has not been described in the literature. In this study, 136 Acinetobacter genomes, including 67 sequenced in this study, were compared to identify the acquisition and loss of genes in the expansion of the Acinetobacter genus. A whole genome phylogeny confirmed that A. baumannii is a monophyletic clade and that the larger Acb complex is also a well-supported monophyletic group. The whole genome phylogeny provided the framework for a global genomic comparison based on a blast score ratio (BSR analysis. The BSR analysis demonstrated that specific genes have been both lost and acquired in the evolution of A. baumannii. In addition, several genes associated with A. baumannii pathogenesis were found to be more conserved in the Acb complex, and especially in A. baumannii, than in other Acinetobacter genomes; until recently, a global analysis of the distribution and conservation of virulence factors across the genus was not possible. The results demonstrate that the acquisition of specific virulence factors has likely contributed to the widespread persistence and virulence of A. baumannii. The identification of novel features associated with transcriptional regulation and acquired by clades in the Acb complex presents targets for better

  17. Combining a nontargeted and targeted metabolomics approach to identify metabolic pathways significantly altered in polycystic ovary syndrome.

    Science.gov (United States)

    Chang, Alice Y; Lalia, Antigoni Z; Jenkins, Gregory D; Dutta, Tumpa; Carter, Rickey E; Singh, Ravinder J; Nair, K Sreekumaran

    2017-06-01

    Polycystic ovary syndrome (PCOS) is a condition of androgen excess and chronic anovulation frequently associated with insulin resistance. We combined a nontargeted and targeted metabolomics approach to identify pathways and metabolites that distinguished PCOS from metabolic syndrome (MetS). Twenty obese women with PCOS were compared with 18 obese women without PCOS. Both groups met criteria for MetS but could not have diabetes mellitus or take medications that treat PCOS or affect lipids or insulin sensitivity. Insulin sensitivity was derived from the frequently sampled intravenous glucose tolerance test. A nontargeted metabolomics approach was performed on fasting plasma samples to identify differentially expressed metabolites, which were further evaluated by principal component and pathway enrichment analysis. Quantitative targeted metabolomics was then applied on candidate metabolites. Measured metabolites were tested for associations with PCOS and clinical variables by logistic and linear regression analyses. This multiethnic, obese sample was matched by age (PCOS, 37±6; MetS, 40±6years) and body mass index (BMI) (PCOS, 34.6±5.1; MetS, 33.7±5.2kg/m 2 ). Principal component analysis of the nontargeted metabolomics data showed distinct group separation of PCOS from MetS controls. From the subset of 385 differentially expressed metabolites, 22% were identified by accurate mass, resulting in 19 canonical pathways significantly altered in PCOS, including amino acid, lipid, steroid, carbohydrate, and vitamin D metabolism. Targeted metabolomics identified many essential amino acids, including branched-chain amino acids (BCAA) that were elevated in PCOS compared with MetS. PCOS was most associated with BCAA (P=.02), essential amino acids (P=.03), the essential amino acid lysine (P=.02), and the lysine metabolite α-aminoadipic acid (P=.02) in models adjusted for surrogate variables representing technical variation in metabolites. No significant differences between

  18. Critical transitions in disturbance-driven ecosystems: identifying Windows of Opportunity for recovery

    NARCIS (Netherlands)

    Balke, T.; Herman, P.M.J.; Bouma, T.J.

    2014-01-01

    Vegetation recovery in disturbance-driven ecosystems is difficult to predict. We demonstrate a concept to analyse time series for short-term variability in external forcing that can identify potential events for sudden vegetation recovery in biogeomorphic ecosystems such as saltmarshes, mangroves,

  19. A systems biology approach to identify intelligence quotient score-related genomic regions, and pathways relevant to potential therapeutic treatments

    Science.gov (United States)

    Zhao, Min; Kong, Lei; Qu, Hong

    2014-01-01

    Although the intelligence quotient (IQ) is the most popular intelligence test in the world, little is known about the underlying biological mechanisms that lead to the differences in human. To improve our understanding of cognitive processes and identify potential biomarkers, we conducted a comprehensive investigation of 158 IQ-related genes selected from the literature. A genomic distribution analysis demonstrated that IQ-related genes were enriched in seven regions of chromosome 7 and the X chromosome. In addition, these genes were enriched in target lists of seven transcription factors and sixteen microRNAs. Using a network-based approach, we further reconstructed an IQ-related pathway from known human pathway interaction data. Based on this reconstructed pathway, we incorporated enriched drugs and described the importance of dopamine and norepinephrine systems in IQ-related biological process. These findings not only reveal several testable genes and processes related to IQ scores, but also have potential therapeutic implications for IQ-related mental disorders. PMID:24566931

  20. Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making.

    Science.gov (United States)

    Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha; Zhou, Xiaolin

    2017-09-01

    The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. © The Author (2017). Published by Oxford University Press.

  1. Robust Selection Algorithm (RSA for Multi-Omic Biomarker Discovery; Integration with Functional Network Analysis to Identify miRNA Regulated Pathways in Multiple Cancers.

    Directory of Open Access Journals (Sweden)

    Vasudha Sehgal

    Full Text Available MicroRNAs (miRNAs play a crucial role in the maintenance of cellular homeostasis by regulating the expression of their target genes. As such, the dysregulation of miRNA expression has been frequently linked to cancer. With rapidly accumulating molecular data linked to patient outcome, the need for identification of robust multi-omic molecular markers is critical in order to provide clinical impact. While previous bioinformatic tools have been developed to identify potential biomarkers in cancer, these methods do not allow for rapid classification of oncogenes versus tumor suppressors taking into account robust differential expression, cutoffs, p-values and non-normality of the data. Here, we propose a methodology, Robust Selection Algorithm (RSA that addresses these important problems in big data omics analysis. The robustness of the survival analysis is ensured by identification of optimal cutoff values of omics expression, strengthened by p-value computed through intensive random resampling taking into account any non-normality in the data and integration into multi-omic functional networks. Here we have analyzed pan-cancer miRNA patient data to identify functional pathways involved in cancer progression that are associated with selected miRNA identified by RSA. Our approach demonstrates the way in which existing survival analysis techniques can be integrated with a functional network analysis framework to efficiently identify promising biomarkers and novel therapeutic candidates across diseases.

  2. Proteomic Approaches Identify Members of Cofilin Pathway Involved in Oral Tumorigenesis

    Science.gov (United States)

    Polachini, Giovana M.; Sobral, Lays M.; Mercante, Ana M. C.; Paes-Leme, Adriana F.; Xavier, Flávia C. A.; Henrique, Tiago; Guimarães, Douglas M.; Vidotto, Alessandra; Fukuyama, Erica E.; Góis-Filho, José F.; Cury, Patricia M.; Curioni, Otávio A.; Michaluart Jr, Pedro; Silva, Adriana M. A.; Wünsch-Filho, Victor; Nunes, Fabio D.; Leopoldino, Andréia M.; Tajara, Eloiza H.

    2012-01-01

    The prediction of tumor behavior for patients with oral carcinomas remains a challenge for clinicians. The presence of lymph node metastasis is the most important prognostic factor but it is limited in predicting local relapse or survival. This highlights the need for identifying biomarkers that may effectively contribute to prediction of recurrence and tumor spread. In this study, we used one- and two-dimensional gel electrophoresis, mass spectrometry and immunodetection methods to analyze protein expression in oral squamous cell carcinomas. Using a refinement for classifying oral carcinomas in regard to prognosis, we analyzed small but lymph node metastasis-positive versus large, lymph node metastasis-negative tumors in order to contribute to the molecular characterization of subgroups with risk of dissemination. Specific protein patterns favoring metastasis were observed in the “more-aggressive” group defined by the present study. This group displayed upregulation of proteins involved in migration, adhesion, angiogenesis, cell cycle regulation, anti-apoptosis and epithelial to mesenchymal transition, whereas the “less-aggressive” group was engaged in keratinocyte differentiation, epidermis development, inflammation and immune response. Besides the identification of several proteins not yet described as deregulated in oral carcinomas, the present study demonstrated for the first time the role of cofilin-1 in modulating cell invasion in oral carcinomas. PMID:23227181

  3. Critical importance of the de novo pyrimidine biosynthesis pathway for Trypanosoma cruzi growth in the mammalian host cell cytoplasm

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Muneaki, E-mail: muneaki@juntendo.ac.jp [Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Morales, Jorge; Fukai, Yoshihisa; Suzuki, Shigeo; Takamiya, Shinzaburo; Tsubouchi, Akiko; Inoue, Syou [Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Inoue, Masayuki [Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Kita, Kiyoshi [Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); Harada, Shigeharu [Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Tanaka, Akiko [Systems and Structural Biology Center, RIKEN, Tsurumi, Yokohama 230-0045 (Japan); Aoki, Takashi [Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Nara, Takeshi, E-mail: tnara@juntendo.ac.jp [Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan)

    2012-01-20

    Highlights: Black-Right-Pointing-Pointer We established Trypanosoma cruzi lacking the gene for carbamoyl phosphate synthetase II. Black-Right-Pointing-Pointer Disruption of the cpsII gene significantly reduced the growth of epimastigotes. Black-Right-Pointing-Pointer In particular, the CPSII-null mutant severely retarded intracellular growth. Black-Right-Pointing-Pointer The de novo pyrimidine pathway is critical for the parasite growth in the host cell. -- Abstract: The intracellular parasitic protist Trypanosoma cruzi is the causative agent of Chagas disease in Latin America. In general, pyrimidine nucleotides are supplied by both de novo biosynthesis and salvage pathways. While epimastigotes-an insect form-possess both activities, amastigotes-an intracellular replicating form of T. cruzi-are unable to mediate the uptake of pyrimidine. However, the requirement of de novo pyrimidine biosynthesis for parasite growth and survival has not yet been elucidated. Carbamoyl-phosphate synthetase II (CPSII) is the first and rate-limiting enzyme of the de novo biosynthetic pathway, and increased CPSII activity is associated with the rapid proliferation of tumor cells. In the present study, we showed that disruption of the T. cruzicpsII gene significantly reduced parasite growth. In particular, the growth of amastigotes lacking the cpsII gene was severely suppressed. Thus, the de novo pyrimidine pathway is important for proliferation of T. cruzi in the host cell cytoplasm and represents a promising target for chemotherapy against Chagas disease.

  4. Novel Host Proteins and Signaling Pathways in Enteropathogenic E. coli Pathogenesis Identified by Global Phosphoproteome Analysis*

    Science.gov (United States)

    Scholz, Roland; Imami, Koshi; Scott, Nichollas E.; Trimble, William S.; Foster, Leonard J.; Finlay, B. Brett

    2015-01-01

    Enteropathogenic Escherichia coli (EPEC) uses a type III secretion system (T3SS) to directly translocate effector proteins into host cells where they play a pivotal role in subverting host cell signaling needed for disease. However, our knowledge of how EPEC affects host protein phosphorylation is limited to a few individual protein studies. We employed a quantitative proteomics approach to globally map alterations in the host phosphoproteome during EPEC infection. By characterizing host phosphorylation events at various time points throughout infection, we examined how EPEC dynamically impacts the host phosphoproteome over time. This experimental setup also enabled identification of T3SS-dependent and -independent changes in host phosphorylation. Specifically, T3SS-regulated events affected various cellular processes that are known EPEC targets, including cytoskeletal organization, immune signaling, and intracellular trafficking. However, the involvement of phosphorylation in these events has thus far been poorly studied. We confirmed the MAPK family as an established key host player, showed its central role in signal transduction during EPEC infection, and extended the repertoire of known signaling hubs with previously unrecognized proteins, including TPD52, CIN85, EPHA2, and HSP27. We identified altered phosphorylation of known EPEC targets, such as cofilin, where the involvement of phosphorylation has so far been undefined, thus providing novel mechanistic insights into the roles of these proteins in EPEC infection. An overlap of regulated proteins, especially those that are cytoskeleton-associated, was observed when compared with the phosphoproteome of Shigella-infected cells. We determined the biological relevance of the phosphorylation of a novel protein in EPEC pathogenesis, septin-9 (SEPT9). Both siRNA knockdown and a phosphorylation-impaired SEPT9 mutant decreased bacterial adherence and EPEC-mediated cell death. In contrast, a phosphorylation

  5. Identifying improvements to complex pathways: evidence synthesis and stakeholder engagement in infant congenital heart disease.

    Science.gov (United States)

    Crowe, Sonya; Knowles, Rachel; Wray, Jo; Tregay, Jenifer; Ridout, Deborah A; Utley, Martin; Franklin, Rodney; Bull, Catherine L; Brown, Katherine L

    2016-06-06

    Many infants die in the year following discharge from hospital after surgical or catheter intervention for congenital heart disease (3-5% of discharged infants). There is considerable variability in the provision of care and support in this period, and some families experience barriers to care. We aimed to identify ways to improve discharge and postdischarge care for this patient group. A systematic evidence synthesis aligned with a process of eliciting the perspectives of families and professionals from community, primary, secondary and tertiary care. UK. A set of evidence-informed recommendations for improving the discharge and postdischarge care of infants following intervention for congenital heart disease was produced. These address known challenges with current care processes and, recognising current resource constraints, are targeted at patient groups based on the number of patients affected and the level and nature of their risk of adverse 1-year outcome. The recommendations include: structured discharge documentation, discharging certain high-risk patients via their local hospital, enhanced surveillance for patients with certain (high-risk) cardiac diagnoses and an early warning tool for parents and community health professionals. Our recommendations set out a comprehensive, system-wide approach for improving discharge and postdischarge services. This approach could be used to address challenges in delivering care for other patient populations that can fall through gaps between sectors and organisations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  6. Identifying the Critical Gaps in Research on Sex Differences in Metabolism Across the Life Span.

    Science.gov (United States)

    Reusch, Jane E B; Kumar, T Rajendra; Regensteiner, Judith G; Zeitler, Philip S

    2018-01-01

    The National Institutes of Health (NIH) Office of Research in Women's Health now functions under a mandate calling for the systematic inclusion of both female and male cells, animals, and human subjects in all types of research, so that sex as a biological variable is understood in health and disease. Sex-specific data can improve disease prevention, diagnosis, and treatment as well as reduce inequities. Inclusion of women in research studies has modestly improved over the last 20 years, yet preclinical research is still primarily done using male animal models and male-derived cells, with the result that many conclusions are made based on incomplete and sex-biased data. There are important, yet poorly studied, sex differences in cardiometabolic disease. To begin to address these sex differences, the Center for Women's Health Research at the University of Colorado held its inaugural National Conference, "Sex Differences Across the Lifespan: A Focus on Metabolism," in September 2016 (cwhr@ucdenver.edu). Research to address the important goal of understanding key sex differences in cardiometabolic disease across the life span is lacking. The goal of this article is to discuss the current state of research addressing sex differences in cardiometabolic health across the life span, to outline critical research gaps that must be addressed in response to NIH mandates, and, importantly, to develop strategies to address sex as a biological variable to understand disease mechanisms as well as develop diagnostic and therapeutic modalities. Copyright © 2018 Endocrine Society.

  7. A pathway closely related to the (D)-tagatose pathway of gram-negative enterobacteria identified in the gram-positive bacterium Bacillus licheniformis.

    Science.gov (United States)

    Van der Heiden, Edwige; Delmarcelle, Michaël; Lebrun, Sarah; Freichels, Régine; Brans, Alain; Vastenavond, Christian M; Galleni, Moreno; Joris, Bernard

    2013-06-01

    We report the first identification of a gene cluster involved in d-tagatose catabolism in Bacillus licheniformis. The pathway is closely related to the d-tagatose pathway of the Gram-negative bacterium Klebsiella oxytoca, in contrast to the d-tagatose 6-phosphate pathway described in the Gram-positive bacterium Staphylococcus aureus.

  8. A Pathway Closely Related to the d-Tagatose Pathway of Gram-Negative Enterobacteria Identified in the Gram-Positive Bacterium Bacillus licheniformis

    Science.gov (United States)

    Van der Heiden, Edwige; Lebrun, Sarah; Freichels, Régine; Brans, Alain; Vastenavond, Christian M.; Galleni, Moreno; Joris, Bernard

    2013-01-01

    We report the first identification of a gene cluster involved in d-tagatose catabolism in Bacillus licheniformis. The pathway is closely related to the d-tagatose pathway of the Gram-negative bacterium Klebsiella oxytoca, in contrast to the d-tagatose 6-phosphate pathway described in the Gram-positive bacterium Staphylococcus aureus. PMID:23524682

  9. A Pathway Closely Related to the d-Tagatose Pathway of Gram-Negative Enterobacteria Identified in the Gram-Positive Bacterium Bacillus licheniformis

    OpenAIRE

    Van der Heiden, Edwige; Delmarcelle, Michaël; Lebrun, Sarah; Freichels, Régine; Brans, Alain; Vastenavond, Christian M.; Galleni, Moreno; Joris, Bernard

    2013-01-01

    We report the first identification of a gene cluster involved in d-tagatose catabolism in Bacillus licheniformis. The pathway is closely related to the d-tagatose pathway of the Gram-negative bacterium Klebsiella oxytoca, in contrast to the d-tagatose 6-phosphate pathway described in the Gram-positive bacterium Staphylococcus aureus.

  10. Novel Host Proteins and Signaling Pathways in Enteropathogenic E. coli Pathogenesis Identified by Global Phosphoproteome Analysis.

    Science.gov (United States)

    Scholz, Roland; Imami, Koshi; Scott, Nichollas E; Trimble, William S; Foster, Leonard J; Finlay, B Brett

    2015-07-01

    Enteropathogenic Escherichia coli (EPEC) uses a type III secretion system (T3SS) to directly translocate effector proteins into host cells where they play a pivotal role in subverting host cell signaling needed for disease. However, our knowledge of how EPEC affects host protein phosphorylation is limited to a few individual protein studies. We employed a quantitative proteomics approach to globally map alterations in the host phosphoproteome during EPEC infection. By characterizing host phosphorylation events at various time points throughout infection, we examined how EPEC dynamically impacts the host phosphoproteome over time. This experimental setup also enabled identification of T3SS-dependent and -independent changes in host phosphorylation. Specifically, T3SS-regulated events affected various cellular processes that are known EPEC targets, including cytoskeletal organization, immune signaling, and intracellular trafficking. However, the involvement of phosphorylation in these events has thus far been poorly studied. We confirmed the MAPK family as an established key host player, showed its central role in signal transduction during EPEC infection, and extended the repertoire of known signaling hubs with previously unrecognized proteins, including TPD52, CIN85, EPHA2, and HSP27. We identified altered phosphorylation of known EPEC targets, such as cofilin, where the involvement of phosphorylation has so far been undefined, thus providing novel mechanistic insights into the roles of these proteins in EPEC infection. An overlap of regulated proteins, especially those that are cytoskeleton-associated, was observed when compared with the phosphoproteome of Shigella-infected cells. We determined the biological relevance of the phosphorylation of a novel protein in EPEC pathogenesis, septin-9 (SEPT9). Both siRNA knockdown and a phosphorylation-impaired SEPT9 mutant decreased bacterial adherence and EPEC-mediated cell death. In contrast, a phosphorylation

  11. Lean Hospital Approach to Identify Critical Waste in the Outpatient Pharmacy Instalation of RSI PKU Muhammadiyah Pekajangan

    Directory of Open Access Journals (Sweden)

    Lusi Rahmani Putri

    2017-07-01

    Full Text Available This Research Purpose to identify critical waste, root cause of critical waste, up to giving recommended improvement to minimize critical waste in the outpatient pharmacy. This research uses qualitative approach with case study design. The health service process is visualized with value stream mapping, the amount of critical waste is obtained by distributing questionnaires, while the root cause of critical waste is acquired by 5 why method of interview. The recommended improvementis accomplished by discussion between team and expert panel. Based on the value stream mapping, it has obtained 16,67% of ratio value added to waste for non concoction prescription and 14.52% of ratio value added to waste for concoction prescription. Based on waste questionnaire distribution, motion got the highest rank as the most often exist waste with 19% percentage. The root causes of this motion waste is nonexistence of a routine schedule on the work space organization, which affecting the effectiveness of pharmacy staff to complete their task. The recommended improvement to minimize this waste motion is to conduct 5S method.

  12. Comparative genomic analyses identify common molecular pathways modulated upon exposure to low doses of arsenic and cadmium

    Directory of Open Access Journals (Sweden)

    Fry Rebecca C

    2011-04-01

    Full Text Available Abstract Background Exposure to the toxic metals arsenic and cadmium is associated with detrimental health effects including cancers of various organs. While arsenic and cadmium are well known to cause adverse health effects at high doses, the molecular impact resulting from exposure to environmentally relevant doses of these metals remains largely unexplored. Results In this study, we examined the effects of in vitro exposure to either arsenic or cadmium in human TK6 lymphoblastoid cells using genomics and systems level pathway mapping approaches. A total of 167 genes with differential expression were identified following exposure to either metal with surprisingly no overlap between the two. Real-time PCR was used to confirm target gene expression changes. The gene sets were overlaid onto protein-protein interaction maps to identify metal-induced transcriptional networks. Interestingly, both metal-induced networks were significantly enriched for proteins involved in common biological processes such as tumorigenesis, inflammation, and cell signaling. These findings were further supported by gene set enrichment analysis. Conclusions This study is the first to compare the transcriptional responses induced by low dose exposure to cadmium and arsenic in human lymphoblastoid cells. These results highlight that even at low levels of exposure both metals can dramatically influence the expression of important cellular pathways.

  13. Identifying Likely Transmission Pathways within a 10-Year Community Outbreak of Tuberculosis by High-Depth Whole Genome Sequencing.

    Science.gov (United States)

    Outhred, Alexander C; Holmes, Nadine; Sadsad, Rosemarie; Martinez, Elena; Jelfs, Peter; Hill-Cawthorne, Grant A; Gilbert, Gwendolyn L; Marais, Ben J; Sintchenko, Vitali

    2016-01-01

    Improved tuberculosis control and the need to contain the spread of drug-resistant strains provide a strong rationale for exploring tuberculosis transmission dynamics at the population level. Whole-genome sequencing provides optimal strain resolution, facilitating detailed mapping of potential transmission pathways. We sequenced 22 isolates from a Mycobacterium tuberculosis cluster in New South Wales, Australia, identified during routine 24-locus mycobacterial interspersed repetitive unit typing. Following high-depth paired-end sequencing using the Illumina HiSeq 2000 platform, two independent pipelines were employed for analysis, both employing read mapping onto reference genomes as well as de novo assembly, to control biases in variant detection. In addition to single-nucleotide polymorphisms, the analyses also sought to identify insertions, deletions and structural variants. Isolates were highly similar, with a distance of 13 variants between the most distant members of the cluster. The most sensitive analysis classified the 22 isolates into 18 groups. Four of the isolates did not appear to share a recent common ancestor with the largest clade; another four isolates had an uncertain ancestral relationship with the largest clade. Whole genome sequencing, with analysis of single-nucleotide polymorphisms, insertions, deletions, structural variants and subpopulations, enabled the highest possible level of discrimination between cluster members, clarifying likely transmission pathways and exposing the complexity of strain origin. The analysis provides a basis for targeted public health intervention and enhanced classification of future isolates linked to the cluster.

  14. Identifying Likely Transmission Pathways within a 10-Year Community Outbreak of Tuberculosis by High-Depth Whole Genome Sequencing.

    Directory of Open Access Journals (Sweden)

    Alexander C Outhred

    Full Text Available Improved tuberculosis control and the need to contain the spread of drug-resistant strains provide a strong rationale for exploring tuberculosis transmission dynamics at the population level. Whole-genome sequencing provides optimal strain resolution, facilitating detailed mapping of potential transmission pathways.We sequenced 22 isolates from a Mycobacterium tuberculosis cluster in New South Wales, Australia, identified during routine 24-locus mycobacterial interspersed repetitive unit typing. Following high-depth paired-end sequencing using the Illumina HiSeq 2000 platform, two independent pipelines were employed for analysis, both employing read mapping onto reference genomes as well as de novo assembly, to control biases in variant detection. In addition to single-nucleotide polymorphisms, the analyses also sought to identify insertions, deletions and structural variants.Isolates were highly similar, with a distance of 13 variants between the most distant members of the cluster. The most sensitive analysis classified the 22 isolates into 18 groups. Four of the isolates did not appear to share a recent common ancestor with the largest clade; another four isolates had an uncertain ancestral relationship with the largest clade.Whole genome sequencing, with analysis of single-nucleotide polymorphisms, insertions, deletions, structural variants and subpopulations, enabled the highest possible level of discrimination between cluster members, clarifying likely transmission pathways and exposing the complexity of strain origin. The analysis provides a basis for targeted public health intervention and enhanced classification of future isolates linked to the cluster.

  15. Identifying the poor for premium exemption: a critical step towards universal health coverage in Sub-Saharan Africa.

    Science.gov (United States)

    Umeh, Chukwuemeka A

    2017-01-01

    Premium exemption for the poor is a critical step towards achieving universal health coverage in sub-Saharan Africa due to the large proportion of the population living in extreme poverty who cannot pay premium. However, identifying the poor for premium exemption has been a big challenge for SSA countries. This paper is a succinct review of four methods available for identifying the poor, outlining the ideal conditions under which each of the methods should be used and the drawbacks associated with using each of the methods.

  16. Frequently Identified Gaps in Antimicrobial Stewardship Programs in Critical Access Hospitals

    Science.gov (United States)

    Chung, Philip; Nailon, Regina; Tyner, Kate; Beach, Sue; Bergman, Scott; Drake, Margaret; Fitzgerald, Teresa; Lyden, Elizabeth; Rupp, Mark E; Schwedhelm, Michelle; Tierney, Maureen; Schooneveld, Trevor Van; Ashraf, Muhammad Salman

    2017-01-01

    Abstract Background Nebraska (NE) Infection Control Assessment and Promotion Program (ICAP) is a CDC funded project. ICAP team works in collaboration with NE Department of Health and Human Services (NEDHHS) to assess and improve infection prevention and control programs (IPCP) in various health care settings including resource limited settings like critical access hospitals (CAH). Little is known about the existing gaps in antimicrobial stewardship programs (ASP) of CAH. Hence, we decided to study the current level of ASP activities and factors associated with these activities in CAH. Methods NE ICAP conducted on-site surveys in 36 CAH from October 2015 to February 2017. ASP activities related to the 7 CDC recommended core elements (CE) including leadership support (LS), accountability, drug expertise (DE), action, tracking, reporting, and education were assessed using a CDC Infection Control Assessment Tool for acute care hospitals. Descriptive analyses evaluated CAH characteristics and frequency of CE implementation. Fisher’s exact, Mann–Whitney, and Kruskal–Wallis tests were used for statistical analyses examining the association of various factors with level of ASP activities. Results The 36 surveyed CAH had a median of 20 (range 10–25) beds and employed a median of 0.4 (range 0.1–1.6) infection preventionist (IP) full-time equivalent (FTE)/25-bed. Frequency of CE implementation varied among CAH with action and LS as the most (69%) and least (28%) frequently implemented elements, respectively. Close to half (47%) of surveyed CAH had implemented ≥4 CE but only 14% of facilities had all 7 CE. Median bed size and IP FTE/25-bed were similar among CAH with 0–2, 3-5, or ≥6 CE in place. CAH with LS or accountability for ASP implemented higher median numbers of the remaining CE compared with CAH without LS or accountability (5 vs. 2, P < 0.01 and 4 vs. 2, P < 0.01, respectively). Facilities with The presence of LS, accountability and drug expertise

  17. Critical research needs for identifying future changes in Gulf coral reef ecosystems

    Science.gov (United States)

    Feary, David A.; Burt, John A.; Bauman, Andrew G.; Al Hazeem, Shaker; Abdel-Moati, Mohamed A.; Al-Khalifa, Khalifa A.; Anderson, Donald M.; Amos, Carl; Baker, Andrew; Bartholomew, Aaron; Bento, Rita; Cavalcante, Geórgenes H.; Chen, Chaolun Allen; Coles, Steve L.; Dab, Koosha; Fowler, Ashley M.; George, David; Grandcourt, Edwin; Hill, Ross; John, David M.; Jones, David A.; Keshavmurthy, Shashank; Mahmoud, Huda; Moradi Och Tapeh, Mahdi; Mostafavi, Pargol Ghavam; Naser, Humood; Pichon, Michel; Purkis, Sam; Riegl, Bernhard; Samimi-Namin, Kaveh; Sheppard, Charles; Vajed Samiei, Jahangir; Voolstra, Christian R.; Wiedenmann, Joerg

    2014-01-01

    Expert opinion was assessed to identify current knowledge gaps in determining future changes in Arabian/ Persian Gulf (thereafter ‘Gulf’) coral reefs. Thirty-one participants submitted 71 research questions that were peer-assessed in terms of scientific importance (i.e., filled a knowledge gap and was a research priority) and efficiency in resource use (i.e., was highly feasible and ecologically broad). Ten research questions, in six major research areas, were highly important for both understanding Gulf coral reef ecosystems and also an efficient use of limited research resources. These questions mirrored global evaluations of the importance of understanding and evaluating biodiversity, determining the potential impacts of climate change, the role of anthropogenic impacts in structuring coral reef communities, and economically evaluating coral reef communities. These questions provide guidance for future research on coral reef ecosystems within the Gulf, and enhance the potential for assessment and management of future changes in this globally significant region. PMID:23643407

  18. Identifying the critical financial ratios for stocks evaluation: A fuzzy delphi approach

    Science.gov (United States)

    Mokhtar, Mazura; Shuib, Adibah; Mohamad, Daud

    2014-12-01

    Stocks evaluation has always been an interesting and challenging problem for both researchers and practitioners. Generally, the evaluation can be made based on a set of financial ratios. Nevertheless, there are a variety of financial ratios that can be considered and if all ratios in the set are placed into the evaluation process, data collection would be more difficult and time consuming. Thus, the objective of this paper is to identify the most important financial ratios upon which to focus in order to evaluate the stock's performance. For this purpose, a survey was carried out using an approach which is based on an expert judgement, namely the Fuzzy Delphi Method (FDM). The results of this study indicated that return on equity, return on assets, net profit margin, operating profit margin, earnings per share and debt to equity are the most important ratios.

  19. Critical research needs for identifying future changes in Gulf coral reef ecosystems

    KAUST Repository

    Feary, David A.

    2013-07-01

    Expert opinion was assessed to identify current knowledge gaps in determining future changes in Arabian/Persian Gulf (thereafter \\'Gulf\\') coral reefs. Thirty-one participants submitted 71 research questions that were peer-assessed in terms of scientific importance (i.e., filled a knowledge gap and was a research priority) and efficiency in resource use (i.e., was highly feasible and ecologically broad). Ten research questions, in six major research areas, were highly important for both understanding Gulf coral reef ecosystems and also an efficient use of limited research resources. These questions mirrored global evaluations of the importance of understanding and evaluating biodiversity, determining the potential impacts of climate change, the role of anthropogenic impacts in structuring coral reef communities, and economically evaluating coral reef communities. These questions provide guidance for future research on coral reef ecosystems within the Gulf, and enhance the potential for assessment and management of future changes in this globally significant region. © 2013 Elsevier Ltd.

  20. Disrupting the Pipeline: Critical Analyses of Student Pathways through Postsecondary STEM Education

    Science.gov (United States)

    Metcalf, Heather E.

    2014-01-01

    Critical mixed methods approaches allow us to reflect upon the ways in which we collect, measure, interpret, and analyze data, providing novel alternatives for quantitative analysis. For institutional researchers, whose work influences institutional policies, programs, and practices, the approach has the transformative ability to expose and create…

  1. Identifying medication error chains from critical incident reports: a new analytic approach.

    Science.gov (United States)

    Huckels-Baumgart, Saskia; Manser, Tanja

    2014-10-01

    Research into the distribution of medication errors usually focuses on isolated stages within the medication use process. Our study aimed to provide a novel process-oriented approach to medication incident analysis focusing on medication error chains. Our study was conducted across a 900-bed teaching hospital in Switzerland. All reported 1,591 medication errors 2009-2012 were categorized using the Medication Error Index NCC MERP and the WHO Classification for Patient Safety Methodology. In order to identify medication error chains, each reported medication incident was allocated to the relevant stage of the hospital medication use process. Only 25.8% of the reported medication errors were detected before they propagated through the medication use process. The majority of medication errors (74.2%) formed an error chain encompassing two or more stages. The most frequent error chain comprised preparation up to and including medication administration (45.2%). "Non-consideration of documentation/prescribing" during the drug preparation was the most frequent contributor for "wrong dose" during the administration of medication. Medication error chains provide important insights for detecting and stopping medication errors before they reach the patient. Existing and new safety barriers need to be extended to interrupt error chains and to improve patient safety. © 2014, The American College of Clinical Pharmacology.

  2. HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants.

    Directory of Open Access Journals (Sweden)

    Michael T Cheeseman

    2011-10-01

    Full Text Available Otitis media with effusion (OME is the commonest cause of hearing loss in children, yet the underlying genetic pathways and mechanisms involved are incompletely understood. Ventilation of the middle ear with tympanostomy tubes is the commonest surgical procedure in children and the best treatment for chronic OME, but the mechanism by which they work remains uncertain. As hypoxia is a common feature of inflamed microenvironments, moderation of hypoxia may be a significant contributory mechanism. We have investigated the occurrence of hypoxia and hypoxia-inducible factor (HIF mediated responses in Junbo and Jeff mouse mutant models, which develop spontaneous chronic otitis media. We found that Jeff and Junbo mice labeled in vivo with pimonidazole showed cellular hypoxia in inflammatory cells in the bulla lumen, and in Junbo the middle ear mucosa was also hypoxic. The bulla fluid inflammatory cell numbers were greater and the upregulation of inflammatory gene networks were more pronounced in Junbo than Jeff. Hif-1α gene expression was elevated in bulla fluid inflammatory cells, and there was upregulation of its target genes including Vegfa in Junbo and Jeff. We therefore investigated the effects in Junbo of small-molecule inhibitors of VEGFR signaling (PTK787, SU-11248, and BAY 43-9006 and destabilizing HIF by inhibiting its chaperone HSP90 with 17-DMAG. We found that both classes of inhibitor significantly reduced hearing loss and the occurrence of bulla fluid and that VEGFR inhibitors moderated angiogenesis and lymphangiogenesis in the inflamed middle ear mucosa. The effectiveness of HSP90 and VEGFR signaling inhibitors in suppressing OM in the Junbo model implicates HIF-mediated VEGF as playing a pivotal role in OM pathogenesis. Our analysis of the Junbo and Jeff mutants highlights the role of hypoxia and HIF-mediated pathways, and we conclude that targeting molecules in HIF-VEGF signaling pathways has therapeutic potential in the treatment of

  3. Transcriptomic analysis in a Drosophila model identifies previously implicated and novel pathways in the therapeutic mechanism in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Priyanka eSingh

    2011-03-01

    Full Text Available We have taken advantage of a newly described Drosophila model to gain insights into the potential mechanism of antiepileptic drugs (AEDs, a group of drugs that are widely used in the treatment of several neurological and psychiatric conditions besides epilepsy. In the recently described Drosophila model that is inspired by pentylenetetrazole (PTZ induced kindling epileptogenesis in rodents, chronic PTZ treatment for seven days causes a decreased climbing speed and an altered CNS transcriptome, with the latter mimicking gene expression alterations reported in epileptogenesis. In the model, an increased climbing speed is further observed seven days after withdrawal from chronic PTZ. We used this post-PTZ withdrawal regime to identify potential AED mechanism. In this regime, treatment with each of the five AEDs tested, namely, ethosuximide (ETH, gabapentin (GBP, vigabatrin (VGB, sodium valproate (NaVP and levetiracetam (LEV, resulted in rescuing of the altered climbing behavior. The AEDs also normalized PTZ withdrawal induced transcriptomic perturbation in fly heads; whereas AED untreated flies showed a large number of up- and down-regulated genes which were enriched in several processes including gene expression and cell communication, the AED treated flies showed differential expression of only a small number of genes that did not enrich gene expression and cell communication processes. Gene expression and cell communication related upregulated genes in AED untreated flies overrepresented several pathways - spliceosome, RNA degradation, and ribosome in the former category, and inositol phosphate metabolism, phosphatidylinositol signaling, endocytosis and hedgehog signaling in the latter. Transcriptome remodeling effect of AEDs was overall confirmed by microarray clustering that clearly separated the profiles of AED treated and untreated flies. Besides being consistent with previously implicated pathways, our results provide evidence for a role of

  4. Identifying Signalling Pathways Regulated by GPRC5B in β-Cells by CRISPR-Cas9-Mediated Genome Editing

    Directory of Open Access Journals (Sweden)

    Patricio Atanes

    2018-01-01

    Full Text Available Background/Aims: CRISPR-Cas9, a RNA-guided targeted genome editing tool, has revolutionized genetic engineering by offering the ability to precisely modify DNA. GPRC5B is an orphan receptor belonging to the group C family of G protein-coupled receptors (GPCRs. In this study, we analysed the functional roles of the Gprc5b receptor in MIN6 β-cells using CRISPR-Cas9 and transient over-expression of Gprc5b. Methods: The optimal transfection reagent for use in MIN6 β-cells was determined by analysing efficiency of GFP plasmid delivery by cell sorting. A MIN6 β-cell line in which Gprc5b expression was knocked down (Gprc5b KD was generated using CRISPR-Cas9 technology. Gprc5b receptor mRNA expression, proliferation, apoptosis, Cignal 45-Pathway Reporter Array signalling and western blot assays were carried out using Gpcr5b KD MIN6 β-cells that had been transiently transfected with different concentrations of mouse Gprc5b plasmid to over-express Gprc5b. Results: JetPRIME® was the best candidate for MIN6 β-cell transfection, providing approximately 30% transfection efficiency. CRISPR-Cas9 technology targeting Gprc5b led to stable knock-down of this receptor in MIN6 β-cells and its re-expression induced proliferation and potentiated cytokine- and palmitate-induced apoptosis. The Cignal 45 Reporter analysis indicated Gprc5b-dependent regulation of apoptotic and proliferative pathways, and western blotting confirmed activation of signalling via TGF-β and IFNγ. Conclusion: This study provides evidence of CRISPR-Cas9 technology being used to down-regulate Gprc5b expression in MIN6 β-cells. This strategy allowed us to identify signalling pathways linking GPRC5B receptor expression to β-cell proliferation and apoptosis.

  5. Inwardly Rectifying Potassium (Kir) Channels Represent a Critical Ion Conductance Pathway in the Nervous Systems of Insects.

    Science.gov (United States)

    Chen, Rui; Swale, Daniel R

    2018-01-25

    A complete understanding of the physiological pathways critical for proper function of the insect nervous system is still lacking. The recent development of potent and selective small-molecule modulators of insect inward rectifier potassium (Kir) channels has enabled the interrogation of the physiological role and toxicological potential of Kir channels within various insect tissue systems. Therefore, we aimed to highlight the physiological and functional role of neural Kir channels the central nervous system, muscular system, and neuromuscular system through pharmacological and genetic manipulations. Our data provide significant evidence that Drosophila neural systems rely on the inward conductance of K + ions for proper function since pharmacological inhibition and genetic ablation of neural Kir channels yielded dramatic alterations of the CNS spike discharge frequency and broadening and reduced amplitude of the evoked EPSP at the neuromuscular junction. Based on these data, we conclude that neural Kir channels in insects (1) are critical for proper function of the insect nervous system, (2) represents an unexplored physiological pathway that is likely to shape the understanding of neuronal signaling, maintenance of membrane potentials, and maintenance of the ionic balance of insects, and (3) are capable of inducing acute toxicity to insects through neurological poisoning.

  6. Investigating the Impact of Maternal Residential Mobility on Identifying Critical Windows of Susceptibility to Ambient Air Pollution During Pregnancy.

    Science.gov (United States)

    Warren, Joshua L; Son, Ji-Young; Pereira, Gavin; Leaderer, Brian P; Bell, Michelle L

    2017-10-19

    Identifying periods of increased vulnerability during pregnancy to air pollution with respect to the development of adverse birth outcomes can improve understanding of possible mechanisms of disease development and provide guidelines for protection of the child. Exposure to air pollution during pregnancy is typically based on the residence at delivery, potentially resulting in exposure misclassification and biasing the estimation of critical windows. In this work, we determine the impact of maternal residential mobility during pregnancy on defining weekly exposure to PM10 and the estimation of windows of susceptibility for term low birth weight utilizing birth cohort datasets from Connecticut (1988-2008) that include information on all residential addresses for each woman between conception and delivery. A simulation study is designed to investigate the impact of increasing levels of mobility on critical window identification. Increased PM10 exposure during pregnancy weeks 16-18 is associated with an increased probability of term low birth weight. Ignoring residential mobility when defining weekly exposure has only minor impact on the identification of critical windows for PM10 and term low birth weight in the data application and simulation study. Critical window identification is robust to exposure misclassification caused by ignoring residential mobility in these Connecticut birth cohorts. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Plant toxin β-ODAP activates integrin β1 and focal adhesion: A critical pathway to cause neurolathyrism.

    Science.gov (United States)

    Tan, Rui-Yue; Xing, Geng-Yan; Zhou, Guang-Ming; Li, Feng-Min; Hu, Wen-Tao; Lambein, Fernand; Xiong, Jun-Lan; Zhang, Sheng-Xiang; Kong, Hai-Yan; Zhu, Hao; Li, Zhi-Xiao; Xiong, You-Cai

    2017-01-17

    Neurolathyrism is a unique neurodegeneration disease caused by β-N-oxalyl-L-α, β- diaminopropionic (β-ODAP) present in grass pea seed (Lathyrus stativus L.) and its pathogenetic mechanism is unclear. This issue has become a critical restriction to take full advantage of drought-tolerant grass pea as an elite germplasm resource under climate change. We found that, in a human glioma cell line, β-ODAP treatment decreased mitochondrial membrane potential, leading to outside release and overfall of Ca 2+ from mitochondria to cellular matrix. Increased Ca 2+ in cellular matrix activated the pathway of ECM, and brought about the overexpression of β1 integrin on cytomembrane surface and the phosphorylation of focal adhesion kinase (FAK). The formation of high concentration of FA units on the cell microfilaments further induced overexpression of paxillin, and then inhibited cytoskeleton polymerization. This phenomenon turned to cause serious cell microfilaments distortion and ultimately cytoskeleton collapse. We also conducted qRT-PCR verification on RNA-sequence data using 8 randomly chosen genes of pathway enrichment, and confirmed that the data was statistically reliable. For the first time, we proposed a relatively complete signal pathway to neurolathyrism. This work would help open a new window to cure neurolathyrism, and fully utilize grass pea germplasm resource under climate change.

  8. Mutagenesis identifies the critical amino acid residues of human endonuclease G involved in catalysis, magnesium coordination, and substrate specificity

    Directory of Open Access Journals (Sweden)

    Wu Shih-Lu

    2009-01-01

    Full Text Available Abstract Background Endonuclease G (EndoG, a member of DNA/RNA nonspecific ββα-Me-finger nucleases, is involved in apoptosis and normal cellular proliferation. In this study, we analyzed the critical amino acid residues of EndoG and proposed the catalytic mechanism of EndoG. Methods To identify the critical amino acid residues of human EndoG, we replaced the conserved histidine, asparagine, and arginine residues with alanine. The catalytic efficacies of Escherichia coli-expressed EndoG variants were further analyzed by kinetic studies. Results Diethyl pyrocarbonate modification assay revealed that histidine residues were involved in EndoG activity. His-141, Asn-163, and Asn-172 in the H-N-H motif of EndoG were critical for catalysis and substrate specificity. H141A mutant required a higher magnesium concentration to achieve its activity, suggesting the unique role of His-141 in both catalysis and magnesium coordination. Furthermore, an additional catalytic residue (Asn-251 and an additional metal ion binding site (Glu-271 of human EndoG were identified. Conclusion Based on the mutational analysis and homology modeling, we proposed that human EndoG shared a similar catalytic mechanism with nuclease A from Anabaena.

  9. What makes the lac-pathway switch: identifying the fluctuations that trigger phenotype switching in gene regulatory systems.

    Science.gov (United States)

    Bhogale, Prasanna M; Sorg, Robin A; Veening, Jan-Willem; Berg, Johannes

    2014-10-01

    Multistable gene regulatory systems sustain different levels of gene expression under identical external conditions. Such multistability is used to encode phenotypic states in processes including nutrient uptake and persistence in bacteria, fate selection in viral infection, cell-cycle control and development. Stochastic switching between different phenotypes can occur as the result of random fluctuations in molecular copy numbers of mRNA and proteins arising in transcription, translation, transport and binding. However, which component of a pathway triggers such a transition is generally not known. By linking single-cell experiments on the lactose-uptake pathway in E. coli to molecular simulations, we devise a general method to pinpoint the particular fluctuation driving phenotype switching and apply this method to the transition between the uninduced and induced states of the lac-genes. We find that the transition to the induced state is not caused only by the single event of lac-repressor unbinding, but depends crucially on the time period over which the repressor remains unbound from the lac-operon. We confirm this notion in strains with a high expression level of the lac-repressor (leading to shorter periods over which the lac-operon remains unbound), which show a reduced switching rate. Our techniques apply to multistable gene regulatory systems in general and allow to identify the molecular mechanisms behind stochastic transitions in gene regulatory circuits. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. Identifying metabolic pathways for production of extracellular polymeric substances by the diatom Fragilariopsis cylindrus inhabiting sea ice.

    Science.gov (United States)

    Aslam, Shazia N; Strauss, Jan; Thomas, David N; Mock, Thomas; Underwood, Graham J C

    2018-05-01

    Diatoms are significant primary producers in sea ice, an ephemeral habitat with steep vertical gradients of temperature and salinity characterizing the ice matrix environment. To cope with the variable and challenging conditions, sea ice diatoms produce polysaccharide-rich extracellular polymeric substances (EPS) that play important roles in adhesion, cell protection, ligand binding and as organic carbon sources. Significant differences in EPS concentrations and chemical composition corresponding to temperature and salinity gradients were present in sea ice from the Weddell Sea and Eastern Antarctic regions of the Southern Ocean. To reconstruct the first metabolic pathway for EPS production in diatoms, we exposed Fragilariopsis cylindrus, a key bi-polar diatom species, to simulated sea ice formation. Transcriptome profiling under varying conditions of EPS production identified a significant number of genes and divergent alleles. Their complex differential expression patterns under simulated sea ice formation was aligned with physiological and biochemical properties of the cells, and with field measurements of sea ice EPS characteristics. Thus, the molecular complexity of the EPS pathway suggests metabolic plasticity in F. cylindrus is required to cope with the challenging conditions of the highly variable and extreme sea ice habitat.

  11. Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease.

    Science.gov (United States)

    Viereckel, Thomas; Dumas, Sylvie; Smith-Anttila, Casey J A; Vlcek, Bianca; Bimpisidis, Zisis; Lagerström, Malin C; Konradsson-Geuken, Åsa; Wallén-Mackenzie, Åsa

    2016-10-20

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders.

  12. Ectopic Pregnancy as a Model to Identify Endometrial Genes and Signaling Pathways Important in Decidualization and Regulated by Local Trophoblast

    Science.gov (United States)

    Burgess, Stewart; McDonald, Sarah E.; Critchley, Hilary O. D.; Horne, Andrew W.

    2011-01-01

    The endometrium in early pregnancy undergoes decidualization and functional changes induced by local trophoblast, which are not fully understood. We hypothesized that endometrium from tubal ectopic pregnancy (EP) could be interrogated to identify novel genes and pathways involved in these processes. Gestation-matched endometrium was collected from women with EP (n = 11) and intrauterine pregnancies (IUP) (n = 13). RNA was extracted from the tissue. In addition, tissues were prepared for histological analysis for degree of decidualization. We compared a) the samples from EP that were decidualized (n = 6) with non-decidualized samples (n = 5), and b) the decidualized EP (n = 6) with decidualization-matched IUP (n = 6) samples using an Affymetrix gene array platform, with Ingenuity Pathway Analysis, combined with quantitative RT-PCR. Expression of PRL and IGFBP1 was used to confirm the degree of decidualization in each group. There were no differences in PRL or IGFBP1 expression in the decidualization-matched samples but a marked reduction (Ppregnancy. PMID:21858178

  13. Integrative analysis of hepatic microRNA and mRNA to identify potential biological pathways associated with monocrotaline-induced liver injury in mice.

    Science.gov (United States)

    Huang, Zhenlin; Chen, Minwei; Zhang, Jiaqi; Sheng, Yuchen; Ji, Lili

    2017-10-15

    Pyrrolizidine alkaloids (PAs) are a type of natural hepatotoxic compounds. Monocrotaline (MCT), belongs to PAs, is a main compound distributed in medicinal herb Crotalaria ferruginea Grah. ex Benth. This study aims to identify the potential biological signaling pathway associated with MCT-induced liver injury by analyzing the integrative altered hepatic microRNA (miRNA) and mRNA expression profile. C57BL/6 mice were orally given with MCT (270, 330mg/kg). Serum alanine/aspartate aminotransferase (ALT/AST) activity, total bilirubin (TBil) amount and liver histological evaluation showed the liver injury induced by MCT. Results of miRNA chip analysis showed that the hepatic expression of 15 miRNAs (whose signal intensity>200) was significantly altered in MCT-treated mice, and among them total 11 miRNAs passed further validation by using Real-time PCR assay. Results of mRNA chip analysis demonstrated that the hepatic expression of 569 genes was up-regulated and of other 417 genes was down-regulated in MCT-treated mice. There are total 426 predicted target genes of those above altered 11 miRNAs, and among them total 10 genes were also altered in mice treated with both MCT (270mg/kg) and MCT (330mg/kg) from the results of mRNA chip. Among these above 10 genes, total 8 genes passed further validation by using Real-time PCR assay. Only 1 biological signaling pathway was annotated by using those above 8 genes, which is phagosome. In conclusion, this study demonstrated the integrative altered expression profile of liver miRNA and mRNA, and identified that innate immunity may be critically involved in MCT-induced liver injury in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Expression patterns of genes critical for BMP signaling pathway in developing human primary tooth germs.

    Science.gov (United States)

    Dong, Xiuqing; Shen, Bin; Ruan, Ningsheng; Guan, Zhen; Zhang, Yanding; Chen, YiPing; Hu, Xuefeng

    2014-12-01

    The developing murine tooth has been used as an excellent model system to study the molecular mechanism of organ development and regeneration. While the expression patterns of numerous regulatory genes have been examined and their roles have begun to be revealed in the developing murine tooth, little is known about gene expression and function in human tooth development. In order to unveil the molecular mechanisms that regulate human tooth morphogenesis, we examined the expression patterns of the major BMP signaling pathway molecules in the developing human tooth germ at the cap and bell stages by in situ hybridization, immunohistochemistry, and real-time RT-PCR. Expression of BMP ligands and antagonist, including BMP2, BMP3, BMP4, BMP7, and NOOGGIN, exhibited uniform patterns in the tooth germs of incisor and molar at the cap and bell stages with stronger expression in the inner dental epithelium than that in the dental mesenchyme. Both type I and type II BMP receptors were present in widespread expression pattern in the whole-enamel organ and the dental mesenchyme with the strongest expression in inner dental epithelium at the cap and bell stages. SMAD4 and SMAD1/5/8 showed an expression pattern similar to that of BMP ligands with more intensive signals in the inner dental epithelium. Despite some unique and distinct patterns as compared to the mouse, the intensive expression of BMP signaling pathway molecules in the developing human tooth strongly suggests conserved functions of BMP signaling during human odontogenesis, such as in mediating tissue interactions and regulating differentiation and organization of odontogenic tissues. Our results provide an important set of documents for studying molecular regulatory mechanisms underlying tooth development and regeneration in humans.

  15. Flow pathways in the evolving critical zone - insights from hydraulic groundwater theory

    Science.gov (United States)

    Harman, C. J.; Cosans, C.; Kim, M.

    2017-12-01

    The geochemical signatures of the evolving critical zone are delivered into streams via saturated lateral flow through hillslopes. Here we will draw on hydraulic groundwater theory and scaling arguments to obtain insights into the first-order controls on the transition from vertical infiltration to lateral flow in the critical zone. Hydraulic groundwater theory aims to provide a simplified description of unconfined, saturated groundwater flow in systems that are substantially larger in lateral than vertical extent. The theory rests on the Dupuit assumptions, which are often erroneously stated as including an assumption of exclusively lateral flow. In fact the full three-dimensional flow field can be approximated from these assumptions. Building on this theory, we examine how overall hillslope structure (slope, permeability, convergence/divergence etc.) determines the direction and magnitude of flow in the vicinity of weathering fronts in the critical zone, and how weathering products are delivered to the hillslope base. The results demonstrate that under certain conditions the mere presence of lateral flow will not disturb the lateral symmetry of reaction fronts along the hillslope. Furthermore, coupling to a simple reaction model with porosity/permeability feedback allows us to examine the implications for weathering front advance where saturated lateral flow occurs as a transient perched aquifer at the weathering front. The overall rate of weathering front advance is found to be primarily determined by the component of flow normal to the weathering front, and only significantly accelerated by the lateral component above the weathering front when parent rock permeability is very low.

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

    Energy Technology Data Exchange (ETDEWEB)

    Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana; Mennecozzi, Milena [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Accordi, Benedetta; Basso, Giuseppe [Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova (Italy); Gaspar, John Antonydas [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Zagoura, Dimitra; Barilari, Manuela; Palosaari, Taina [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Sachinidis, Agapios [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Bremer-Hoffmann, Susanne, E-mail: susanne.bremer@jrc.ec.europa.eu [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy)

    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.

  17. Critical mid-term uncertainties in long-term decarbonisation pathways

    International Nuclear Information System (INIS)

    Usher, Will; Strachan, Neil

    2012-01-01

    Over the next decade, large energy investments are required in the UK to meet growing energy service demands and legally binding emission targets under a pioneering policy agenda. These are necessary despite deep mid-term (2025–2030) uncertainties over which national policy makers have little control. We investigate the effect of two critical mid-term uncertainties on optimal near-term investment decisions using a two-stage stochastic energy system model. The results show that where future fossil fuel prices are uncertain: (i) the near term hedging strategy to 2030 differs from any one deterministic fuel price scenario and is structurally dissimilar to a simple ‘average’ of the deterministic scenarios, and (ii) multiple recourse strategies from 2030 are perturbed by path dependencies caused by hedging investments. Evaluating the uncertainty under a decarbonisation agenda shows that fossil fuel price uncertainty is very expensive at around £20 billion. The addition of novel mitigation options reduces the value of fossil fuel price uncertainty to £11 billion. Uncertain biomass import availability shows a much lower value of uncertainty at £300 million. This paper reveals the complex relationship between the flexibility of the energy system and mitigating the costs of uncertainty due to the path-dependencies caused by the long-life times of both infrastructures and generation technologies. - Highlights: ► Critical mid-term uncertainties affect near-term investments in UK energy system. ► Deterministic scenarios give conflicting near-term actions. ► Stochastic scenarios give one near-term hedging strategy. ► Technologies exhibit path dependency or flexibility. ► Fossil fuel price uncertainty is very expensive, biomass availability uncertainty is not.

  18. Evaluation of an inpatient fall risk screening tool to identify the most critical fall risk factors in inpatients.

    Science.gov (United States)

    Hou, Wen-Hsuan; Kang, Chun-Mei; Ho, Mu-Hsing; Kuo, Jessie Ming-Chuan; Chen, Hsiao-Lien; Chang, Wen-Yin

    2017-03-01

    To evaluate the accuracy of the inpatient fall risk screening tool and to identify the most critical fall risk factors in inpatients. Variations exist in several screening tools applied in acute care hospitals for examining risk factors for falls and identifying high-risk inpatients. Secondary data analysis. A subset of inpatient data for the period from June 2011-June 2014 was extracted from the nursing information system and adverse event reporting system of an 818-bed teaching medical centre in Taipei. Data were analysed using descriptive statistics, receiver operating characteristic curve analysis and logistic regression analysis. During the study period, 205 fallers and 37,232 nonfallers were identified. The results revealed that the inpatient fall risk screening tool (cut-off point of ≥3) had a low sensitivity level (60%), satisfactory specificity (87%), a positive predictive value of 2·0% and a negative predictive value of 99%. The receiver operating characteristic curve analysis revealed an area under the curve of 0·805 (sensitivity, 71·8%; specificity, 78%). To increase the sensitivity values, the Youden index suggests at least 1·5 points to be the most suitable cut-off point for the inpatient fall risk screening tool. Multivariate logistic regression analysis revealed a considerably increased fall risk in patients with impaired balance and impaired elimination. The fall risk factor was also significantly associated with days of hospital stay and with admission to surgical wards. The findings can raise awareness about the two most critical risk factors for falls among future clinical nurses and other healthcare professionals and thus facilitate the development of fall prevention interventions. This study highlights the needs for redefining the cut-off points of the inpatient fall risk screening tool to effectively identify inpatients at a high risk of falls. Furthermore, inpatients with impaired balance and impaired elimination should be closely

  19. MelanomaDB: a Web Tool for Integrative Analysis of Melanoma Genomic Information to Identify Disease-Associated Molecular Pathways

    Directory of Open Access Journals (Sweden)

    Alexander Joseph Trevarton

    2013-07-01

    Full Text Available Despite on-going research, metastatic melanoma survival rates remain low and treatment options are limited. Researchers can now access a rapidly growing amount of molecular and clinical information about melanoma. This information is becoming difficult to assemble and interpret due to its dispersed nature, yet as it grows it becomes increasingly valuable for understanding melanoma. Integration of this information into a comprehensive resource to aid rational experimental design and patient stratification is needed. As an initial step in this direction, we have assembled a web-accessible melanoma database, MelanomaDB, which incorporates clinical and molecular data from publically available sources, which will be regularly updated as new information becomes available. This database allows complex links to be drawn between many different aspects of melanoma biology: genetic changes (e.g. mutations in individual melanomas revealed by DNA sequencing, associations between gene expression and patient survival, data concerning drug targets, biomarkers, druggability and clinical trials, as well as our own statistical analysis of relationships between molecular pathways and clinical parameters that have been produced using these data sets. The database is freely available at http://genesetdb.auckland.ac.nz/melanomadb/about.html . A subset of the information in the database can also be accessed through a freely available web application in the Illumina genomic cloud computing platform BaseSpace at http://www.biomatters.com/apps/melanoma-profiler-for-research . This illustrates dysregulation of specific signalling pathways, both across 310 exome-sequenced melanomas and in individual tumours and identifies novel features about the distribution of somatic variants in melanoma. We suggest that this database can provide a context in which to interpret the tumour molecular profiles of individual melanoma patients relative to biological information and available

  20. Development and implementation of a critical pathway for prevention of adverse reactions to contrast media for computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Keun Jo [Presbyterian Medical Center, Seoul (Korea, Republic of); Kweon, Dae Cheol; Kim, Myeong Goo [Seoul National University Hospital, Seoul (Korea, Republic of); Yoo, Beong Gyu [Wonkwang Health Science College, Iksan (Korea, Republic of)

    2007-03-15

    The purpose of this study is to develop a critical pathway (CP) for the prevention of adverse reactions to contrast media for computed tomography. The CP was developed and implemented by a multidisciplinary group is Seoul National University Hospital. The CP was applied to CT patients. Patients who underwent CT scanning were included in the CP group from March in 2004. The satisfaction of the patients with CP was compared with non-CP groups. We also investigated the degree of satisfaction among the radiological technologists and nurses. The degree of patient satisfaction with the care process increased patient information (24%), prevention of adverse reactions to contrast media (19%), pre-cognitive effect of adverse reactions to contrast media (39%) and information degree of adverse reactions to contrast media (19%). This CP program can be used as one of the patient care tools for reducing the adverse reactions to contrast media and increasing the efficiency of care process in CT examination settings.

  1. Development and implementation of a critical pathway for prevention of adverse reactions to contrast media for computed tomography

    International Nuclear Information System (INIS)

    Jang, Keun Jo; Kweon, Dae Cheol; Kim, Myeong Goo; Yoo, Beong Gyu

    2007-01-01

    The purpose of this study is to develop a critical pathway (CP) for the prevention of adverse reactions to contrast media for computed tomography. The CP was developed and implemented by a multidisciplinary group is Seoul National University Hospital. The CP was applied to CT patients. Patients who underwent CT scanning were included in the CP group from March in 2004. The satisfaction of the patients with CP was compared with non-CP groups. We also investigated the degree of satisfaction among the radiological technologists and nurses. The degree of patient satisfaction with the care process increased patient information (24%), prevention of adverse reactions to contrast media (19%), pre-cognitive effect of adverse reactions to contrast media (39%) and information degree of adverse reactions to contrast media (19%). This CP program can be used as one of the patient care tools for reducing the adverse reactions to contrast media and increasing the efficiency of care process in CT examination settings

  2. Barriers, pathways and processes for uptake, translocation and accumulation of nanomaterials in plants--Critical review.

    Science.gov (United States)

    Schwab, Fabienne; Zhai, Guangshu; Kern, Meaghan; Turner, Amalia; Schnoor, Jerald L; Wiesner, Mark R

    2016-01-01

    Uptake, transport and toxicity of engineered nanomaterials (ENMs) into plant cells are complex processes that are currently still not well understood. Parts of this problem are the multifaceted plant anatomy, and analytical challenges to visualize and quantify ENMs in plants. We critically reviewed the currently known ENM uptake, translocation, and accumulation processes in plants. A vast number of studies showed uptake, clogging, or translocation in the apoplast of plants, most notably of nanoparticles with diameters much larger than the commonly assumed size exclusion limit of the cell walls of ∼5-20 nm. Plants that tended to translocate less ENMs were those with low transpiration, drought-tolerance, tough cell wall architecture, and tall growth. In the absence of toxicity, accumulation was often linearly proportional to exposure concentration. Further important factors strongly affecting ENM internalization are the cell wall composition, mucilage, symbiotic microorganisms (mycorrhiza), the absence of a cuticle (submerged plants) and stomata aperture. Mostly unexplored are the roles of root hairs, leaf repellency, pit membrane porosity, xylem segmentation, wounding, lateral roots, nodes, the Casparian band, hydathodes, lenticels and trichomes. The next steps towards a realistic risk assessment of nanoparticles in plants are to measure ENM uptake rates, the size exclusion limit of the apoplast and to unravel plant physiological features favoring uptake.

  3. Reduction in diabetic amputations over 15 years in a defined Spain population. Benefits of a critical pathway approach and multidisciplinary team work.

    Science.gov (United States)

    Martínez-Gómez, D A; Moreno-Carrillo, M A; Campillo-Soto, A; Carrillo-García, A; Aguayo-Albasini, J L

    2014-09-01

    To assess changes in diabetic lower-extremity amputations (LEA) rates in a defined population over a 15-year period, following a multidisciplinary approach including a critical pathway in an inpatient setting with standardized preoperative and postoperative care, as well as in an outpatient setting through the establishment of a diabetic foot clinic. This is a study of the incidence and types of LEAs performed in patients with diabetic foot disease complicated admitted to Morales Meseguer Hospital (Murcia, Spain), a large district general hospital, before (1998-2000) and after (2001-2012) of the introduction of better organized diabetes foot care. Hospital and clinic characteristics to the success of the programme are described. All cases of LEA in diabetic patients (1998-2012) within the area were identified by ICD-9-Clinical modification (CM) diagnostic codes. A chi square test was used to compare the frequency and level of amputations. Over all inpatients with diabetes admitted with foot infections and gangrene, there was a significant decrease in the proportion of total major amputations (47%) and elective major amputations (66%) (p<0.001). The incidence of total major amputations rates per 100.000 of the general population fell with statistical significance (p=0.009). The biggest improvement in LEA incidence was seen in the reduction of major elective amputation with fell 60%, from 7.6 to 3.1 per 100,000 (p<0.001). Significant reductions in total and major amputations rates occurred over the 15-year period following improvements in foot care services included multidisciplinary teamwork (critical pathway and diabetic foot clinic).

  4. Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.

    Science.gov (United States)

    Novak, Rachel L; Harper, David P; Caudell, David; Slape, Christopher; Beachy, Sarah H; Aplan, Peter D

    2012-12-01

    NUP98-HOXD13 (NHD13) and CALM-AF10 (CA10) are oncogenic fusion proteins produced by recurrent chromosomal translocations in patients with acute myeloid leukemia (AML). Transgenic mice that express these fusions develop AML with a long latency and incomplete penetrance, suggesting that collaborating genetic events are required for leukemic transformation. We employed genetic techniques to identify both preleukemic abnormalities in healthy transgenic mice as well as collaborating events leading to leukemic transformation. Candidate gene resequencing revealed that 6 of 27 (22%) CA10 AMLs spontaneously acquired a Ras pathway mutation and 8 of 27 (30%) acquired an Flt3 mutation. Two CA10 AMLs acquired an Flt3 internal-tandem duplication, demonstrating that these mutations can be acquired in murine as well as human AML. Gene expression profiles revealed a marked upregulation of Hox genes, particularly Hoxa5, Hoxa9, and Hoxa10 in both NHD13 and CA10 mice. Furthermore, mir196b, which is embedded within the Hoxa locus, was overexpressed in both CA10 and NHD13 samples. In contrast, the Hox cofactors Meis1 and Pbx3 were differentially expressed; Meis1 was increased in CA10 AMLs but not NHD13 AMLs, whereas Pbx3 was consistently increased in NHD13 but not CA10 AMLs. Silencing of Pbx3 in NHD13 cells led to decreased proliferation, increased apoptosis, and decreased colony formation in vitro, suggesting a previously unexpected role for Pbx3 in leukemic transformation. Published by Elsevier Inc.

  5. Identifying early pathways of risk and resilience: The codevelopment of internalizing and externalizing symptoms and the role of harsh parenting.

    Science.gov (United States)

    Wiggins, Jillian Lee; Mitchell, Colter; Hyde, Luke W; Monk, Christopher S

    2015-11-01

    Psychological disorders co-occur often in children, but little has been done to document the types of conjoint pathways internalizing and externalizing symptoms may take from the crucial early period of toddlerhood or how harsh parenting may overlap with early symptom codevelopment. To examine symptom codevelopment trajectories, we identified latent classes of individuals based on internalizing and externalizing symptoms across ages 3-9 and found three symptom codevelopment classes: normative symptoms (low), severe-decreasing symptoms (initially high but rapidly declining), and severe symptoms (high) trajectories. Next, joint models examined how parenting trajectories overlapped with internalizing and externalizing symptom trajectories. These trajectory classes demonstrated that, normatively, harsh parenting increased after toddlerhood, but the severe symptoms class was characterized by a higher level and a steeper increase in harsh parenting and the severe-decreasing class by high, stable harsh parenting. In addition, a transactional model examined the bidirectional relationships among internalizing and externalizing symptoms and harsh parenting because they may cascade over time in this early period. Harsh parenting uniquely contributed to externalizing symptoms, controlling for internalizing symptoms, but not vice versa. In addition, internalizing symptoms appeared to be a mechanism by which externalizing symptoms increase. Results highlight the importance of accounting for both internalizing and externalizing symptoms from an early age to understand risk for developing psychopathology and the role harsh parenting plays in influencing these trajectories.

  6. Comparative genomic analysis of Lactobacillus mucosae LM1 identifies potential niche-specific genes and pathways for gastrointestinal adaptation.

    Science.gov (United States)

    Valeriano, Valerie Diane V; Oh, Ju Kyoung; Bagon, Bernadette B; Kim, Heebal; Kang, Dae-Kyung

    2017-12-23

    Lactobacillus mucosae is currently of interest as putative probiotics due to their metabolic capabilities and ability to colonize host mucosal niches. L. mucosae LM1 has been studied in its functions in cell adhesion and pathogen inhibition, etc. It demonstrated unique abilities to use energy from carbohydrate and non-carbohydrate sources. Due to these functions, we report the first complete genome sequence of an L. mucosae strain, L. mucosae LM1. Analysis of the pan-genome in comparison with closely-related Lactobacillus species identified a complete glycogen metabolism pathway, as well as folate biosynthesis, complementing previous proteomic data on the LM1 strain. It also revealed common and unique niche-adaptation genes among the various L. mucosae strains. The aim of this study was to derive genomic information that would reveal the probable mechanisms underlying the probiotic effect of L. mucosae LM1, and provide a better understanding of the nature of L. mucosae sp. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Quantitative Proteomic Analyses Identify ABA-related Proteins and Signal Pathways in Maize Leaves Under Drought Conditions

    Directory of Open Access Journals (Sweden)

    zhao Yulong

    2016-12-01

    Full Text Available Drought stress is one of major factors resulting in maize yield loss. The roles of abscisic acid (ABA have been widely studied in crops in response to drought stress. However, more attention is needed to identify key ABA-related proteins and also gain deeper molecular insights about drought stress in maize. Based on this need, the physiology and proteomics of the ABA-deficient maize mutant vp5 and its wild-type Vp5 under drought stress were examined and analyzed. Malondialdehyde content increased and quantum efficiency of photosystem II decreased under drought stress in both genotypes. However, the magnitude of the increase or decrease was significantly higher in vp5 than in Vp5. A total of 7051 proteins with overlapping expression patterns among three replicates in the two genotypes were identified by Multiplex run iTRAQ-based quantitative proteomic and liquid chromatography-tandem mass spectrometry methods, of which the expression of only 150 proteins (130 in Vp5, 27 in vp5 showed changes of at least 1.5-fold under drought stress. Among the 150 proteins, 67 and 60 proteins were up-regulated and down-regulated by drought stress in an ABA-dependent way, respectively. ABA was found to play active roles in regulating signaling pathways related to photosynthesis, oxidative phosphorylation (mainly related to ATP synthesis, and glutathione metabolism (involved in antioxidative reaction in the maize response to drought stress. Our results provide an extensive dataset of ABA-dependent, drought-regulated proteins in maize plants, which may help to elucidate the underlying mechanisms of ABA-enhanced tolerance to drought stress in maize.

  8. Transcriptional Analysis of Murine Macrophages Infected with Different Toxoplasma Strains Identifies Novel Regulation of Host Signaling Pathways

    Science.gov (United States)

    Melo, Mariane B.; Nguyen, Quynh P.; Cordeiro, Cynthia; Hassan, Musa A.; Yang, Ninghan; McKell, Renée; Rosowski, Emily E.; Julien, Lindsay; Butty, Vincent; Dardé, Marie-Laure; Ajzenberg, Daniel; Fitzgerald, Katherine; Young, Lucy H.; Saeij, Jeroen P. J.

    2013-01-01

    Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts. PMID:24367253

  9. Spatial-temporal modeling of the association between air pollution exposure and preterm birth: identifying critical windows of exposure.

    Science.gov (United States)

    Warren, Joshua; Fuentes, Montserrat; Herring, Amy; Langlois, Peter

    2012-12-01

    Exposure to high levels of air pollution during the pregnancy is associated with increased probability of preterm birth (PTB), a major cause of infant morbidity and mortality. New statistical methodology is required to specifically determine when a particular pollutant impacts the PTB outcome, to determine the role of different pollutants, and to characterize the spatial variability in these results. We develop a new Bayesian spatial model for PTB which identifies susceptible windows throughout the pregnancy jointly for multiple pollutants (PM(2.5) , ozone) while allowing these windows to vary continuously across space and time. We geo-code vital record birth data from Texas (2002-2004) and link them with standard pollution monitoring data and a newly introduced EPA product of calibrated air pollution model output. We apply the fully spatial model to a region of 13 counties in eastern Texas consisting of highly urban as well as rural areas. Our results indicate significant signal in the first two trimesters of pregnancy with different pollutants leading to different critical windows. Introducing the spatial aspect uncovers critical windows previously unidentified when space is ignored. A proper inference procedure is introduced to correctly analyze these windows. © 2012, The International Biometric Society.

  10. Identifying critical success factors (CSFs) of Facilities Management (FM) in non-low cost high-rise residential buildings

    Science.gov (United States)

    Dahlan, F. M.; Zainuddin, A.

    2018-02-01

    Critical success factors (CSFs) are important key areas of activity that must be performed well in any Facilities Management (FM) organisation to achieve its missions, objectives or goals. Before implementing CSFs, an FM organisation must identify the key areas where things must be done properly to enable the business to flourish. Although many performance measurements in FM organisation have been discussed in previous research, not much research has been done on CSFs from the perspective of FM business in non-low cost high-rise residential buildings. The purpose of this study is to develop a methodology in developing the CSFs group and CSFs for FM organisation in non-low cost residential buildings. This research will involve three (3) phases of research strategy to achieve the objective of this research.

  11. Gene Expression Analysis before and after Treatment with Adalimumab in Patients with Ankylosing Spondylitis Identifies Molecular Pathways Associated with Response to Therapy

    OpenAIRE

    Dolcino, Marzia; Tinazzi, Elisa; Pelosi, Andrea; Patuzzo, Giuseppe; Moretta, Francesca; Lunardi, Claudio; Puccetti, Antonio

    2017-01-01

    The etiology of Ankylosing spondylitis (AS) is still unknown and the identification of the involved molecular pathogenetic pathways is a current challenge in the study of the disease. Adalimumab (ADA), an anti-tumor necrosis factor (TNF)-alpha agent, is used in the treatment of AS. We aimed at identifying pathogenetic pathways modified by ADA in patients with a good response to the treatment. Gene expression analysis of Peripheral Blood Cells (PBC) from six responders and four not responder p...

  12. Selection of personalized patient therapy through the use of knowledge-based computational models that identify tumor-driving signal transduction pathways.

    Science.gov (United States)

    Verhaegh, Wim; van Ooijen, Henk; Inda, Márcia A; Hatzis, Pantelis; Versteeg, Rogier; Smid, Marcel; Martens, John; Foekens, John; van de Wiel, Paul; Clevers, Hans; van de Stolpe, Anja

    2014-06-01

    Increasing knowledge about signal transduction pathways as drivers of cancer growth has elicited the development of "targeted drugs," which inhibit aberrant signaling pathways. They require a companion diagnostic test that identifies the tumor-driving pathway; however, currently available tests like estrogen receptor (ER) protein expression for hormonal treatment of breast cancer do not reliably predict therapy response, at least in part because they do not adequately assess functional pathway activity. We describe a novel approach to predict signaling pathway activity based on knowledge-based Bayesian computational models, which interpret quantitative transcriptome data as the functional output of an active signaling pathway, by using expression levels of transcriptional target genes. Following calibration on only a small number of cell lines or cohorts of patient data, they provide a reliable assessment of signaling pathway activity in tumors of different tissue origin. As proof of principle, models for the canonical Wnt and ER pathways are presented, including initial clinical validation on independent datasets from various cancer types. ©2014 American Association for Cancer Research.

  13. RADAR study: protocol for an observational cohort study to identify early warning signals on the pathways to alcohol use disorder.

    Science.gov (United States)

    Slade, Tim; Swift, Wendy; Mewton, Louise; Kypri, Kypros; Lynskey, Michael T; Butterworth, Peter; Tibbetts, Joel; McCraw, Stacey; Upton, Emily

    2017-08-21

    Harmful alcohol consumption, particularly alcohol use disorder (AUD), is a worldwide health priority, contributing substantially to global morbidity and mortality. The peak age of onset of AUD is 18-24, thus a deeper understanding of the young adult experience is vital if we are to identify modifiable risk factors and intervene early in the developmental course of this disabling disorder. Critical unanswered questions include: How soon after drinking initiation do AUD symptoms begin to emerge? Which symptoms come first? Do the symptoms unfold in a predictable pattern? In what ways do the emerging symptoms interact with individual, peer, family and environmental risk factors to impact on the transition to disorder? The proposed RADAR study will examine the prospective development of AUD symptoms over the young adulthood (18-24) years. We will capitalise on an existing cohort of 1911 community-based adolescents who were recruited at age 13 and have completed a baseline and five annual follow-up assessments as part of an observational cohort study. We will interview these adolescents every 6 months between the ages of 19 and 23 to derive monthly histories of both alcohol use and AUD symptomatology, along with a comprehensive battery of risk and protective factor scales hypothesised to predict the emergence and course of AUD. The results of this study will inform the natural history of AUD and will be used to identify specific targets for prevention and early intervention of AUD. Ethical approval has already been granted for the study (UNSW HREC 10144). We will disseminate the results of the study through published manuscripts, conferences and seminar presentations. Data used in published manuscripts will be made available through a suitable online repository (eg, Dryad-datadryad.org). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly

  14. Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma.

    Science.gov (United States)

    Hass, Holger G; Vogel, Ulrich; Scheurlen, Michael; Jobst, Jürgen

    2016-10-01

    Hepatocellular carcinoma comprises of a group of heterogeneous tumors of different etiologies. The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. The molecular pathways and driver mutations involved are still under investigation. DNA micorarray technology was used to identify differentially expressed genes between human hepatocarcinoma and non-tumorous liver tissues to establish a unique specific gene-expression profile independent of the underlying liver disease. The validity of this global gene-expression profile was tested for its robustness against biopsies from other liver entities (cirrhotic and non-cirrhotic liver) by diagnosing HCC in blinded samples. Most of the consistently and strongly overexpressed genes were related to cell-cycle regulation and DNA replication [27 genes, e.g. cyclin B1, karyopherin alpha 2 (KPNA2), cyclin-dependent kinase 2 (CDC2)], G-protein depending signaling [e.g. Rac GTPase activating protein 1 (RACGAP1), Rab GTPase YPT1 homolog (RAB1), and ADP-ribosylation factor-like 2 (ARL2)] and extracellular matrix re-modelling or cytoskeleton structure [22 genes, e.g. serine proteinase inhibitor 1 kazal-type (SPINK1), osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), collagen type 1 alpha2 (COL1A2), integrin alpha6 (ITGA6), and metalloproteinase 12 (MMP12)]. Furthermore, significantly differentially expressed genes (e.g. calcium-binding proteins, G-proteins, oncofetal proteins) in relation to tumor differentiation were detected using gene-expression analysis. It is suggested that these significantly dysregulated genes are highly specific and potentially utilizable as prognostic markers and may lead to a better understanding of human hepatocarcinogenesis. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. A data mining approach for identifying pathway-gene biomarkers for predicting clinical outcome: A case study of erlotinib and sorafenib.

    Directory of Open Access Journals (Sweden)

    David G Covell

    Full Text Available A novel data mining procedure is proposed for identifying potential pathway-gene biomarkers from preclinical drug sensitivity data for predicting clinical responses to erlotinib or sorafenib. The analysis applies linear ridge regression modeling to generate a small (N~1000 set of baseline gene expressions that jointly yield quality predictions of preclinical drug sensitivity data and clinical responses. Standard clustering of the pathway-gene combinations from gene set enrichment analysis of this initial gene set, according to their shared appearance in molecular function pathways, yields a reduced (N~300 set of potential pathway-gene biomarkers. A modified method for quantifying pathway fitness is used to determine smaller numbers of over and under expressed genes that correspond with favorable and unfavorable clinical responses. Detailed literature-based evidence is provided in support of the roles of these under and over expressed genes in compound efficacy. RandomForest analysis of potential pathway-gene biomarkers finds average treatment prediction errors of 10% and 22%, respectively, for patients receiving erlotinib or sorafenib that had a favorable clinical response. Higher errors were found for both compounds when predicting an unfavorable clinical response. Collectively these results suggest complementary roles for biomarker genes and biomarker pathways when predicting clinical responses from preclinical data.

  16. Morphological covariance in anatomical MRI scans can identify discrete neural pathways in the brain and their disturbances in persons with neuropsychiatric disorders.

    Science.gov (United States)

    Bansal, Ravi; Hao, Xuejun; Peterson, Bradley S

    2015-05-01

    We hypothesize that coordinated functional activity within discrete neural circuits induces morphological organization and plasticity within those circuits. Identifying regions of morphological covariation that are independent of morphological covariation in other regions therefore may therefore allow us to identify discrete neural systems within the brain. Comparing the magnitude of these variations in individuals who have psychiatric disorders with the magnitude of variations in healthy controls may allow us to identify aberrant neural pathways in psychiatric illnesses. We measured surface morphological features by applying nonlinear, high-dimensional warping algorithms to manually defined brain regions. We transferred those measures onto the surface of a unit sphere via conformal mapping and then used spherical wavelets and their scaling coefficients to simplify the data structure representing these surface morphological features of each brain region. We used principal component analysis (PCA) to calculate covariation in these morphological measures, as represented by their scaling coefficients, across several brain regions. We then assessed whether brain subregions that covaried in morphology, as identified by large eigenvalues in the PCA, identified specific neural pathways of the brain. To do so, we spatially registered the subnuclei for each eigenvector into the coordinate space of a Diffusion Tensor Imaging dataset; we used these subnuclei as seed regions to track and compare fiber pathways with known fiber pathways identified in neuroanatomical atlases. We applied these procedures to anatomical MRI data in a cohort of 82 healthy participants (42 children, 18 males, age 10.5 ± 2.43 years; 40 adults, 22 males, age 32.42 ± 10.7 years) and 107 participants with Tourette's Syndrome (TS) (71 children, 59 males, age 11.19 ± 2.2 years; 36 adults, 21 males, age 37.34 ± 10.9 years). We evaluated the construct validity of the identified covariation in morphology

  17. Whole genome association study identifies regions of the bovine genome and biological pathways involved in carcass trait performance in Holstein-Friesian cattle.

    Science.gov (United States)

    Doran, Anthony G; Berry, Donagh P; Creevey, Christopher J

    2014-10-01

    Four traits related to carcass performance have been identified as economically important in beef production: carcass weight, carcass fat, carcass conformation of progeny and cull cow carcass weight. Although Holstein-Friesian cattle are primarily utilized for milk production, they are also an important source of meat for beef production and export. Because of this, there is great interest in understanding the underlying genomic structure influencing these traits. Several genome-wide association studies have identified regions of the bovine genome associated with growth or carcass traits, however, little is known about the mechanisms or underlying biological pathways involved. This study aims to detect regions of the bovine genome associated with carcass performance traits (employing a panel of 54,001 SNPs) using measures of genetic merit (as predicted transmitting abilities) for 5,705 Irish Holstein-Friesian animals. Candidate genes and biological pathways were then identified for each trait under investigation. Following adjustment for false discovery (q-value 0.5) with at least one of the four traits. In total, 557 unique bovine genes, which mapped to 426 human orthologs, were within 500kbs of QTL found associated with a trait using the Bayesian approach. Using this information, 24 significantly over-represented pathways were identified across all traits. The most significantly over-represented biological pathway was the peroxisome proliferator-activated receptor (PPAR) signaling pathway. A large number of genomic regions putatively associated with bovine carcass traits were detected using two different statistical approaches. Notably, several significant associations were detected in close proximity to genes with a known role in animal growth such as glucagon and leptin. Several biological pathways, including PPAR signaling, were shown to be involved in various aspects of bovine carcass performance. These core genes and biological processes may form the

  18. NAViGaTing the micronome--using multiple microRNA prediction databases to identify signalling pathway-associated microRNAs.

    Directory of Open Access Journals (Sweden)

    Elize A Shirdel

    2011-02-01

    Full Text Available MicroRNAs are a class of small RNAs known to regulate gene expression at the transcript level, the protein level, or both. Since microRNA binding is sequence-based but possibly structure-specific, work in this area has resulted in multiple databases storing predicted microRNA:target relationships computed using diverse algorithms. We integrate prediction databases, compare predictions to in vitro data, and use cross-database predictions to model the microRNA:transcript interactome--referred to as the micronome--to study microRNA involvement in well-known signalling pathways as well as associations with disease. We make this data freely available with a flexible user interface as our microRNA Data Integration Portal--mirDIP (http://ophid.utoronto.ca/mirDIP.mirDIP integrates prediction databases to elucidate accurate microRNA:target relationships. Using NAViGaTOR to produce interaction networks implicating microRNAs in literature-based, KEGG-based and Reactome-based pathways, we find these signalling pathway networks have significantly more microRNA involvement compared to chance (p<0.05, suggesting microRNAs co-target many genes in a given pathway. Further examination of the micronome shows two distinct classes of microRNAs; universe microRNAs, which are involved in many signalling pathways; and intra-pathway microRNAs, which target multiple genes within one signalling pathway. We find universe microRNAs to have more targets (p<0.0001, to be more studied (p<0.0002, and to have higher degree in the KEGG cancer pathway (p<0.0001, compared to intra-pathway microRNAs.Our pathway-based analysis of mirDIP data suggests microRNAs are involved in intra-pathway signalling. We identify two distinct classes of microRNAs, suggesting a hierarchical organization of microRNAs co-targeting genes both within and between pathways, and implying differential involvement of universe and intra-pathway microRNAs at the disease level.

  19. Identifying a breeding habitat of a critically endangered fish, Acheilognathus typus, in a natural river in Japan

    Science.gov (United States)

    Sakata, Masayuki K.; Maki, Nobutaka; Sugiyama, Hideki; Minamoto, Toshifumi

    2017-12-01

    Freshwater biodiversity has been severely threatened in recent years, and to conserve endangered species, their distribution and breeding habitats need to be clarified. However, identifying breeding sites in a large area is generally difficult. Here, by combining the emerging environmental DNA (eDNA) analysis with subsequent traditional collection surveys, we successfully identified a breeding habitat for the critically endangered freshwater fish Acheilognathus typus in the mainstream of Omono River in Akita Prefecture, Japan, which is one of the original habitats of this species. Based on DNA cytochrome B sequences of A. typus and closely related species, we developed species-specific primers and a probe that were used in real-time PCR for detecting A. typus eDNA. After verifying the specificity and applicability of the primers and probe on water samples from known artificial habitats, eDNA analysis was applied to water samples collected at 99 sites along Omono River. Two of the samples were positive for A. typus eDNA, and thus, small fixed nets and bottle traps were set out to capture adult fish and verify egg deposition in bivalves (the preferred breeding substrate for A. typus) in the corresponding regions. Mature female and male individuals and bivalves containing laid eggs were collected at one of the eDNA-positive sites. This was the first record of adult A. typus in Omono River in 11 years. This study highlights the value of eDNA analysis to guide conventional monitoring surveys and shows that combining both methods can provide important information on breeding sites that is essential for species' conservation.

  20. Transcriptome analysis in prenatal IGF1-deficient mice identifies molecular pathways and target genes involved in distal lung differentiation.

    Directory of Open Access Journals (Sweden)

    Rosete Sofía Pais

    Full Text Available BACKGROUND: Insulin-like Growth Factor 1 (IGF1 is a multifunctional regulator of somatic growth and development throughout evolution. IGF1 signaling through IGF type 1 receptor (IGF1R controls cell proliferation, survival and differentiation in multiple cell types. IGF1 deficiency in mice disrupts lung morphogenesis, causing altered prenatal pulmonary alveologenesis. Nevertheless, little is known about the cellular and molecular basis of IGF1 activity during lung development. METHODS/PRINCIPAL FINDINGS: Prenatal Igf1(-/- mutant mice with a C57Bl/6J genetic background displayed severe disproportional lung hypoplasia, leading to lethal neonatal respiratory distress. Immuno-histological analysis of their lungs showed a thickened mesenchyme, alterations in extracellular matrix deposition, thinner smooth muscles and dilated blood vessels, which indicated immature and delayed distal pulmonary organogenesis. Transcriptomic analysis of Igf1(-/- E18.5 lungs using RNA microarrays identified deregulated genes related to vascularization, morphogenesis and cellular growth, and to MAP-kinase, Wnt and cell-adhesion pathways. Up-regulation of immunity-related genes was verified by an increase in inflammatory markers. Increased expression of Nfib and reduced expression of Klf2, Egr1 and Ctgf regulatory proteins as well as activation of ERK2 MAP-kinase were corroborated by Western blot. Among IGF-system genes only IGFBP2 revealed a reduction in mRNA expression in mutant lungs. Immuno-staining patterns for IGF1R and IGF2, similar in both genotypes, correlated to alterations found in specific cell compartments of Igf1(-/- lungs. IGF1 addition to Igf1(-/- embryonic lungs cultured ex vivo increased airway septa remodeling and distal epithelium maturation, processes accompanied by up-regulation of Nfib and Klf2 transcription factors and Cyr61 matricellular protein. CONCLUSIONS/SIGNIFICANCE: We demonstrated the functional tissue specific implication of IGF1 on fetal

  1. Using multiobjective tradeoff sets and Multivariate Regression Trees to identify critical and robust decisions for long term water utility planning

    Science.gov (United States)

    Smith, R.; Kasprzyk, J. R.; Balaji, R.

    2017-12-01

    In light of deeply uncertain factors like future climate change and population shifts, responsible resource management will require new types of information and strategies. For water utilities, this entails potential expansion and efficient management of water supply infrastructure systems for changes in overall supply; changes in frequency and severity of climate extremes such as droughts and floods; and variable demands, all while accounting for conflicting long and short term performance objectives. Multiobjective Evolutionary Algorithms (MOEAs) are emerging decision support tools that have been used by researchers and, more recently, water utilities to efficiently generate and evaluate thousands of planning portfolios. The tradeoffs between conflicting objectives are explored in an automated way to produce (often large) suites of portfolios that strike different balances of performance. Once generated, the sets of optimized portfolios are used to support relatively subjective assertions of priorities and human reasoning, leading to adoption of a plan. These large tradeoff sets contain information about complex relationships between decisions and between groups of decisions and performance that, until now, has not been quantitatively described. We present a novel use of Multivariate Regression Trees (MRTs) to analyze tradeoff sets to reveal these relationships and critical decisions. Additionally, when MRTs are applied to tradeoff sets developed for different realizations of an uncertain future, they can identify decisions that are robust across a wide range of conditions and produce fundamental insights about the system being optimized.

  2. Improved fermentative L-cysteine overproduction by enhancing a newly identified thiosulfate assimilation pathway in Escherichia coli.

    Science.gov (United States)

    Kawano, Yusuke; Onishi, Fumito; Shiroyama, Maeka; Miura, Masashi; Tanaka, Naoyuki; Oshiro, Satoshi; Nonaka, Gen; Nakanishi, Tsuyoshi; Ohtsu, Iwao

    2017-09-01

    Sulfate (SO 4 2- ) is an often-utilized and well-understood inorganic sulfur source in microorganism culture. Recently, another inorganic sulfur source, thiosulfate (S 2 O 3 2- ), was proposed to be more advantageous in microbial growth and biotechnological applications. Although its assimilation pathway is known to depend on O-acetyl-L-serine sulfhydrylase B (CysM in Escherichia coli), its metabolism has not been extensively investigated. Therefore, we aimed to explore another yet-unidentified CysM-independent thiosulfate assimilation pathway in E. coli. ΔcysM cells could accumulate essential L-cysteine from thiosulfate as the sole sulfur source and could grow, albeit slowly, demonstrating that a CysM-independent thiosulfate assimilation pathway is present in E. coli. This pathway is expected to consist of the initial part of the thiosulfate to sulfite (SO 3 2- ) conversion, and the latter part might be shared with the final part of the known sulfate assimilation pathway [sulfite → sulfide (S 2- ) → L-cysteine]. This is because thiosulfate-grown ΔcysM cells could accumulate a level of sulfite and sulfide equivalent to that of wild-type cells. The catalysis of thiosulfate to sulfite is at least partly mediated by thiosulfate sulfurtransferase (GlpE), because its overexpression could enhance cellular thiosulfate sulfurtransferase activity in vitro and complement the slow-growth phenotype of thiosulfate-grown ΔcysM cells in vivo. GlpE is therefore concluded to function in the novel CysM-independent thiosulfate assimilation pathway by catalyzing thiosulfate to sulfite. We applied this insight to L-cysteine overproduction in E. coli and succeeded in enhancing it by GlpE overexpression in media containing glucose or glycerol as the main carbon source, by up to ~1.7-fold (1207 mg/l) or ~1.5-fold (1529 mg/l), respectively.

  3. Effect of the systematised critical pathway protocol on emptying failure as a secondary complication of radical hysterectomy due to uterine cervix cancer.

    Science.gov (United States)

    Oh, Jin Kyu; Park, Noh-Hyun; Oh, Seung-June

    2014-06-01

    To evaluate the usefulness of this pathway in managing postoperative emptying failure as a secondary complication of radical hysterectomy. Postoperative urological management after radical hysterectomy has not been effective. We designed and prospectively applied a critical pathway for effective postoperative urological management after radical hysterectomy, based on early catheter removal and application of clean intermittent catheterisation. Retrospective qualitative study. Retrospective review of results from a database of patients who underwent radical hysterectomy and pelvic lymphadenectomy for the treatment of uterine cervical cancer from 2004-2008 and analysis of questionnaires from ward nurses (Appendix 1) who were directly involved in patient care for measuring the clinical effectiveness. Data from a total of 185 patients were analysed. Mean period of the indwelling catheter was 8·3 (SD 1·1), 13·0 (SD 1·1) and 13·1 (SD 3·3) days in the critical pathway (CP), parallel control (PC) and historical control (HC) groups, respectively. Among CP, HC and PC groups, the overall hospital stays were 14·1 (SD 4·8), 20·2 (SD 10) and 18·2 (SD 8·8) days and the periods of time for the indwelling catheters were 8·31 (SD 1·1), 13·1 (SD 3·3) and 13·0 (SD 1·1) days, respectively. Significant differences in the overall hospital stay and the postoperative hospital stay were observed between CP group and the other groups. Analysis of the questionnaires showed that 67% of nurses agreed that the critical pathway was more effective than the previous management pathway system. Our results demonstrated that CP is an effective treatment modality for the management of postoperative emptying failure after radical hysterectomy. Our critical pathway may be applicable to postoperative urological management of radical pelvic surgeries. It may help patients in understanding their hospital course of treatment and encourage patients to participate in their postoperative care

  4. Identifying critical nitrogen application rate for maize yield and nitrate leaching in a Haplic Luvisol soil using the DNDC model.

    Science.gov (United States)

    Zhang, Yitao; Wang, Hongyuan; Liu, Shen; Lei, Qiuliang; Liu, Jian; He, Jianqiang; Zhai, Limei; Ren, Tianzhi; Liu, Hongbin

    2015-05-01

    Identification of critical nitrogen (N) application rate can provide management supports for ensuring grain yield and reducing amount of nitrate leaching to ground water. A five-year (2008-2012) field lysimeter (1 m × 2 m × 1.2 m) experiment with three N treatments (0, 180 and 240 kg Nha(-1)) was conducted to quantify maize yields and amount of nitrate leaching from a Haplic Luvisol soil in the North China Plain. The experimental data were used to calibrate and validate the process-based model of Denitrification-Decomposition (DNDC). After this, the model was used to simulate maize yield production and amount of nitrate leaching under a series of N application rates and to identify critical N application rate based on acceptable yield and amount of nitrate leaching for this cropping system. The results of model calibration and validation indicated that the model could correctly simulate maize yield and amount of nitrate leaching, with satisfactory values of RMSE-observation standard deviation ratio, model efficiency and determination coefficient. The model simulations confirmed the measurements that N application increased maize yield compared with the control, but the high N rate (240 kg Nha(-1)) did not produce more yield than the low one (120 kg Nha(-1)), and that the amount of nitrate leaching increased with increasing N application rate. The simulation results suggested that the optimal N application rate was in a range between 150 and 240 kg ha(-1), which would keep the amount of nitrate leaching below 18.4 kg NO₃(-)-Nha(-1) and meanwhile maintain acceptable maize yield above 9410 kg ha(-1). Furthermore, 180 kg Nha(-1) produced the highest yields (9837 kg ha(-1)) and comparatively lower amount of nitrate leaching (10.0 kg NO₃(-)-Nha(-1)). This study will provide a valuable reference for determining optimal N application rate (or range) in other crop systems and regions in China. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection

    DEFF Research Database (Denmark)

    Ali, Youssif M; Lynch, Nicholas J; Haleem, Kashif S

    2012-01-01

    The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation...... pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan...... to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse...

  6. The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection.

    Directory of Open Access Journals (Sweden)

    Youssif M Ali

    Full Text Available The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2 and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL, are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae. We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci.

  7. Evaluation of critical pathways, radionuclides, and remedial measures for reducing the radiological dose to returning populations at a former nuclear test site

    Energy Technology Data Exchange (ETDEWEB)

    Robison, W. L., LLNL

    1997-11-01

    Bikini Island, the major residence island at Bikini Atoll, was contaminated with radioactive fallout as a result of the BRAVO test conducted on March 1, 1954. We have identified the critical radionuclides and supplied radiological data needed to develop dose estimates for all possible exposure pathways. These estimates show that the major dose to returning populations would result from ingestion of cesium-137 (137 Cs) in locally grown terrestrial foods where the predicted population average effective dose exceeds current federal guidelines. Consequently, we designed several long-term field experiments to develop and evaluate methods to reduce the 137 Cs content in locally grown foods.This paper gives a general outline of the remediation experiments with a more detailed description of a preferred combined option. Our comparative evaluation on various remedial methods show that the combined option--potassium treatment of the entire islands with limited excavation of soil in village an d housing areas--will be effective in reducing the dose to about 10% of pretreatment levels, and offers very significant benefits with respect to adverse environmental impacts as well as savings in overall costs, time, and required expert resources.

  8. Gene Expression Meta-Analysis identifies Cytokine Pathways and 5q Aberrations involved in Metastasis of ERBB2 Amplified and Basal Breast Cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Tan, Qihua; Burton, Mark

    2013-01-01

    mechanisms, aside from the subtypes, were identified in a training set of 1,239 tumors and confirmed by survival analysis in two independent validation datasets from the same type of platform and consisting of very comparable node-negative patients that did not receive adjuvant medical therapy. The results...... show that high expression of 5q14 genes and low levels of TNFR2 pathway genes were associated with poor survival in basal-like cancers. Furthermore, low expression of 5q33 genes and interleukin-12 pathway genes were associated with poor outcome exclusively in ERBB2-like tumors. Conclusion...

  9. [Pathways of flowering regulation in plants].

    Science.gov (United States)

    Liu, Yongping; Yang, Jing; Yang, Mingfeng

    2015-11-01

    Flowering, the floral transition from vegetative growth to reproductive growth, is induced by diverse endogenous and exogenous cues, such as photoperiod, temperature, hormones and age. Precise flowering time is critical to plant growth and evolution of species. The numerous renewal molecular and genetic results have revealed five flowering time pathways, including classical photoperiod pathway, vernalization pathway, autonomous pathway, gibberellins (GA) pathway and newly identified age pathway. These pathways take on relatively independent role, and involve extensive crosstalks and feedback loops. This review describes the complicated regulatory network of this floral transition to understand the molecular mechanism of flowering and provide references for further research in more plants.

  10. Native fluorescence spectroscopy of blood plasma of rats with experimental diabetes: identifying fingerprints of glucose-related metabolic pathways.

    Science.gov (United States)

    Shirshin, Evgeny; Cherkasova, Olga; Tikhonova, Tatiana; Berlovskaya, Elena; Priezzhev, Alexander; Fadeev, Victor

    2015-05-01

    We present the results of a native fluorescence spectroscopy study of blood plasma of rats with experimental diabetes. It was shown that the fluorescence emission band shape at 320 nm excitation is the most indicative of hyperglycemia in the blood plasma samples. We provide the interpretation of this fact based on the changes in reduced nicotinamide adenine dinucleotide phosphate concentration due to glucose-related metabolic pathways and protein fluorescent cross-linking formation following nonenzymatic glycation.

  11. A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments

    Science.gov (United States)

    Mohni, Kareem N.; Thompson, Petria S.; Luzwick, Jessica W.; Glick, Gloria G.; Pendleton, Christopher S.; Lehmann, Brian D.; Pietenpol, Jennifer A.; Cortez, David

    2015-01-01

    The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic. PMID:25965342

  12. WORKSHOP TO IDENTIFY CRITICAL WINDOWS OF EXPOSURE FOR CHILDREN'S HEALTH: REPRODUCTIVE HEALTH IN CHILDREN AND ADOLESCENTS WORK GROUP SUMMARY

    Science.gov (United States)

    This workgroup report addresses the central question: what are the critical windows during development (pre-conception through puberty) when exposure to xenobiotics may have the greatest adverse impact on subsequent reproductive health. The reproductive system develops in stages...

  13. Differential Expression of Wnt Pathway Genes in Sporadic Hepatocellular Carcinomas Infected With Hepatitis B Virus Identified With OligoGE Arrays.

    Science.gov (United States)

    Lin, Xiaoyan; Wang, Qiangxiu; Cao, Zhixin; Geng, Ming; Cao, Yongcheng; Liu, Xiaohong

    2013-01-01

    Epidemiological evidence has clearly indicated that chronic infection with the hepatitis B virus (HBV) is the major risk factor for developing hepatocellular carcinoma (HCC). Nonetheless, the mechanisms by which HBV contributes to the pathogenesis of HCC have not been fully elucidated. Our aim was to characterize differential gene expression profiles related to the Wnt signaling pathway between primary tumor and adjacent normal tissues in HCC patients with concomitant HBVinfection . An oligoGEArray® (an oligonucleotide-based gene expression array platform) containing 126 Wnt signaling pathway-related genes was used to compare gene expressions between primary HCC and adjacent non-tumorous liver tissues from 10 patients with HCC. Selected differential genes were identified with real-time RT-PCR and immunohistochemistry (IHC). In particular, the protein of the differential gene DVL3 (disheveled, dsh homolog 3 [Drosophila]) was chosen to investigate whether it is up regulated in primary tumor correlated with the clinic pathological characteristics of HCC patients. For this purpose we examined 56 HCC tissue samples via IHC for the presence of DVL3 protein. Sixteen genes were identified with significant differential expression between HCC and adjacent non-tumorous liver tissue. These genes have been previously associated with the Frizzled signaling pathway, cell cycle, transcription, or protein degradation. All (100%) of the tumor samples results from 56 HCC patients tested were positive for DVL3 via IHC. Based on the intensity of DVL3 immunoreactivity, 25 (44.6%) and 31 (55.4%) of the patients were classified aslow and high-DVL3, respectively, which correlated with tumor stage (P = 0.029). This study clarified a number of Wnt pathway-related genes which are dysregulated in HBV-associated HCC. These genes may be contributedto the frequent activation of the Wnt signaling pathway. Our results promote the role of the Wnt signaling pathway in HBV-associated HCC.

  14. Transcript Profiling of Paoenia ostii during Artificial Chilling Induced Dormancy Release Identifies Activation of GA Pathway and Carbohydrate Metabolism

    Science.gov (United States)

    Liu, Chunying; Zhang, Yang; Zheng, Guosheng

    2013-01-01

    Endo-dormant flower buds must pass through a period of chilling to reinitiate growth and subsequent flowering, which is a major obstacle to the forcing culture of tree peony in winter. Customized cDNA microarray (8×15 K element) was used to investigate gene expression profiling in tree peony ‘Feng Dan Bai’ buds during 24 d chilling treatment at 0–4°C. According to the morphological changes after the whole plants were transferred to green house, endo-dormancy was released after 18 d chilling treatment, and prolonged chilling treatment increased bud break rate. Pearson correlation hierarchical clustering of sample groups was highly consistent with the dormancy transitions revealed by morphological changes. Totally 3,174 significantly differentially-expressed genes (Pdormancy release process, of which the number of up-regulated (1,611) and that of down-regulated (1,563) was almost the same. Functional annotation of differentially-expressed genes revealed that cellular process, metabolic process, response to stimulus, regulation of biological process and development process were well-represented. Hierarchical clustering indicated that activation of genes involved in carbohydrate metabolism (Glycolysis, Citrate cycle and Pentose phosphate pathway), energy metabolism and cell growth. Based on the results of GO analysis, totally 51 probes presented in the microarray were associated with GA response and GA signaling pathway, and 22 of them were differently expressed. The expression profiles also revealed that the genes of GA biosynthesis, signaling and response involved in endo-dormancy release. We hypothesized that activation of GA pathway played a central role in the regulation of dormancy release in tree peony. PMID:23405132

  15. DMPD: Bruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15081522 Bruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signall...ruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? PubmedID 15081522 Title Bruton...'s tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? Authors

  16. Gene Expression Analysis before and after Treatment with Adalimumab in Patients with Ankylosing Spondylitis Identifies Molecular Pathways Associated with Response to Therapy

    Directory of Open Access Journals (Sweden)

    Marzia Dolcino

    2017-04-01

    Full Text Available The etiology of Ankylosing spondylitis (AS is still unknown and the identification of the involved molecular pathogenetic pathways is a current challenge in the study of the disease. Adalimumab (ADA, an anti-tumor necrosis factor (TNF-alpha agent, is used in the treatment of AS. We aimed at identifying pathogenetic pathways modified by ADA in patients with a good response to the treatment. Gene expression analysis of Peripheral Blood Cells (PBC from six responders and four not responder patients was performed before and after treatment. Differentially expressed genes (DEGs were submitted to functional enrichment analysis and network analysis, followed by modules selection. Most of the DEGs were involved in signaling pathways and in immune response. We identified three modules that were mostly impacted by ADA therapy and included genes involved in mitogen activated protein (MAP kinase, wingless related integration site (Wnt, fibroblast growth factor (FGF receptor, and Toll-like receptor (TCR signaling. A separate analysis showed that a higher percentage of DEGs was modified by ADA in responders (44% compared to non-responders (12%. Moreover, only in the responder group, TNF, Wnt, TLRs and type I interferon signaling were corrected by the treatment. We hypothesize that these pathways are strongly associated to AS pathogenesis and that they might be considered as possible targets of new drugs in the treatment of AS.

  17. Gene Expression Analysis before and after Treatment with Adalimumab in Patients with Ankylosing Spondylitis Identifies Molecular Pathways Associated with Response to Therapy.

    Science.gov (United States)

    Dolcino, Marzia; Tinazzi, Elisa; Pelosi, Andrea; Patuzzo, Giuseppe; Moretta, Francesca; Lunardi, Claudio; Puccetti, Antonio

    2017-04-24

    The etiology of Ankylosing spondylitis (AS) is still unknown and the identification of the involved molecular pathogenetic pathways is a current challenge in the study of the disease. Adalimumab (ADA), an anti-tumor necrosis factor (TNF)-alpha agent, is used in the treatment of AS. We aimed at identifying pathogenetic pathways modified by ADA in patients with a good response to the treatment. Gene expression analysis of Peripheral Blood Cells (PBC) from six responders and four not responder patients was performed before and after treatment. Differentially expressed genes (DEGs) were submitted to functional enrichment analysis and network analysis, followed by modules selection. Most of the DEGs were involved in signaling pathways and in immune response. We identified three modules that were mostly impacted by ADA therapy and included genes involved in mitogen activated protein (MAP) kinase, wingless related integration site (Wnt), fibroblast growth factor (FGF) receptor, and Toll-like receptor (TCR) signaling. A separate analysis showed that a higher percentage of DEGs was modified by ADA in responders (44%) compared to non-responders (12%). Moreover, only in the responder group, TNF, Wnt, TLRs and type I interferon signaling were corrected by the treatment. We hypothesize that these pathways are strongly associated to AS pathogenesis and that they might be considered as possible targets of new drugs in the treatment of AS.

  18. Critical pathway studies for selected radionuclides. Part of a coordinated programme on environmental monitoring for radiological protection in Asia and the Far East

    International Nuclear Information System (INIS)

    Bhat, I.S.

    1980-04-01

    The programme carried out critical pathway studies for selected radionuclides ( 60 Co, 63 Ni, 59 Fe, 54 Mn, sup(110m)Ag, 106 Ru and 144 Ce) and assessed population exposure in the vicinity of Tarapur Atomic Power Station. The following topics are covered under the programme. (i) Demographic study of dietary habits and consumption data for Tarapur population. (ii) Concentration and accumulation of radionuclides in food products. (iii) Determination of radionuclides in sea water, silt, marine algae and marine organisms at Tarapur Atomic Power Station (TAPS) Site. (iv) Behaviour of radionuclides released to marine environment. (v) Evaluation of critical exposure pathway. (vi) Population exposure in the vicinity of Tarapur Atomic Power Station

  19. Identifying the Gene Signatures from Gene-Pathway Bipartite Network Guarantees the Robust Model Performance on Predicting the Cancer Prognosis

    Directory of Open Access Journals (Sweden)

    Li He

    2014-01-01

    Full Text Available For the purpose of improving the prediction of cancer prognosis in the clinical researches, various algorithms have been developed to construct the predictive models with the gene signatures detected by DNA microarrays. Due to the heterogeneity of the clinical samples, the list of differentially expressed genes (DEGs generated by the statistical methods or the machine learning algorithms often involves a number of false positive genes, which are not associated with the phenotypic differences between the compared clinical conditions, and subsequently impacts the reliability of the predictive models. In this study, we proposed a strategy, which combined the statistical algorithm with the gene-pathway bipartite networks, to generate the reliable lists of cancer-related DEGs and constructed the models by using support vector machine for predicting the prognosis of three types of cancers, namely, breast cancer, acute myeloma leukemia, and glioblastoma. Our results demonstrated that, combined with the gene-pathway bipartite networks, our proposed strategy can efficiently generate the reliable cancer-related DEG lists for constructing the predictive models. In addition, the model performance in the swap analysis was similar to that in the original analysis, indicating the robustness of the models in predicting the cancer outcomes.

  20. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

    NARCIS (Netherlands)

    Stolk, Lisette; Perry, John R. B.; Chasman, Daniel I.; He, Chunyan; Mangino, Massimo; Sulem, Patrick; Barbalic, Maja; Broer, Linda; Byrne, Enda M.; Ernst, Florian; Esko, Tonu; Franceschini, Nora; Gudbjartsson, Daniel F.; Hottenga, Jouke-Jan; Kraft, Peter; McArdle, Patrick F.; Porcu, Eleonora; Shin, So-Youn; Smith, Albert V.; van Wingerden, Sophie; Zhai, Guangju; Zhuang, Wei V.; Albrecht, Eva; Alizadeh, Behrooz Z.; Aspelund, Thor; Bandinelli, Stefania; Lauc, Lovorka Barac; Beckmann, Jacques S.; Boban, Mladen; Boerwinkle, Eric; Broekmans, Frank J.; Burri, Andrea; Campbell, Harry; Chanock, Stephen J.; Chen, Constance; Cornelis, Marilyn C.; Corre, Tanguy; Coviello, Andrea D.; d'Adamo, Pio; Davies, Gail; de Faire, Ulf; de Geus, Eco J. C.; Deary, Ian J.; Dedoussis, George V. Z.; Deloukas, Panagiotis; Ebrahim, Shah; Eiriksdottir, Gudny; Emilsson, Valur; Eriksson, Johan G.; Fauser, Bart C. J. M.; Ferreli, Liana; Ferrucci, Luigi; Fischer, Krista; Folsom, Aaron R.; Garcia, Melissa E.; Gasparini, Paolo; Gieger, Christian; Glazer, Nicole; Grobbee, Diederick E.; Hall, Per; Haller, Toomas; Hankinson, Susan E.; Hass, Merli; Hayward, Caroline; Heath, Andrew C.; Hofman, Albert; Ingelsson, Erik; Janssens, A. Cecile J. W.; Johnson, Andrew D.; Karasik, David; Kardia, Sharon L. R.; Keyzer, Jules; Kiel, Douglas P.; Kolcic, Ivana; Kutalik, Zoltan; Lahti, Jari; Lai, Sandra; Laisk, Triin; Laven, Joop S. E.; Lawlor, Debbie A.; Liu, Jianjun; Lopez, Lorna M.; Louwers, Yvonne V.; Magnusson, Patrik K. E.; Marongiu, Mara; Martin, Nicholas G.; Klaric, Irena Martinovic; Masciullo, Corrado; McKnight, Barbara; Medland, Sarah E.; Melzer, David; Mooser, Vincent; Navarro, Pau; Newman, Anne B.; Nyholt, Dale R.; Onland-Moret, N. Charlotte; Palotie, Aarno; Pare, Guillaume; Parker, Alex N.; Pedersen, Nancy L.; Peeters, Petra H. M.; Pistis, Giorgio; Plump, Andrew S.; Polasek, Ozren; Pop, Victor J. M.; Psaty, Bruce M.; Raikkonen, Katri; Rehnberg, Emil; Rotter, Jerome I.; Rudan, Igor; Sala, Cinzia; Salumets, Andres; Scuteri, Angelo; Singleton, Andrew; Smith, Jennifer A.; Snieder, Harold; Soranzo, Nicole; Stacey, Simon N.; Starr, John M.; Stathopoulou, Maria G.; Stirrups, Kathleen; Stolk, Ronald P.; Styrkarsdottir, Unnur; Sun, Yan V.; Tenesa, Albert; Thorand, Barbara; Toniolo, Daniela; Tryggvadottir, Laufey; Tsui, Kim; Ulivi, Sheila; van Dam, Rob M.; van der Schouw, Yvonne T.; van Gils, Carla H.; van Nierop, Peter; Vink, Jacqueline M.; Visscher, Peter M.; Voorhuis, Marlies; Waeber, Gerard; Wallaschofski, Henri; Wichmann, H. Erich; Widen, Elisabeth; Wijnands-van Gent, Colette J. M.; Willemsen, Gonneke; Wilson, James F.; Wolffenbuttel, Bruce H. R.; Wright, Alan F.; Yerges-Armstrong, Laura M.; Zemunik, Tatijana; Zgaga, Lina; Zillikens, M. Carola; Zygmunt, Marek; Arnold, Alice M.; Boomsma, Dorret I.; Buring, Julie E.; Crisponi, Laura; Demerath, Ellen W.; Gudnason, Vilmundur; Harris, Tamara B.; Hu, Frank B.; Hunter, David J.; Launer, Lenore J.; Metspalu, Andres; Montgomery, Grant W.; Oostra, Ben A.; Ridker, Paul M.; Sanna, Serena; Schlessinger, David; Spector, Tim D.; Stefansson, Kari; Streeten, Elizabeth A.; Thorsteinsdottir, Unnur; Uda, Manuela; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Voelzke, Henry; Murray, Anna; Murabito, Joanne M.; Visser, Jenny A.; Lunetta, Kathryn L.

    To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural

  1. Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

    Directory of Open Access Journals (Sweden)

    Jenifer L Marks

    2007-05-01

    Full Text Available Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16 of FGFR4 (Glu681Lys, identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr in a lung adenocarcinoma cell line.This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

  2. Identifying early pathways of risk and resilience: The co-development of internalizing and externalizing symptoms and the role of harsh parenting

    OpenAIRE

    Wiggins, Jillian Lee; Mitchell, Colter; Hyde, Luke W.; Monk, Christopher S.

    2015-01-01

    Psychological disorders co-occur often in children, but little has been done to document the types of conjoint pathways internalizing and externalizing symptoms may take from the crucial early period of toddlerhood or how harsh parenting may overlap with early symptom co-development. To examine symptom co-development trajectories, we identified latent classes of individuals based on internalizing and externalizing symptoms across ages 3–9 and found three symptom co-development classes: normat...

  3. Engaging the Public to Identify Opportunities to Improve Critical Care: A Qualitative Analysis of an Open Community Forum.

    Science.gov (United States)

    Potestio, Melissa L; Boyd, Jamie M; Bagshaw, Sean M; Heyland, Daren; Oxland, Peter; Doig, Christopher J; Zygun, Dave; Stelfox, Henry T

    2015-01-01

    To engage the public to understand how to improve the care of critically ill patients. A qualitative content analysis of an open community forum (Café Scientifique). Public venue in Calgary, Alberta, Canada. Members of the general public including patients, families of patients, health care providers, and members of the community at large. A panel of researchers, decision-makers, and a family member led a Café Scientifique, an informal dialogue between the populace and experts, over three-hours to engage the public to understand how to improve the care of critically ill patients. Conventional qualitative content analysis was used to analyze the data. The inductive analysis occurred in three phases: coding, categorizing, and developing themes. Thirty-eight members of the public (former ICU patients, family members of patients, providers, community members) attended. Participants focused the discussion and provided concrete suggestions for improvement around communication (family as surrogate voice, timing of conversations, decision tools) and provider well-being and engagement, as opposed to medical interventions in critical care. Café participants believe patient and family centered care is important to ensure high-quality care in the ICU. A Café Scientifique is a valuable forum to engage the public to contribute to priority setting areas for research in critical care, as well as a platform to share lived experience. Research stakeholders including health care organizations, governments, and funding organizations should provide more opportunities for the public to engage in meaningful conversations about how to best improve healthcare.

  4. Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts.

    Directory of Open Access Journals (Sweden)

    Michael E Johnson

    Full Text Available Genome-wide expression profiling in systemic sclerosis (SSc has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like, each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling.

  5. Comparative proteomics as a tool for identifying specific alterations within interferon response pathways in human glioblastoma multiforme cells

    DEFF Research Database (Denmark)

    Tarasova, Irina A; Tereshkova, Alesya V; Lobas, Anna A

    2018-01-01

    oncolytic virus therapy would be most effective. We quantified changes in protein abundances in two glioblastoma multiforme (GBM) cell lines that differ in the ability to induce resistance to vesicular stomatitis virus (VSV) infection in response to type I interferon (IFN) treatment. In IFN-treated samples...... we observed an up-regulation of protein products of some IFN-regulated genes (IRGs). In total, the proteome analysis revealed up to 20% more proteins encoded by IRGs in the glioblastoma cell line, which develops resistance to VSV infection after pre-treatment with IFN. In both cell lines protein......-protein interaction and signaling pathway analyses have revealed a significant stimulation of processes related to type I IFN signaling and defense responses to viruses. However, we observed a deficiency in STAT2 protein in the VSV-sensitive cell line that suggests a de-regulation of the JAK/STAT/IRF9 signaling...

  6. Identifying and assessing uncertainty in hydrological pathways: a novel approach to end member mixing in a Scottish agricultural catchment

    Science.gov (United States)

    Soulsby, C.; Petry, J.; Brewer, M. J.; Dunn, S. M.; Ott, B.; Malcolm, I. A.

    2003-04-01

    A hydrograph separation based upon end member mixing was carried out to assess the relative importance of the hydrological pathways providing the main sources of runoff during five storm events in a 14.5 km 2 agricultural catchment in north east Scotland. The method utilised event specific end member chemistries to differentiate three catchment-scale hydrological pathways on the basis of observed Si and NO 3-N concentrations in sampled source waters. These were overland flow (OF) (low Si and intermediate NO 3-N); subsurface storm flow (high Si and high NO 3-N) and groundwater flow (high Si and intermediate NO 3-N). The hydrograph separation explicitly accounted for uncertainty in the spatial and temporal variation in end member chemistry using Bayesian statistical methods which assumed that each end member arose from a bivariate normal distribution whose mean vectors and co-variance matrices could be estimated. Markov Chain-Monte Carlo methods were used to model the average and 95 percentile maximum and minimum contributions that each end member made to stream water samples during storm events. Although there is large uncertainty over the contributions of each end member to specific events, the analysis produced hydrograph separations that were broadly believable on the basis of hydrometric observations in the catchment. Moreover, by using event specific end member compositions, the method appeared sensitive to the unique combination of event characteristics, antecedent conditions and seasonality in terms of producing feasible separations for very different events. It is concluded that OF generally dominates the storm peak and provides the main flow path by which P is transferred to stream channels during storm events, whilst subsurface storm flows usually dominate the storm hydrograph volumetrically and route NO 3-rich soil water into streams. Consequently, nutrient enrichment in such streams is largely mediated by event-based hydrological flow paths, a finding

  7. Intestinal Epithelial Cell-Intrinsic Deletion of Setd7 Identifies Role for Developmental Pathways in Immunity to Helminth Infection

    Science.gov (United States)

    Chenery, Alistair L.; Redpath, Stephen A.; Braam, Mitchell J.; Perona-Wright, Georgia

    2016-01-01

    The intestine is a common site for a variety of pathogenic infections. Helminth infections continue to be major causes of disease worldwide, and are a significant burden on health care systems. Lysine methyltransferases are part of a family of novel attractive targets for drug discovery. SETD7 is a member of the Suppressor of variegation 3-9-Enhancer of zeste-Trithorax (SET) domain-containing family of lysine methyltransferases, and has been shown to methylate and alter the function of a wide variety of proteins in vitro. A few of these putative methylation targets have been shown to be important in resistance against pathogens. We therefore sought to study the role of SETD7 during parasitic infections. We find that Setd7 -/- mice display increased resistance to infection with the helminth Trichuris muris but not Heligmosomoides polygyrus bakeri. Resistance to T. muris relies on an appropriate type 2 immune response that in turn prompts intestinal epithelial cells (IECs) to alter differentiation and proliferation kinetics. Here we show that SETD7 does not affect immune cell responses during infection. Instead, we found that IEC-specific deletion of Setd7 renders mice resistant to T. muris by controlling IEC turnover, an important aspect of anti-helminth immune responses. We further show that SETD7 controls IEC turnover by modulating developmental signaling pathways such as Hippo/YAP and Wnt/β-Catenin. We show that the Hippo pathway specifically is relevant during T. muris infection as verteporfin (a YAP inhibitor) treated mice became susceptible to T. muris. We conclude that SETD7 plays an important role in IEC biology during infection. PMID:27598373

  8. Identification of a specific assembly of the G protein Golf as a critical and regulated module of dopamine and adenosine-activated cAMP pathways in the striatum

    Directory of Open Access Journals (Sweden)

    Denis eHervé

    2011-08-01

    Full Text Available In the principal neurons of striatum (medium spiny neurons, MSNs, cAMP pathway is primarily activated through the stimulation of dopamine D1 and adenosine A2A receptors, these receptors being mainly expressed in striatonigral and striatopallidal MSNs, respectively. Since cAMP signaling pathway could be altered in various physiological and pathological situations, including drug addiction and Parkinson’s disease, it is of crucial importance to identify the molecular components involved in the activation of this pathway. In MSNs, cAMP pathway activation is not dependent on the classical Gs GTP-binding protein but requires a specific G protein subunit heterotrimer containing Galpha-olf/beta2/gamma7 in particular association with adenylate cyclase type 5. This assembly forms an authentic functional signaling unit since loss of one of its members leads to defects of cAMP pathway activation in response to D1 or A2A receptor stimulation, inducing dramatic impairments of behavioral responses dependent on these receptors. Interestingly, D1 receptor-dependent cAMP signaling is modulated by the neuronal levels of Galpha-olf, indicating that Galpha-olf represents the rate-limiting step in this signaling cascade and could constitute a critical element for regulation of D1 receptor responses. In both Parkinsonian patients and several animal models of Parkinson’s disease, the lesion of dopamine neurons produces a prolonged elevation of Galpha-olf levels. This observation gives an explanation for the cAMP pathway hypersensitivity to D1 stimulation, occurring despite an unaltered D1 receptor density. In conclusion, alterations in the highly specialized assembly of Galpha-olf/beta2/gamma7 subunits can happen in pathological conditions, such as Parkinson’s disease, and it could have important functional consequences in relation to changes in D1 receptor signaling in the striatum.

  9. Integrated Proteomic and Transcriptomic-Based Approaches to Identifying Signature Biomarkers and Pathways for Elucidation of Daoy and UW228 Subtypes

    Directory of Open Access Journals (Sweden)

    Roger Higdon

    2017-02-01

    Full Text Available Medulloblastoma (MB is the most common malignant pediatric brain tumor. Patient survival has remained largely the same for the past 20 years, with therapies causing significant health, cognitive, behavioral and developmental complications for those who survive the tumor. In this study, we profiled the total transcriptome and proteome of two established MB cell lines, Daoy and UW228, using high-throughput RNA sequencing (RNA-Seq and label-free nano-LC-MS/MS-based quantitative proteomics, coupled with advanced pathway analysis. While Daoy has been suggested to belong to the sonic hedgehog (SHH subtype, the exact UW228 subtype is not yet clearly established. Thus, a goal of this study was to identify protein markers and pathways that would help elucidate their subtype classification. A number of differentially expressed genes and proteins, including a number of adhesion, cytoskeletal and signaling molecules, were observed between the two cell lines. While several cancer-associated genes/proteins exhibited similar expression across the two cell lines, upregulation of a number of signature proteins and enrichment of key components of SHH and WNT signaling pathways were uniquely observed in Daoy and UW228, respectively. The novel information on differentially expressed genes/proteins and enriched pathways provide insights into the biology of MB, which could help elucidate their subtype classification.

  10. Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

    Energy Technology Data Exchange (ETDEWEB)

    Fukunaga, Satoki [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Kakehashi, Anna [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki [Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Gi, Min [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

    2015-08-01

    To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.

  11. In vivo functional analysis of L-rhamnose metabolic pathway in Aspergillus niger: a tool to identify the potential inducer of RhaR.

    Science.gov (United States)

    Khosravi, Claire; Kun, Roland Sándor; Visser, Jaap; Aguilar-Pontes, María Victoria; de Vries, Ronald P; Battaglia, Evy

    2017-11-06

    The genes of the non-phosphorylative L-rhamnose catabolic pathway have been identified for several yeast species. In Schefferomyces stipitis, all L-rhamnose pathway genes are organized in a cluster, which is conserved in Aspergillus niger, except for the lra-4 ortholog (lraD). The A. niger cluster also contains the gene encoding the L-rhamnose responsive transcription factor (RhaR) that has been shown to control the expression of genes involved in L-rhamnose release and catabolism. In this paper, we confirmed the function of the first three putative L-rhamnose utilisation genes from A. niger through gene deletion. We explored the identity of the inducer of the pathway regulator (RhaR) through expression analysis of the deletion mutants grown in transfer experiments to L-rhamnose and L-rhamnonate. Reduced expression of L-rhamnose-induced genes on L-rhamnose in lraA and lraB deletion strains, but not on L-rhamnonate (the product of LraB), demonstrate that the inducer of the pathway is of L-rhamnonate or a compound downstream of it. Reduced expression of these genes in the lraC deletion strain on L-rhamnonate show that it is in fact a downstream product of L-rhamnonate. This work showed that the inducer of RhaR is beyond L-rhamnonate dehydratase (LraC) and is likely to be the 2-keto-3-L-deoxyrhamnonate.

  12. [The application of cortical and subcortical stimulation threshold in identifying the motor pathway and guiding the resection of gliomas in the functional areas].

    Science.gov (United States)

    Ren, X H; Yang, X C; Huang, W; Yang, K Y; Liu, L; Qiao, H; Guo, L J; Cui, Y; Lin, S

    2018-03-06

    Objective: This study aimed to analyze the application of cortical and subcortical stimulation threshold in identifying the motor pathway and guiding the resection of gliomas in the functional area, and to illustrate the minimal safe threshold by ROC method. Methods: Fifty-seven patients with gliomas in the functional areas were enrolled in the study at Beijing Tiantan Hospital from 2015 to 2017. Anesthesia was maintained intravenously with propofol 10% and remifentanil. Throughout the resection process, cortical or subcortical stimulation threshold was determined along tumor border using monopolar or bipolar electrodes. The motor pathway was identified and protected from resection according to the stimulation threshold and transcranial MEPs. Minimal threshold in each case was recorded. Results: Total resection was achieved in 32 cases(56.1%), sub-total resection in 22 cases(38.6%), and partial resection in 3 cases(5.3%). Pre-operative motor disability was found in 9 cases. Compared with pre-operative motor scores, 19 exhibited impaired motor functions on day 1 after surgery, 5 had quick recovery by day 7 after surgery, and 7 had late recovery by 3 months after surgery. At 3 months, 7 still had impaired motor function. The frequency of intraoperative seizure was 1.8%(1/57). No other side effect was found during electronic monitoring in the operation. The ROC curve revealed that the minimal safe monopolar subcortical threshold was 5.70 mA for strength deterioration on day 1 and day 7 after surgery. Univariate analysis revealed that decreased transcranial MEPs and minimal subcortical threshold ≤5.7 mA were correlated with postoperative strength deterioration. Conclusions: Cortical and subcortical stimulation threshold has its merit in identifying the motor pathway and guiding the resection for tumors within the functional areas. 5.7 mA can be used as the minimal safe threshold to protect the motor pathway from injury.

  13. RIP2 Is a Critical Regulator for NLRs Signaling and MHC Antigen Presentation but Not for MAPK and PI3K/Akt Pathways.

    Science.gov (United States)

    Wu, Xiao Man; Chen, Wen Qin; Hu, Yi Wei; Cao, Lu; Nie, Pin; Chang, Ming Xian

    2018-01-01

    RIP2 is an adaptor protein which is essential for the activation of NF-κB and NOD1- and NOD2-dependent signaling. Although NOD-RIP2 axis conservatively existed in the teleost, the function of RIP2 was only reported in zebrafish, goldfish, and rainbow trout in vitro . Very little is known about the role and mechanisms of piscine NOD-RIP2 axis in vivo . Our previous study showed the protective role of zebrafish NOD1 in larval survival through CD44a-mediated activation of PI3K-Akt signaling. In this study, we examined whether RIP2 was required for larval survival with or without pathogen infection, and determined the signaling pathways modulated by RIP2. Based on our previous report and the present study, our data demonstrated that NOD1-RIP2 axis was important for larval survival in the early ontogenesis. Similar to NOD1, RIP2 deficiency significantly affected immune system processes. The significantly enriched pathways were mainly involved in immune system, such as "Antigen processing and presentation" and "NOD-like receptor signaling pathway" and so on. Furthermore, both transcriptome analysis and qRT-PCR revealed that RIP2 was a critical regulator for expression of NLRs (NOD-like receptors) and those genes involved in MHC antigen presentation. Different from NOD1, the present study showed that NOD1, but not RIP2 deficiency significantly impaired protein levels of MAPK pathways. Although RIP2 deficiency also significantly impaired the expression of CD44a, the downstream signaling of CD44a-Lck-PI3K-Akt pathway remained unchanged. Collectively, our works highlight the similarity and discrepancy of NOD1 and RIP2 in the regulation of immune signaling pathways in the zebrafish early ontogenesis, and confirm the crucial role of RIP2 in NLRs signaling and MHC antigen presentation, but not for MAPK and PI3K/Akt pathways.

  14. Genome-wide methylation profiling of ovarian cancer patient-derived xenografts treated with the demethylating agent decitabine identifies novel epigenetically regulated genes and pathways

    Directory of Open Access Journals (Sweden)

    Tushar Tomar

    2016-10-01

    Full Text Available Abstract Background In high-grade serous ovarian cancer (HGSOC, intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far. Aims of this study were to explore how representative HGSOC PDXs are of their corresponding patient tumor methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. Methods Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450 K methylation arrays. Furthermore, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the prognostic value of the identified genes. Results Only 0.6–1.0 % of all analyzed CpGs (388,696 CpGs changed significantly (p < 0.01 during propagation, showing that HGSOC PDXs were epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6 % of CpG sites in comparison to untreated PDXs (p < 0.01, false discovery rate <10 %. Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g., the Src family kinase

  15. Critical role of ROR-γt in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation.

    Science.gov (United States)

    Michel, Marie-Laure; Mendes-da-Cruz, Daniella; Keller, Alexandre Castro; Lochner, Matthias; Schneider, Elke; Dy, Michel; Eberl, Gérard; Leite-de-Moraes, Maria C

    2008-12-16

    Invariant natural killer T (iNKT) cells constitute a subpopulation of T cells that recognize glycolipids presented by CD1d molecules. They are characterized by their prompt production of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), which enables them to modulate diverse immune responses. Recently, we enlarged this concept by identifying a distinct IL-17-producing iNKT cell subset, named iNKT17 cells. The mechanisms leading to the acquisition of this new iNKT cell activity are unknown. Herein we show that IL-17-producing iNKT cells are already present in the thymus, predominantly among a subset regarded so far as an immature stage of thymic iNKT cell development, the CD1d tetramer(pos)CD44(pos)NK1.1(neg)CD4(neg) cells. Using EGFP reporter mice, we demonstrate that the transcription factor ROR-gammat is critical for the thymic differentiation of this subset because only ROR-gammat(pos) iNKT cells are capable of massively secreting IL-17. Moreover, IL-17-producing CD1d tetramer(pos)CD44(pos)NK1.1(neg)CD4(neg) thymic iNKT cells have reached a mature differentiation stage because they fail to generate other cell subsets in fetal thymic organ culture. Conversely, thymic ROR-gammat(neg) iNKT cell precursors give rise to progeny, but acquire neither ROR-gammat expression nor the ability to secrete IL-17. In conclusion, our findings demonstrate an alternative thymic pathway leading to the development of iNKT17 cells that requires ROR-gammat expression.

  16. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD.

    Directory of Open Access Journals (Sweden)

    Nathalie Busso

    Full Text Available Nicotinamide phosphoribosyltransferase (NAMPT, also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFalpha levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders.

  17. National Assessment of College Student Learning: Identifying College Graduates' Essential Skills in Writing, Speech and Listening, and Critical Thinking. Final Project Report.

    Science.gov (United States)

    Jones, Elizabeth A.; And Others

    This study used an iterative Delphi survey process of about 600 faculty, employers, and policymakers to identify writing, speech and listening, and critical thinking skills that college graduates should achieve to become effective employees and citizens (National Education Goal 6). Participants reached a consensus about the importance in critical…

  18. Comparative proteomics as a tool for identifying specific alterations within interferon response pathways in human glioblastoma multiforme cells

    DEFF Research Database (Denmark)

    Tarasova, Irina A; Tereshkova, Alesya V; Lobas, Anna A

    2018-01-01

    An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where on...

  19. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.

    Science.gov (United States)

    Koenekoop, Robert K; Wang, Hui; Majewski, Jacek; Wang, Xia; Lopez, Irma; Ren, Huanan; Chen, Yiyun; Li, Yumei; Fishman, Gerald A; Genead, Mohammed; Schwartzentruber, Jeremy; Solanki, Naimesh; Traboulsi, Elias I; Cheng, Jingliang; Logan, Clare V; McKibbin, Martin; Hayward, Bruce E; Parry, David A; Johnson, Colin A; Nageeb, Mohammed; Poulter, James A; Mohamed, Moin D; Jafri, Hussain; Rashid, Yasmin; Taylor, Graham R; Keser, Vafa; Mardon, Graeme; Xu, Huidan; Inglehearn, Chris F; Fu, Qing; Toomes, Carmel; Chen, Rui

    2012-09-01

    Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder.

  20. Developing an easy-to-apply model for identifying relevant pathogen pathways into surface waters used for recreational purposes.

    Science.gov (United States)

    Tondera, Katharina; Klaer, Kassandra; Roder, Silke; Brueckner, Ira; Strathmann, Martin; Kistemann, Thomas; Schreiber, Christiane; Pinnekamp, Johannes

    2016-10-01

    Swimming in inner-city surface waters is popular in the warm season, but can have negative consequences such as gastro-intestinal, ear and skin infections. The pathogens causing these infections commonly enter surface waters via several point source discharges such as the effluents from wastewater treatment plants and sewer overflows, as well as through diffuse non-point sources such as surface runoff. Nonetheless, the recreational use of surface waters is attractive for residents. In order to save financial and organizational resources, local authorities need to estimate the most relevant pathways of pathogens into surface waters. In particular, when detailed data on a local scale are missing, this is quite difficult to achieve. For this reason, we have developed an easy-to-apply model using the example of Escherichia coli and intestinal enterococci as a first approach to the local situation, where missing data can be replaced by data from literature. The model was developed based on a case study of a river arm monitored in western Germany and will be generalized for future applications. Although the limits of the EU Bathing Water Directive are already fulfilled during dry weather days, we showed that the effluent of wastewater treatment plants and overland flow had the most relevant impact on the microbial surface water quality. On rainy weather days, combined sewer overflows are responsible for the highest microbial pollution loads. The results obtained in this study can help decision makers to focus on reducing the relevant pathogen sources within a catchment area. Copyright © 2015 Elsevier GmbH. All rights reserved.

  1. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

    Science.gov (United States)

    Jin, Ying; Andersen, Genevieve; Yorgov, Daniel; Ferrara, Tracey M; Ben, Songtao; Brownson, Kelly M; Holland, Paulene J; Birlea, Stanca A; Siebert, Janet; Hartmann, Anke; Lienert, Anne; van Geel, Nanja; Lambert, Jo; Luiten, Rosalie M; Wolkerstorfer, Albert; van der Veen, JP Wietze; Bennett, Dorothy C; Taïeb, Alain; Ezzedine, Khaled; Kemp, E Helen; Gawkrodger, David J; Weetman, Anthony P; Kõks, Sulev; Prans, Ele; Kingo, Külli; Karelson, Maire; Wallace, Margaret R; McCormack, Wayne T; Overbeck, Andreas; Moretti, Silvia; Colucci, Roberta; Picardo, Mauro; Silverberg, Nanette B; Olsson, Mats; Valle, Yan; Korobko, Igor; Böhm, Markus; Lim, Henry W.; Hamzavi, Iltefat; Zhou, Li; Mi, Qing-Sheng; Fain, Pamela R.; Santorico, Stephanie A; Spritz, Richard A

    2016-01-01

    Vitiligo is an autoimmune disease in which depigmented skin results from destruction of melanocytes1, with epidemiologic association with other autoimmune diseases2. In previous linkage and genome-wide association studies (GWAS1, GWAS2), we identified 27 vitiligo susceptibility loci in patients of European (EUR) ancestry. We carried out a third GWAS (GWAS3) in EUR subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new loci and 7 suggestive loci, most encoding immune and apoptotic regulators, some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some corresponding to eQTL at these loci. Together, the identified genes provide a framework for vitiligo genetic architecture and pathobiology, highlight relationships to other autoimmune diseases and melanoma, and offer potential targets for treatment. PMID:27723757

  2. IL-1β but not programmed death-1 and programmed death-ligand pathway is critical for the human Th17 response to M. tuberculosis

    Directory of Open Access Journals (Sweden)

    Emmanuel Stephen-Victor

    2016-11-01

    Full Text Available The programmed death-1 (PD-1- programmed death ligand-1 (PD-L1 and PD-L2 co-inhibitory pathway has been implicated in the evasion strategies of Mycobacterium tuberculosis. Specifically, M. tuberculosis-induced PD-L1 orchestrates expansion of regulatory T cells (Tregs and suppression of Th1 response. However, the role of PD pathway in regulating Th17 response to M. tuberculosis has not been investigated. In the present report, we demonstrate that M. tuberculosis and M. tuberculosis-derived antigen fractions have differential abilities to mediate human monocyte and dendritic cell (DC-mediated Th17 response and were independent of expression of PD-L1 or PD-L2 on aforementioned antigen-presenting cells. Importantly, we observed that blockade of PD-L1 or PD-1 did not significantly modify either the frequencies of Th17 cells or the production of IL-17 from CD4+ T cells though IFN-γ response was significantly enhanced. On the contrary, IL-1β from monocytes and DCs were critical for the Th17 response to M. tuberculosis. Together, our results indicate that IL-1β but not members of the programmed death pathway is critical for human Th17 response to M. tuberculosis

  3. IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

    Science.gov (United States)

    Stephen-Victor, Emmanuel; Sharma, Varun Kumar; Das, Mrinmoy; Karnam, Anupama; Saha, Chaitrali; Lecerf, Maxime; Galeotti, Caroline; Kaveri, Srinivas V.; Bayry, Jagadeesh

    2016-01-01

    The programed death-1 (PD-1)–programed death ligand-1 (PD-L1) and PD-L2 co-inhibitory pathway has been implicated in the evasion strategies of Mycobacterium tuberculosis. Specifically, M. tuberculosis-induced PD-L1 orchestrates expansion of regulatory T cells and suppression of Th1 response. However, the role of PD pathway in regulating Th17 response to M. tuberculosis has not been investigated. In the present report, we demonstrate that M. tuberculosis and M. tuberculosis-derived antigen fractions have differential abilities to mediate human monocyte- and dendritic cell (DC)-mediated Th17 response and were independent of expression of PD-L1 or PD-L2 on aforementioned antigen-presenting cells. Importantly, we observed that blockade of PD-L1 or PD-1 did not significantly modify either the frequencies of Th17 cells or the production of IL-17 from CD4+ T cells though IFN-γ response was significantly enhanced. On the contrary, IL-1β from monocytes and DCs were critical for the Th17 response to M. tuberculosis. Together, our results indicate that IL-1β, but not members of the programed death pathway, is critical for human Th17 response to M. tuberculosis. PMID:27867382

  4. A genome-wide association study of the maize hypersensitive defense response identifies genes that cluster in related pathways.

    Directory of Open Access Journals (Sweden)

    Bode A Olukolu

    2014-08-01

    Full Text Available Much remains unknown of molecular events controlling the plant hypersensitive defense response (HR, a rapid localized cell death that limits pathogen spread and is mediated by resistance (R- genes. Genetic control of the HR is hard to quantify due to its microscopic and rapid nature. Natural modifiers of the ectopic HR phenotype induced by an aberrant auto-active R-gene (Rp1-D21, were mapped in a population of 3,381 recombinant inbred lines from the maize nested association mapping population. Joint linkage analysis was conducted to identify 32 additive but no epistatic quantitative trait loci (QTL using a linkage map based on more than 7000 single nucleotide polymorphisms (SNPs. Genome-wide association (GWA analysis of 26.5 million SNPs was conducted after adjusting for background QTL. GWA identified associated SNPs that colocalized with 44 candidate genes. Thirty-six of these genes colocalized within 23 of the 32 QTL identified by joint linkage analysis. The candidate genes included genes predicted to be in involved programmed cell death, defense response, ubiquitination, redox homeostasis, autophagy, calcium signalling, lignin biosynthesis and cell wall modification. Twelve of the candidate genes showed significant differential expression between isogenic lines differing for the presence of Rp1-D21. Low but significant correlations between HR-related traits and several previously-measured disease resistance traits suggested that the genetic control of these traits was substantially, though not entirely, independent. This study provides the first system-wide analysis of natural variation that modulates the HR response in plants.

  5. A Genome-Wide Association Study of the Maize Hypersensitive Defense Response Identifies Genes That Cluster in Related Pathways

    Science.gov (United States)

    Venkata, Bala P.; Marla, Sandeep; Ji, Jiabing; Gachomo, Emma; Chu, Kevin; Negeri, Adisu; Benson, Jacqueline; Nelson, Rebecca; Bradbury, Peter; Nielsen, Dahlia; Holland, James B.; Balint-Kurti, Peter J.; Johal, Gurmukh

    2014-01-01

    Much remains unknown of molecular events controlling the plant hypersensitive defense response (HR), a rapid localized cell death that limits pathogen spread and is mediated by resistance (R-) genes. Genetic control of the HR is hard to quantify due to its microscopic and rapid nature. Natural modifiers of the ectopic HR phenotype induced by an aberrant auto-active R-gene (Rp1-D21), were mapped in a population of 3,381 recombinant inbred lines from the maize nested association mapping population. Joint linkage analysis was conducted to identify 32 additive but no epistatic quantitative trait loci (QTL) using a linkage map based on more than 7000 single nucleotide polymorphisms (SNPs). Genome-wide association (GWA) analysis of 26.5 million SNPs was conducted after adjusting for background QTL. GWA identified associated SNPs that colocalized with 44 candidate genes. Thirty-six of these genes colocalized within 23 of the 32 QTL identified by joint linkage analysis. The candidate genes included genes predicted to be in involved programmed cell death, defense response, ubiquitination, redox homeostasis, autophagy, calcium signalling, lignin biosynthesis and cell wall modification. Twelve of the candidate genes showed significant differential expression between isogenic lines differing for the presence of Rp1-D21. Low but significant correlations between HR-related traits and several previously-measured disease resistance traits suggested that the genetic control of these traits was substantially, though not entirely, independent. This study provides the first system-wide analysis of natural variation that modulates the HR response in plants. PMID:25166276

  6. Exploring critical uncertainties in pathway assessments of human-assisted introductions of alien forest species in Canada

    Science.gov (United States)

    Denys Yemshanov; Frank H. Koch; Mark J. Ducey; Marty Siltanen; Kirsty Wilson; Klaus Koehler

    2013-01-01

    Long-distance introductions of alien species are often driven by socioeconomic factors, such that conventional “biological” invasion models may not be capable of estimating spread fully and reliably. In this study, we demonstrate a new technique for assessing and reconstructing human-mediated pathways of alien forest species entries to major settlements in Canada via...

  7. Global transcriptome analysis identifies regulated transcripts and pathways activated during oogenesis and early embryogenesis in Atlantic cod.

    Science.gov (United States)

    Kleppe, Lene; Edvardsen, Rolf Brudvik; Furmanek, Tomasz; Taranger, Geir Lasse; Wargelius, Anna

    2014-07-01

    The molecular mechanisms underlying oogenesis and maternally controlled embryogenesis in fish are not fully understood, especially in marine species. Our aim was to study the egg and embryo transcriptome during oogenesis and early embryogenesis in Atlantic cod. Follicles from oogenesis stages (pre-, early-, and late-vitellogenic), ovulated eggs, and two embryonic stages (blastula, gastrula) were collected from broodstock fish and fertilized eggs. Gene expression profiles were measured in a 44 K oligo microarray consisting of 23,000 cod genes. Hundreds of differentially expressed genes (DEGs) were identified in the follicle stages investigated, implicating a continuous accumulation and degradation of polyadenylated transcripts throughout oogenesis. Very few DEGs were identified from ovulated egg to blastula, showing a more stable maternal RNA pool in early embryonic stages. The highest induction of expression was observed between blastula and gastrula, signifying the onset of zygotic transcription. During early vitellogenesis, several of the most upregulated genes are linked to nervous system signaling, suggesting increasing requirements for ovarian synaptic signaling to stimulate the rapid growth of oocytes. Highly upregulated genes during late vitellogenesis are linked to protein processing, fat metabolism, osmoregulation, and arrested meiosis. One of the genes with the highest upregulation in the ovulated egg is involved in oxidative phosphorylation, reflecting increased energy requirements during fertilization and the first rapid cell divisions of early embryogenesis. In conclusion, this study provides a large-scale presentation of the Atlantic cod's maternally controlled transcriptome in ovarian follicles through oogenesis, ovulated eggs, and early embryos. Published 2014 Wiley Periodicals, Inc.

  8. Genome Comparison of Erythromycin Resistant Campylobacter from Turkeys Identifies Hosts and Pathways for Horizontal Spread of erm(B Genes

    Directory of Open Access Journals (Sweden)

    Diego Florez-Cuadrado

    2017-11-01

    Full Text Available Pathogens in the genus Campylobacter are the most common cause of food-borne bacterial gastro-enteritis. Campylobacteriosis, caused principally by Campylobacter jejuni and Campylobacter coli, is transmitted to humans by food of animal origin, especially poultry. As for many pathogens, antimicrobial resistance in Campylobacter is increasing at an alarming rate. Erythromycin prescription is the treatment of choice for clinical cases requiring antimicrobial therapy but this is compromised by mobility of the erythromycin resistance gene erm(B between strains. Here, we evaluate resistance to six antimicrobials in 170 Campylobacter isolates (133 C. coli and 37 C. jejuni from turkeys. Erythromycin resistant isolates (n = 85; 81 C. coli and 4 C. jejuni were screened for the presence of the erm(B gene, that has not previously been identified in isolates from turkeys. The genomes of two positive C. coli isolates were sequenced and in both isolates the erm(B gene clustered with resistance determinants against aminoglycosides plus tetracycline, including aad9, aadE, aph(2″-IIIa, aph(3′-IIIa, and tet(O genes. Comparative genomic analysis identified identical erm(B sequences among Campylobacter from turkeys, Streptococcus suis from pigs and Enterococcus faecium and Clostridium difficile from humans. This is consistent with multiple horizontal transfer events among different bacterial species colonizing turkeys. This example highlights the potential for dissemination of antimicrobial resistance across bacterial species boundaries which may compromise their effectiveness in antimicrobial therapy.

  9. How to Identify Negative Attitudes towards Inclusive Education: Critical Discourse Analysis of Russian Transcripts Using Role and Reference Grammar

    Directory of Open Access Journals (Sweden)

    Mariia Rubtcova

    2016-09-01

    Full Text Available This paper presents the Role and Reference Grammar (RRG analysis that aims to reveal possibilities required for carrying out the interdisciplinary research development within Critical Discourse Analysis (CDA. It takes a closer look at conflicts, considering the example of a conflict situation occurred in reaction to the opening of the inclusive academic programme at one of St. Petersburg’s secondary schools. Role and Reference Grammar application demonstrates that the use of different verb types and macroroles has led to the various interpretations. These findings confirm that RRG could influence the increase of objectivity of the transcript analysis in qualitative social research. RRG provides new information which in combination with other methods can help us to understand the positions of participants involved into conflicts

  10. Thigh Ultrasound Monitoring Identifies Decreases in Quadriceps Femoris Thickness as a Frequent Observation in Critically Ill Children.

    Science.gov (United States)

    Valla, Frederic V; Young, David K; Rabilloud, Muriel; Periasami, Uvaraj; John, Manoj; Baudin, Florent; Vuillerot, Carole; Portefaix, Aurélie; White, Deborah; Ridout, Jenna A; Meyer, Rosan; Gaillard Le Roux, Bénédicte; Javouhey, Etienne; Pathan, Nazima

    2017-08-01

    Significant muscle wasting develops in critically ill adults, with subsequent worse outcomes. In the pediatric setting, occurrence and effects of muscle wasting are undescribed; this is in part due to a lack of validated, objective methods for assessing muscle wasting. A single measurement of quadriceps femoris thickness has failed to show consistent reproducibility. We hypothesized that averaging repeated measurements could afford good reproducibility to allow for quadriceps femoris thickness decline detection and monitoring. A prospective bedside observational study. Two PICUs. Mechanically ventilated critically ill children were 15 years and younger. Transverse and longitudinal axis measurements of quadriceps femoris anterior thickness were undertaken using bedside ultrasound. The average of four measurement values was recorded. The location of measurement was marked for consistency within subsequent measurements by the same or another trained operator, to assess intra- and interoperator repeatability and reproducibility of the technique. Where feasible, serial measurements were undertaken until the time of extubation in a group of children with prolonged PICU stay (> 5 d). Seventy-three children were enrolled to assess intra- and interoperator ultrasound reliability. Their median (25-75 interquartile range) age and weight were 30 months (4.5-96) and 10 kg (5-23.5). In the intraoperator repeatability study, mean relative difference in quadriceps femoris muscle thickness was 0.36% ± 2.5% (lower and upper limits of agreement: -4.5/+5.2%). In the interoperator reproducibility study, intraclass correlation coefficient was 0.998. In the 17 children monitored over their PICU stay, quadriceps femoris thickness significantly decreased at day 5 by 9.8% (p = 0.006) and by 13.3% (guide rehabilitation and nutrition interventions.

  11. Biochemical and Phylogenetic Characterization of a Novel Diaminopimelate Biosynthesis Pathway in Prokaryotes Identifies a Diverged Form of ll-Diaminopimelate Aminotransferase▿ †

    OpenAIRE

    Hudson, André O.; Gilvarg, Charles; Leustek, Thomas

    2008-01-01

    A variant of the diaminopimelate (DAP)-lysine biosynthesis pathway uses an ll-DAP aminotransferase (DapL, EC 2.6.1.83) to catalyze the direct conversion of l-2,3,4,5-tetrahydrodipicolinate to ll-DAP. Comparative genomic analysis and experimental verification of DapL candidates revealed the existence of two diverged forms of DapL (DapL1 and DapL2). DapL orthologs were identified in eubacteria and archaea. In some species the corresponding dapL gene was found to lie in genomic contiguity with o...

  12. RNA Sequencing Identifies Upregulated Kyphoscoliosis Peptidase and Phosphatidic Acid Signaling Pathways in Muscle Hypertrophy Generated by Transgenic Expression of Myostatin Propeptide

    Directory of Open Access Journals (Sweden)

    Yuanxin Miao

    2015-04-01

    Full Text Available Myostatin (MSTN, a member of the transforming growth factor-β superfamily, plays a crucial negative role in muscle growth. MSTN mutations or inhibitions can dramatically increase muscle mass in most mammal species. Previously, we generated a transgenic mouse model of muscle hypertrophy via the transgenic expression of the MSTN N-terminal propeptide cDNA under the control of the skeletal muscle-specific MLC1 promoter. Here, we compare the mRNA profiles between transgenic mice and wild-type littermate controls with a high-throughput RNA sequencing method. The results show that 132 genes were significantly differentially expressed between transgenic mice and wild-type control mice; 97 of these genes were up-regulated, and 35 genes were down-regulated in the skeletal muscle. Several genes that had not been reported to be involved in muscle hypertrophy were identified, including up-regulated myosin binding protein H (mybph, and zinc metallopeptidase STE24 (Zmpste24. In addition, kyphoscoliosis peptidase (Ky, which plays a vital role in muscle growth, was also up-regulated in the transgenic mice. Interestingly, a pathway analysis based on grouping the differentially expressed genes uncovered that cardiomyopathy-related pathways and phosphatidic acid (PA pathways (Dgki, Dgkz, Plcd4 were up-regulated. Increased PA signaling may increase mTOR signaling, resulting in skeletal muscle growth. The findings of the RNA sequencing analysis help to understand the molecular mechanisms of muscle hypertrophy caused by MSTN inhibition.

  13. RNA sequencing identifies upregulated kyphoscoliosis peptidase and phosphatidic acid signaling pathways in muscle hypertrophy generated by transgenic expression of myostatin propeptide.

    Science.gov (United States)

    Miao, Yuanxin; Yang, Jinzeng; Xu, Zhong; Jing, Lu; Zhao, Shuhong; Li, Xinyun

    2015-04-09

    Myostatin (MSTN), a member of the transforming growth factor-β superfamily, plays a crucial negative role in muscle growth. MSTN mutations or inhibitions can dramatically increase muscle mass in most mammal species. Previously, we generated a transgenic mouse model of muscle hypertrophy via the transgenic expression of the MSTN N-terminal propeptide cDNA under the control of the skeletal muscle-specific MLC1 promoter. Here, we compare the mRNA profiles between transgenic mice and wild-type littermate controls with a high-throughput RNA sequencing method. The results show that 132 genes were significantly differentially expressed between transgenic mice and wild-type control mice; 97 of these genes were up-regulated, and 35 genes were down-regulated in the skeletal muscle. Several genes that had not been reported to be involved in muscle hypertrophy were identified, including up-regulated myosin binding protein H (mybph), and zinc metallopeptidase STE24 (Zmpste24). In addition, kyphoscoliosis peptidase (Ky), which plays a vital role in muscle growth, was also up-regulated in the transgenic mice. Interestingly, a pathway analysis based on grouping the differentially expressed genes uncovered that cardiomyopathy-related pathways and phosphatidic acid (PA) pathways (Dgki, Dgkz, Plcd4) were up-regulated. Increased PA signaling may increase mTOR signaling, resulting in skeletal muscle growth. The findings of the RNA sequencing analysis help to understand the molecular mechanisms of muscle hypertrophy caused by MSTN inhibition.

  14. Biochemical and phylogenetic characterization of a novel diaminopimelate biosynthesis pathway in prokaryotes identifies a diverged form of LL-diaminopimelate aminotransferase.

    Science.gov (United States)

    Hudson, André O; Gilvarg, Charles; Leustek, Thomas

    2008-05-01

    A variant of the diaminopimelate (DAP)-lysine biosynthesis pathway uses an LL-DAP aminotransferase (DapL, EC 2.6.1.83) to catalyze the direct conversion of L-2,3,4,5-tetrahydrodipicolinate to LL-DAP. Comparative genomic analysis and experimental verification of DapL candidates revealed the existence of two diverged forms of DapL (DapL1 and DapL2). DapL orthologs were identified in eubacteria and archaea. In some species the corresponding dapL gene was found to lie in genomic contiguity with other dap genes, suggestive of a polycistronic structure. The DapL candidate enzymes were found to cluster into two classes sharing approximately 30% amino acid identity. The function of selected enzymes from each class was studied. Both classes were able to functionally complement Escherichia coli dapD and dapE mutants and to catalyze LL-DAP transamination, providing functional evidence for a role in DAP/lysine biosynthesis. In all cases the occurrence of dapL in a species correlated with the absence of genes for dapD and dapE representing the acyl DAP pathway variants, and only in a few cases was dapL coincident with ddh encoding meso-DAP dehydrogenase. The results indicate that the DapL pathway is restricted to specific lineages of eubacteria including the Cyanobacteria, Desulfuromonadales, Firmicutes, Bacteroidetes, Chlamydiae, Spirochaeta, and Chloroflexi and two archaeal groups, the Methanobacteriaceae and Archaeoglobaceae.

  15. Analysis of the Protein Kinase A-Regulated Proteome of Cryptococcus neoformans Identifies a Role for the Ubiquitin-Proteasome Pathway in Capsule Formation

    Directory of Open Access Journals (Sweden)

    J. M. H. Geddes

    2016-01-01

    Full Text Available The opportunistic fungal pathogen Cryptococcus neoformans causes life-threatening meningitis in immunocompromised individuals. The expression of virulence factors, including capsule and melanin, is in part regulated by the cyclic-AMP/protein kinase A (cAMP/PKA signal transduction pathway. In this study, we investigated the influence of PKA on the composition of the intracellular proteome to obtain a comprehensive understanding of the regulation that underpins virulence. Through quantitative proteomics, enrichment and bioinformatic analyses, and an interactome study, we uncovered a pattern of PKA regulation for proteins associated with translation, the proteasome, metabolism, amino acid biosynthesis, and virulence-related functions. PKA regulation of the ubiquitin-proteasome pathway in C. neoformans showed a striking parallel with connections between PKA and protein degradation in chronic neurodegenerative disorders and other human diseases. Further investigation of proteasome function with the inhibitor bortezomib revealed an impact on capsule production as well as hypersusceptibility for strains with altered expression or activity of PKA. Parallel studies with tunicamycin also linked endoplasmic reticulum stress with capsule production and PKA. Taken together, the data suggest a model whereby expression of PKA regulatory and catalytic subunits and the activation of PKA influence proteostasis and the function of the endoplasmic reticulum to control the elaboration of the polysaccharide capsule. Overall, this study revealed both broad and conserved influences of the cAMP/PKA pathway on the proteome and identified proteostasis as a potential therapeutic target for the treatment of cryptococcosis.

  16. Large-Scale microRNA Expression Profiling Identifies Putative Retinal miRNA-mRNA Signaling Pathways Underlying Form-Deprivation Myopia in Mice.

    Science.gov (United States)

    Tkatchenko, Andrei V; Luo, Xiaoyan; Tkatchenko, Tatiana V; Vaz, Candida; Tanavde, Vivek M; Maurer-Stroh, Sebastian; Zauscher, Stefan; Gonzalez, Pedro; Young, Terri L

    2016-01-01

    Development of myopia is associated with large-scale changes in ocular tissue gene expression. Although differential expression of coding genes underlying development of myopia has been a subject of intense investigation, the role of non-coding genes such as microRNAs in the development of myopia is largely unknown. In this study, we explored myopia-associated miRNA expression profiles in the retina and sclera of C57Bl/6J mice with experimentally induced myopia using microarray technology. We found a total of 53 differentially expressed miRNAs in the retina and no differences in miRNA expression in the sclera of C57BL/6J mice after 10 days of visual form deprivation, which induced -6.93 ± 2.44 D (p myopia. We also identified their putative mRNA targets among mRNAs found to be differentially expressed in myopic retina and potential signaling pathways involved in the development of form-deprivation myopia using miRNA-mRNA interaction network analysis. Analysis of myopia-associated signaling pathways revealed that myopic response to visual form deprivation in the retina is regulated by a small number of highly integrated signaling pathways. Our findings highlighted that changes in microRNA expression are involved in the regulation of refractive eye development and predicted how they may be involved in the development of myopia by regulating retinal gene expression.

  17. Large-Scale microRNA Expression Profiling Identifies Putative Retinal miRNA-mRNA Signaling Pathways Underlying Form-Deprivation Myopia in Mice.

    Directory of Open Access Journals (Sweden)

    Andrei V Tkatchenko

    Full Text Available Development of myopia is associated with large-scale changes in ocular tissue gene expression. Although differential expression of coding genes underlying development of myopia has been a subject of intense investigation, the role of non-coding genes such as microRNAs in the development of myopia is largely unknown. In this study, we explored myopia-associated miRNA expression profiles in the retina and sclera of C57Bl/6J mice with experimentally induced myopia using microarray technology. We found a total of 53 differentially expressed miRNAs in the retina and no differences in miRNA expression in the sclera of C57BL/6J mice after 10 days of visual form deprivation, which induced -6.93 ± 2.44 D (p < 0.000001, n = 12 of myopia. We also identified their putative mRNA targets among mRNAs found to be differentially expressed in myopic retina and potential signaling pathways involved in the development of form-deprivation myopia using miRNA-mRNA interaction network analysis. Analysis of myopia-associated signaling pathways revealed that myopic response to visual form deprivation in the retina is regulated by a small number of highly integrated signaling pathways. Our findings highlighted that changes in microRNA expression are involved in the regulation of refractive eye development and predicted how they may be involved in the development of myopia by regulating retinal gene expression.

  18. Genome-wide siRNA-based functional genomics of pigmentation identifies novel genes and pathways that impact melanogenesis in human cells.

    Directory of Open Access Journals (Sweden)

    Anand K Ganesan

    2008-12-01

    Full Text Available Melanin protects the skin and eyes from the harmful effects of UV irradiation, protects neural cells from toxic insults, and is required for sound conduction in the inner ear. Aberrant regulation of melanogenesis underlies skin disorders (melasma and vitiligo, neurologic disorders (Parkinson's disease, auditory disorders (Waardenburg's syndrome, and opthalmologic disorders (age related macular degeneration. Much of the core synthetic machinery driving melanin production has been identified; however, the spectrum of gene products participating in melanogenesis in different physiological niches is poorly understood. Functional genomics based on RNA-mediated interference (RNAi provides the opportunity to derive unbiased comprehensive collections of pharmaceutically tractable single gene targets supporting melanin production. In this study, we have combined a high-throughput, cell-based, one-well/one-gene screening platform with a genome-wide arrayed synthetic library of chemically synthesized, small interfering RNAs to identify novel biological pathways that govern melanin biogenesis in human melanocytes. Ninety-two novel genes that support pigment production were identified with a low false discovery rate. Secondary validation and preliminary mechanistic studies identified a large panel of targets that converge on tyrosinase expression and stability. Small molecule inhibition of a family of gene products in this class was sufficient to impair chronic tyrosinase expression in pigmented melanoma cells and UV-induced tyrosinase expression in primary melanocytes. Isolation of molecular machinery known to support autophagosome biosynthesis from this screen, together with in vitro and in vivo validation, exposed a close functional relationship between melanogenesis and autophagy. In summary, these studies illustrate the power of RNAi-based functional genomics to identify novel genes, pathways, and pharmacologic agents that impact a biological phenotype

  19. Cellular adhesome screen identifies critical modulators of focal adhesion dynamics, cellular traction forces and cell migration behaviour

    Science.gov (United States)

    Fokkelman, Michiel; Balcıoğlu, Hayri E.; Klip, Janna E.; Yan, Kuan; Verbeek, Fons J.; Danen, Erik H. J.; van de Water, Bob

    2016-01-01

    Cancer cells migrate from the primary tumour into surrounding tissue in order to form metastasis. Cell migration is a highly complex process, which requires continuous remodelling and re-organization of the cytoskeleton and cell-matrix adhesions. Here, we aimed to identify genes controlling aspects of tumour cell migration, including the dynamic organization of cell-matrix adhesions and cellular traction forces. In a siRNA screen targeting most cell adhesion-related genes we identified 200+ genes that regulate size and/or dynamics of cell-matrix adhesions in MCF7 breast cancer cells. In a subsequent secondary screen, the 64 most effective genes were evaluated for growth factor-induced cell migration and validated by tertiary RNAi pool deconvolution experiments. Four validated hits showed significantly enlarged adhesions accompanied by reduced cell migration upon siRNA-mediated knockdown. Furthermore, loss of PPP1R12B, HIPK3 or RAC2 caused cells to exert higher traction forces, as determined by traction force microscopy with elastomeric micropillar post arrays, and led to considerably reduced force turnover. Altogether, we identified genes that co-regulate cell-matrix adhesion dynamics and traction force turnover, thereby modulating overall motility behaviour. PMID:27531518

  20. SFGD: a comprehensive platform for mining functional information from soybean transcriptome data and its use in identifying acyl-lipid metabolism pathways.

    Science.gov (United States)

    Yu, Juan; Zhang, Zhenhai; Wei, Jiangang; Ling, Yi; Xu, Wenying; Su, Zhen

    2014-04-08

    Soybean (Glycine max L.) is one of the world's most important leguminous crops producing high-quality protein and oil. Increasing the relative oil concentration in soybean seeds is many researchers' goal, but a complete analysis platform of functional annotation for the genes involved in the soybean acyl-lipid pathway is still lacking. Following the success of soybean whole-genome sequencing, functional annotation has become a major challenge for the scientific community. Whole-genome transcriptome analysis is a powerful way to predict genes with biological functions. It is essential to build a comprehensive analysis platform for integrating soybean whole-genome sequencing data, the available transcriptome data and protein information. This platform could also be used to identify acyl-lipid metabolism pathways. In this study, we describe our construction of the Soybean Functional Genomics Database (SFGD) using Generic Genome Browser (Gbrowse) as the core platform. We integrated microarray expression profiling with 255 samples from 14 groups' experiments and mRNA-seq data with 30 samples from four groups' experiments, including spatial and temporal transcriptome data for different soybean development stages and environmental stresses. The SFGD includes a gene co-expression regulatory network containing 23,267 genes and 1873 miRNA-target pairs, and a group of acyl-lipid pathways containing 221 enzymes and more than 1550 genes. The SFGD also provides some key analysis tools, i.e. BLAST search, expression pattern search and cis-element significance analysis, as well as gene ontology information search and single nucleotide polymorphism display. The SFGD is a comprehensive database integrating genome and transcriptome data, and also for soybean acyl-lipid metabolism pathways. It provides useful toolboxes for biologists to improve the accuracy and robustness of soybean functional genomics analysis, further improving understanding of gene regulatory networks for effective

  1. Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Gaora Peadar Ó

    2010-10-01

    Full Text Available Abstract Background Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray technology in the clinical setting. Two key challenges in clinical bioinformatics involve appropriate statistical modelling of dynamic transcriptomic changes, and extraction of clinically relevant meaning from very large datasets. Results Here, we apply an approach to gene set enrichment analysis that allows for detection of bi-directional enrichment within a gene set. Furthermore, we apply canonical correlation analysis and Fisher's exact test, using plasma marker data with known clinical relevance to aid identification of the most important gene and pathway changes in our transcriptomic dataset. After a 28-day dietary intervention with high-CLA beef, a range of plasma markers indicated a marked improvement in the metabolic health of genetically obese mice. Tissue transcriptomic profiles indicated that the effects were most dramatic in liver (1270 genes significantly changed; p Conclusion Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of

  2. TU-CD-BRB-10: 18F-FDG PET Image-Derived Tumor Features Highlight Altered Pathways Identified by Trancriptomic Analysis in Head and Neck Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tixier, F [CHU Miletrie, Poitiers (France); INSERM UMR1101 LaTIM, Brest (France); Cheze-Le-Rest, C; Dufour, X [CHU Miletrie, Poitiers (France); Hatt, M; Visvikis, D [INSERM UMR1101 LaTIM, Brest (France); Valette, G; Potard, G [CHRU Brest, Brest (France); Corcos, L [INSERM, UMR 1078, Brest (France)

    2015-06-15

    Purpose: Several quantitative features can be extracted from 18F-FDG PET images, such as standardized uptake values (SUVs), metabolic tumor volume (MTV), shape characterization (SC) or intra-tumor radiotracer heterogeneity quantification (HQ). Some of these features calculated from baseline 18F-FDG PET images have shown a prognostic and predictive clinical value. It has been hypothesized that these features highlight underlying tumor patho-physiological processes at smaller scales. The objective of this study was to investigate the ability of recovering alterations of signaling pathways from FDG PET image-derived features. Methods: 52 patients were prospectively recruited from two medical centers (Brest and Poitiers). All patients underwent an FDG PET scan for staging and biopsies of both healthy and primary tumor tissues. Biopsies went through a transcriptomic analysis performed in four spates on 4×44k chips (Agilent™). Primary tumors were delineated in the PET images using the Fuzzy Locally Adaptive Bayesian algorithm and characterized using 10 features including SUVs, SC and HQ. A module network algorithm followed by functional annotation was exploited in order to link PET features with signaling pathways alterations. Results: Several PET-derived features were found to discriminate differentially expressed genes between tumor and healthy tissue (fold-change >2, p<0.01) into 30 co-regulated groups (p<0.05). Functional annotations applied to these groups of genes highlighted associations with well-known pathways involved in cancer processes, such as cell proliferation and apoptosis, as well as with more specific ones such as unsaturated fatty acids. Conclusion: Quantitative features extracted from baseline 18F-FDG PET images usually exploited only for diagnosis and staging, were identified in this work as being related to specific altered pathways and may show promise as tools for personalizing treatment decisions.

  3. A system biology approach to identify regulatory pathways underlying the neuroendocrine control of female puberty in rats and nonhuman primates.

    Science.gov (United States)

    Lomniczi, Alejandro; Wright, Hollis; Castellano, Juan Manuel; Sonmez, Kemal; Ojeda, Sergio R

    2013-07-01

    This article is part of a Special Issue "Puberty and Adolescence". Puberty is a major developmental milestone controlled by the interaction of genetic factors and environmental cues of mostly metabolic and circadian nature. An increased pulsatile release of the decapeptide gonadotropin releasing hormone (GnRH) from hypothalamic neurosecretory neurons is required for both the initiation and progression of the pubertal process. This increase is brought about by coordinated changes that occur in neuronal and glial networks associated with GnRH neurons. These changes ultimately result in increased neuronal and glial stimulatory inputs to the GnRH neuronal network and a reduction of transsynaptic inhibitory influences. While some of the major players controlling pubertal GnRH secretion have been identified using gene-centric approaches, much less is known about the system-wide control of the overall process. Because the pubertal activation of GnRH release involves a diversity of cellular phenotypes, and a myriad of intracellular and cell-to-cell signaling molecules, it appears that the overall process is controlled by a highly coordinated and interactive regulatory system involving hundreds, if not thousands, of gene products. In this article we will discuss emerging evidence suggesting that these genes are arranged as functionally connected networks organized, both internally and across sub-networks, in a hierarchical fashion. According to this concept, the core of these networks is composed of transcriptional regulators that, by directing expression of downstream subordinate genes, provide both stability and coordination to the cellular networks involved in initiating the pubertal process. The integrative response of these gene networks to external inputs is postulated to be coordinated by epigenetic mechanisms. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Antibody Epitopes Identified in Critical Regions of Dengue Virus Nonstructural 1 Protein in Mouse Vaccination and Natural Human Infections.

    Science.gov (United States)

    Hertz, Tomer; Beatty, P Robert; MacMillen, Zachary; Killingbeck, Sarah S; Wang, Chunling; Harris, Eva

    2017-05-15

    Dengue is a global public health problem and is caused by four dengue virus (DENV) serotypes (DENV1-4). A major challenge in dengue vaccine development is that cross-reactive anti-DENV Abs can be protective or potentially increase disease via Ab-dependent enhancement. DENV nonstructural protein 1 (NS1) has long been considered a vaccine candidate as it avoids Ab-dependent enhancement. In this study, we evaluated survival to challenge in a lethal DENV vascular leak model in mice immunized with NS1 combined with aluminum and magnesium hydroxide, monophosphoryl lipid A + AddaVax, or Sigma adjuvant system+CpG DNA, compared with mice infected with a sublethal dose of DENV2 and mice immunized with OVA (negative control). We characterized Ab responses to DENV1, 2, and 3 NS1 using an Ag microarray tiled with 20-mer peptides overlapping by 15 aa and identified five regions of DENV NS1 with significant levels of Ab reactivity in the NS1 + monophosphoryl lipid A + AddaVax group. Additionally, we profiled the Ab responses to NS1 of humans naturally infected with DENV2 or DENV3 in serum samples from Nicaragua collected at acute, convalescent, and 12-mo timepoints. One region in the wing domain of NS1 was immunodominant in both mouse vaccination and human infection studies, and two regions were identified only in NS1-immunized mice; thus, vaccination can generate Abs to regions that are not targeted in natural infection and could provide additional protection against lethal DENV infection. Overall, we identified a small number of immunodominant regions, which were in functionally important locations on the DENV NS1 protein and are potential correlates of protection. Copyright © 2017 by The American Association of Immunologists, Inc.

  5. Identifying ozone-sensitive communities of (semi-)natural vegetation suitable for mapping exceedance of critical levels

    International Nuclear Information System (INIS)

    Mills, G.; Hayes, F.; Jones, M.L.M.; Cinderby, S.

    2007-01-01

    Using published data on the responses of individual species to ozone, 54 EUNIS (European Nature Information System) level 4 communities with six or more ozone-sensitive species (%OS) and c. 20% or more species tested for ozone sensitivity, were identified as potentially ozone-sensitive. The largest number of these communities (23) was associated with Grasslands, with Heathland, scrub and tundra, and Mires, bogs and fens having the next highest representation at 11 and 8 level 4 communities each respectively. Within the grasslands classification, E4 (Alpine and sub-alpine grasslands), E5 (Woodland fringes and clearings) and E1 (Dry grasslands) were the most sensitive with 68.1, 51.6 and 48.6%OS respectively. It is feasible to map the land-cover for these and other communities at level 2, but it may not be currently possible to map the land-cover for all communities identified to be ozone-sensitive at levels 3 and 4. - Grassland communities such as alpine and sub-alpine grasslands have the highest potential sensitivity ozone, based on the responses of their component species

  6. A modified Delphi process to identify clinical and research priorities in patient and family centred critical care.

    Science.gov (United States)

    Oczkowski, Simon J W; Au, Selena; des Ordons, Amanda Roze; Gill, Marlyn; Potestio, Melissa L; Smith, Orla; Sinuff, Tasnim; Stelfox, Henry T; Fox-Robichaud, Alison E

    2017-12-01

    To identify elements which enable patient and family centred care (PFCC) in the intensive care unit (ICU) and priorities for PFCC research. We engaged a panel of multidisciplinary stakeholders in a modified Delphi process. Items generated from a literature review and panelist suggestions were rated in 3 successive rounds on a scale from 1 to 7. Median score was used to rate each item's priority, with 5 or more indicating "essential priority," 4 or 5 "moderate priority" and 3 or less "low priority." Interquartile range (IQR) was used to measure consensus, with IQR of 1 indicating "high" consensus, 2 "moderate" consensus, and 3 or greater "low" consensus. Six items were rated essential elements for facilitating PFCC with high consensus (flexible visiting hours, family participation in bedside care, trained family support person, interventions to facilitate continuity of care, staff education to support families, continuity of staff assignments). Three items were rated essential research topics: interventions to facilitate continuity of care following ICU discharge (moderate consensus), family participation in bedside care (low consensus), and decision aids for end of life decision-making (low consensus). Stakeholders identified clear and distinct priorities for PFCC in clinical care and research, though there was greater consensus for clinical care. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Pathway-Based Analysis of Genome-Wide Association Data Identified SNPs in HMMR as Biomarker for Chemotherapy- Induced Neutropenia in Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Behzad Bidadi

    2018-03-01

    Full Text Available Neutropenia secondary to chemotherapy in breast cancer patients can be life-threatening and there are no biomarkers available to predict the risk of drug-induced neutropenia in those patients. We previously performed a genome-wide association study (GWAS for neutropenia events in women with breast cancer who were treated with 5-fluorouracil, epirubicin and cyclophosphamide and recruited to the SUCCESS-A trial. A genome-wide significant single-nucleotide polymorphism (SNP signal in the tumor necrosis factor superfamily member 13B (TNFSF13B gene, encoding the cytokine B-cell activating factor (BAFF, was identified in that GWAS. Taking advantage of these existing GWAS data, in the present study we utilized a pathway-based analysis approach by leveraging knowledge of the pharmacokinetics and pharmacodynamics of drugs and breast cancer pathophysiology to identify additional SNPs/genes associated with the underlying etiology of chemotherapy-induced neutropenia. We identified three SNPs in the hyaluronan mediated motility receptor (HMMR gene that were significantly associated with neutropenia (p < 1.0E-04. Those three SNPs were trans-expression quantitative trait loci for the expression of TNFSF13B (p < 1.0E-04. The minor allele of these HMMR SNPs was associated with a decreased TNFSF13B mRNA level. Additional functional studies performed with lymphoblastoid cell lines (LCLs demonstrated that LCLs possessing the minor allele for the HMMR SNPs were more sensitive to drug treatment. Knock-down of TNFSF13B in LCLs and HL-60 promyelocytic cells and treatment of those cells with BAFF modulated the cell sensitivity to chemotherapy treatment. These results demonstrate that HMMR SNP-dependent cytotoxicity of these chemotherapeutic agents might be related to TNFSF13B expression level. In summary, utilizing a pathway-based approach for the analysis of GWAS data, we identified additional SNPs in the HMMR gene that were associated with neutropenia and also were

  8. Use of a Web-based Delphi for identifying critical components of a professional science master's program in biotechnology

    Science.gov (United States)

    Kantz, Jeannine Wells

    The primary purpose of this research was to develop a model for a professional science master's program combining biotechnology and business. The objectives were to identify stakeholder preferences for various dimensions of a professional science master's program combining biotechnology and business and to identify differences in priorities between subgroups. A secondary purpose was to examine user preferences between Web-based and traditional methods of conducting a Delphi study and the panelist's impressions of its usefulness for program development. Prior to the first round, demographic data were collected on panelists regarding their gender, age, years experience in their current field, position title and education levels. Round 1 started with eight open-ended questions designed to investigate (a) learning objectives, (b) internships, (c) thesis vs. non-thesis degrees, (d) program focus (e) possible entry level positions, (f) roles for the industry advisory board, (g) recommended hours of hands-on experience and (h) other issues of importance. The final round ended with three questions to assess the panelists' perception of the usefulness of the Delphi for program development in higher education. Twenty-four panelists started Round 1 and participation in subsequent rounds varied from 17 in Round 2 to 11 in Round 4. Education level varied and included all levels of education in science and business. Issues emerged early in the study regarding development of different program tracks and the program goals, which were clarified in subsequent rounds. Significant differences occurred between industry and academic subgroups for two tracks, six skills designated for tracks, method of evaluating the internship, and entry-level positions appropriate for new graduates. When analyzed by level of confidence (high confidence vs. low confidence), significant differences occurred for (a) the number of semesters of hands-on experience students should have upon graduation, (b

  9. Time-tradeoff utilities for identifying and evaluating a minimum data set for time-critical biosurveillance.

    Science.gov (United States)

    Doctor, Jason N; Baseman, Janet G; Lober, William B; Davies, Jac; Kobayashi, John; Karras, Bryant T; Fuller, Sherrilynne

    2008-01-01

    Researchers and policy makers are interested in identifying, implementing, and evaluating a national minimum data set for biosurveillance. However, work remains to be done to establish methods for measuring the value of such data. The purpose of this article is to establish and evaluate a method for measuring the utility of biosurveillance data. The authors derive an expected utility model in which the value of data may be determined by trading data relevance for time delay in receiving data. In a sample of 23 disease surveillance practitioners, the authors test if such tradeoffs are sensitive to the types of data elements involved (chief complaint v. emergency department [ED] log of visit) and proportional changes to the time horizon needed for receiving data (24 v. 48 h). In addition, they evaluate the logical error rate: the proportion of responses that scored less relevant data as having higher utility. Utilities of chief complaints were significantly higher than ED log of visit, F(1, 21)= 5.60, P biosurveillance data. Empirically, the method shows initial promise for evaluating a minimum data set for biosurveillance. Future applications of this approach may prove useful in disease surveillance planning and evaluation.

  10. Identifying Critical Habitat for Australian Freshwater Turtles in a Large Regulated Floodplain: Implications for Environmental Water Management

    Science.gov (United States)

    Ocock, J. F.; Bino, G.; Wassens, S.; Spencer, J.; Thomas, R. F.; Kingsford, R. T.

    2018-03-01

    Freshwater turtles face many threats, including habitat loss and river regulation reducing occupancy and contributing to population decline. Limited knowledge of hydrological conditions required to maintain viable turtle populations in large floodplain wetlands hinders effective adaptive management of environmental water in regulated rivers. We surveyed three turtle species over 4 years across the Lower Murrumbidgee River floodplain, a large wetland complex with a long history of water resource development. Using site and floodplain metrics and generalized linear models, within a Bayesian Model Averaging framework, we quantified the main drivers affecting turtle abundance. We also used a hierarchical modeling approach, requiring large sample sizes, quantifying possible environmental effects while accounting for detection probabilities of the eastern long-necked turtle ( Chelodina longicollis). The three species varied in their responses to hydrological conditions and connectivity to the main river channel. Broad-shelled turtles ( Chelodina expansa) and Macquarie River turtles ( Emydura macquarii macquarii) had restricted distributions, centered on frequently inundated wetlands close to the river, whereas the eastern long-necked turtles were more widely distributed, indicating an ability to exploit variable habitats. We conclude that turtle communities would benefit from long-term management strategies that maintain a spatiotemporal mosaic of hydrological conditions. More specifically, we identified characteristics of refuge habitats and stress the importance of maintaining their integrity during dry periods. Neighboring habitats can be targeted during increased water availability years to enhance feeding and dispersal opportunities for freshwater turtles.

  11. Critical role of SDF-1/CXCR4 signaling pathway in stem cell homing in the deafened rat cochlea after acoustic trauma.

    Science.gov (United States)

    Peyvandi, Ali Asghar; Roozbahany, Navid Ahmady; Peyvandi, Hassan; Abbaszadeh, Hojjat-Allah; Majdinasab, Niloofar; Faridan, Mohammad; Niknazar, Somayeh

    2018-01-01

    Previous animal studies have shown that stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling pathway plays an important role in the targeted migration of bone marrow-derived mesenchymal stem cells (BMSCs) to the injured area. In the present study, we aimed to investigate the potential role of chemotactic SDF-1/CXCR4 signaling pathway in the homing of transplanted BMSCs to the injured cochlea after noise-induced hearing loss (NIHL) in a rat model. White noise exposure (110 dB) paradigm was used for hearing loss induction in male rats for 6 hours in 5 days. Distortion-product otoacoustic emission (DPOAE) responses were recorded before the experiment and post noise exposure. Hoechst 33342-labeled BMSCs and CXCR4 antagonist (AMD3100)-treated BMSCs were injected into the rat cochlea through the round window. SDF-1 protein expression in the cochlear tissue was assayed using western blot assay. The number of labeled BMSCs reaching the endolymph was determined after 24 hours. SDF-1 was significantly increased in the cochlear tissue of rats in the noise exposure group than in the control group. The number of Hoechst 33342-labeled BMSCs reaching the endolymph of the cochlea was significantly smaller in the AMD3100-treated BMSCs group than in the normal BMSCs group. Our present findings suggest that the SDF-1/CXCR4 signaling pathway has a critical role in BMSCs migration to the injured cochlea in a rat model of noise-induced hearing loss.

  12. Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss.

    Directory of Open Access Journals (Sweden)

    Joel Lavinsky

    2015-04-01

    Full Text Available In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP to a 10 kHz octave band noise at 108 dB for 2 hours and assessed the permanent threshold shift 2 weeks post exposure using frequency specific stimuli. These data were then used in a genome-wide association study (GWAS using the Efficient Mixed Model Analysis (EMMA to control for population structure. In this manuscript we describe our GWAS, with an emphasis on a significant peak for susceptibility to NIHL on chromosome 17 within a haplotype block containing NADPH oxidase-3 (Nox3. Our peak was detected after an 8 kHz tone burst stimulus. Nox3 mutants and heterozygotes were then tested to validate our GWAS. The mutants and heterozygotes demonstrated a greater susceptibility to NIHL specifically at 8 kHz both on measures of distortion product otoacoustic emissions (DPOAE and on auditory brainstem response (ABR. We demonstrate that this sensitivity resides within the synaptic ribbons of the cochlea in the mutant animals specifically at 8 kHz. Our work is the first GWAS for NIHL in mice and elucidates the power of our approach to identify tonotopic genetic susceptibility to NIHL.

  13. Identifying critical steps towards improved access to innovation in cancer care: a European CanCer Organisation position paper.

    Science.gov (United States)

    Aapro, Matti; Astier, Alain; Audisio, Riccardo; Banks, Ian; Bedossa, Pierre; Brain, Etienne; Cameron, David; Casali, Paolo; Chiti, Arturo; De Mattos-Arruda, Leticia; Kelly, Daniel; Lacombe, Denis; Nilsson, Per J; Piccart, Martine; Poortmans, Philip; Riklund, Katrine; Saeter, Gunnar; Schrappe, Martin; Soffietti, Riccardo; Travado, Luzia; van Poppel, Hein; Wait, Suzanne; Naredi, Peter

    2017-09-01

    In recent decades cancer care has seen improvements in the speed and accuracy of diagnostic procedures; the effectiveness of surgery, radiation therapy and medical treatments; the power of information technology; and the development of multidisciplinary, specialist-led approaches to care. Such innovations are essential if we are to continue improving the lives of cancer patients across Europe despite financial pressures on our healthcare systems. Investment in innovation must be balanced with the need to ensure the sustainability of healthcare budgets, and all health professionals have a responsibility to help achieve this balance. It requires scrutiny of the way care is delivered; we must be ready to discontinue practices or interventions that are inefficient, and prioritise innovations that may deliver the best outcomes possible for patients within the limits of available resources. Decisions on innovations should take into account their long-term impact on patient outcomes and costs, not just their immediate costs. Adopting a culture of innovation requires a multidisciplinary team approach, with the patient at the centre and an integral part of the team. It must take a whole-system and whole-patient perspective on cancer care and be guided by high-quality real-world data, including outcomes relevant to the patient and actual costs of care; this accurately reflects the impact of any innovation in clinical practice. The European CanCer Organisation is committed to working with its member societies, patient organisations and the cancer community at large to find sustainable ways to identify and integrate the most meaningful innovations into all aspects of cancer care. Copyright © 2017. Published by Elsevier Ltd.

  14. A critical evaluation of the use of cluster analysis to identify contaminated sediments in the Ria de Vigo

    Energy Technology Data Exchange (ETDEWEB)

    Rubio, B; Nombela, M. A; Vilas, F [Departamento de Geociencias Marinas y Ordenacion del Territorio, Vigo, Espana (Spain)

    2001-06-01

    The indiscriminate use of cluster analysis to distinguish contaminated and non-contaminated sediments has led us to make a comparative evaluation of different cluster analysis procedures as applied to heavy metal concentrations in subtidal sediments from the Ria de Vigo, NW Spain. The use of different clusters algorithms and other transformations from the same departing set of data lead to the formation of different clusters with a clear inconclusive result about the contamination status of the sediments. The results show that this approach is better suited to identifying groups of samples differing in sedimentological characteristics, such as grain size, rather than in the degree of contamination. Our main aim is to call attention to these aspects in cluster analysis and to suggest that researches should be rigorous with this kind of analysis. Finally, the use of discriminate analysis allows us to find a discriminate function that separates the samples into two clearly differentiated groups, which should not be treated jointly. [Spanish] El uso indiscriminado del analisis cluster para distinguir sedimentos contaminados y no contaminados nos ha llevado a realizar una evaluacion comparativa entre los diferentes procedimientos de estos analisis aplicada a la concentracion de metales pesados en sedimentos submareales de la Ria de Vigo, NW de Espana. La utilizacion de distintos algoritmos de cluster, asi como otras transformaciones de la misma matriz de datos conduce a la formacion de diferentes clusters con un resultado inconcluso sobre el estado de contaminacion de los sedimentos. Los resultados muestran que esta aproximacion se ajusta mejor para identificar grupos de muestras que difieren en caracteristicas sedimentologicas, tal como el tamano de grano, mas que el grado de contaminacion. El principal objetivo es llamar la atencion sobre estos aspectos del analisis cluster y sugerir a los investigadores que sean rigurosos con este tipo de analisis. Finalmente el uso

  15. A care pathway analysis of tuberculosis patients in benin: Highlights on direct costs and critical stages for an evidence-based decision-making.

    Directory of Open Access Journals (Sweden)

    Samia Laokri

    Full Text Available BACKGROUND: Free tuberculosis control fail to protect patients from substantial medical and non-medical expenditure, thus a greater degree of disaggregation of patient cost is needed to fully capture their context and inform policymaking. METHODS: A retrospective cross-sectional study was conducted on a convenience sample of six health districts of Southern Benin. From August 2008 to February 2009, we recruited all smear-positive pulmonary tuberculosis patients treated under the national strategy in the selected districts. Direct out-of-pocket costs associated with tuberculosis, time delays, and care-seeking pattern were collected from symptom onset to end of treatment. RESULTS: Population description and outcome data were reported for 245 patients of whom 153 completed their care pathway. For them, the median overall direct cost was USD 183 per patient. Payments to traditional healers, self-medication drugs, travel, and food expenditures contributed largely to this cost burden. Patient, provider, and treatment delays were also reported. Pre-diagnosis and intensive treatment stages were the most critical stages, with median expenditure of USD 43 per patient and accounting for 38% and 29% of the overall direct cost, respectively. However, financial barriers differed depending on whether the patient lived in urban or rural areas. CONCLUSIONS: This study delivers new evidence about bottlenecks encountered during the TB care pathway. Financial barriers to accessing the free-of-charge tuberculosis control strategy in Benin remain substantial for low-income households. Irregular time delays and hidden costs, often generated by multiple visits to various care providers, impair appropriate patient pathways. Particular attention should be paid to pre-diagnosis and intensive treatment. Cost assessment and combined targeted interventions embodied by a patient-centered approach on the specific critical stages would likely deliver better program outcomes.

  16. Global Gene-Expression Analysis to Identify Differentially Expressed Genes Critical for the Heat Stress Response in Brassica rapa.

    Directory of Open Access Journals (Sweden)

    Xiangshu Dong

    Full Text Available Genome-wide dissection of the heat stress response (HSR is necessary to overcome problems in crop production caused by global warming. To identify HSR genes, we profiled gene expression in two Chinese cabbage inbred lines with different thermotolerances, Chiifu and Kenshin. Many genes exhibited >2-fold changes in expression upon exposure to 0.5- 4 h at 45°C (high temperature, HT: 5.2% (2,142 genes in Chiifu and 3.7% (1,535 genes in Kenshin. The most enriched GO (Gene Ontology items included 'response to heat', 'response to reactive oxygen species (ROS', 'response to temperature stimulus', 'response to abiotic stimulus', and 'MAPKKK cascade'. In both lines, the genes most highly induced by HT encoded small heat shock proteins (Hsps and heat shock factor (Hsf-like proteins such as HsfB2A (Bra029292, whereas high-molecular weight Hsps were constitutively expressed. Other upstream HSR components were also up-regulated: ROS-scavenging genes like glutathione peroxidase 2 (BrGPX2, Bra022853, protein kinases, and phosphatases. Among heat stress (HS marker genes in Arabidopsis, only exportin 1A (XPO1A (Bra008580, Bra006382 can be applied to B. rapa for basal thermotolerance (BT and short-term acquired thermotolerance (SAT gene. CYP707A3 (Bra025083, Bra021965, which is involved in the dehydration response in Arabidopsis, was associated with membrane leakage in both lines following HS. Although many transcription factors (TF genes, including DREB2A (Bra005852, were involved in HS tolerance in both lines, Bra024224 (MYB41 and Bra021735 (a bZIP/AIR1 [Anthocyanin-Impaired-Response-1] were specific to Kenshin. Several candidate TFs involved in thermotolerance were confirmed as HSR genes by real-time PCR, and these assignments were further supported by promoter analysis. Although some of our findings are similar to those obtained using other plant species, clear differences in Brassica rapa reveal a distinct HSR in this species. Our data could also provide a

  17. Biochemical and Phylogenetic Characterization of a Novel Diaminopimelate Biosynthesis Pathway in Prokaryotes Identifies a Diverged Form of ll-Diaminopimelate Aminotransferase▿ †

    Science.gov (United States)

    Hudson, André O.; Gilvarg, Charles; Leustek, Thomas

    2008-01-01

    A variant of the diaminopimelate (DAP)-lysine biosynthesis pathway uses an ll-DAP aminotransferase (DapL, EC 2.6.1.83) to catalyze the direct conversion of l-2,3,4,5-tetrahydrodipicolinate to ll-DAP. Comparative genomic analysis and experimental verification of DapL candidates revealed the existence of two diverged forms of DapL (DapL1 and DapL2). DapL orthologs were identified in eubacteria and archaea. In some species the corresponding dapL gene was found to lie in genomic contiguity with other dap genes, suggestive of a polycistronic structure. The DapL candidate enzymes were found to cluster into two classes sharing approximately 30% amino acid identity. The function of selected enzymes from each class was studied. Both classes were able to functionally complement Escherichia coli dapD and dapE mutants and to catalyze ll-DAP transamination, providing functional evidence for a role in DAP/lysine biosynthesis. In all cases the occurrence of dapL in a species correlated with the absence of genes for dapD and dapE representing the acyl DAP pathway variants, and only in a few cases was dapL coincident with ddh encoding meso-DAP dehydrogenase. The results indicate that the DapL pathway is restricted to specific lineages of eubacteria including the Cyanobacteria, Desulfuromonadales, Firmicutes, Bacteroidetes, Chlamydiae, Spirochaeta, and Chloroflexi and two archaeal groups, the Methanobacteriaceae and Archaeoglobaceae. PMID:18310350

  18. Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson’s Disease

    Science.gov (United States)

    Viereckel, Thomas; Dumas, Sylvie; Smith-Anttila, Casey J. A.; Vlcek, Bianca; Bimpisidis, Zisis; Lagerström, Malin C.; Konradsson-Geuken, Åsa; Wallén-Mackenzie, Åsa

    2016-01-01

    The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson’s disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders. PMID:27762319

  19. Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses

    Directory of Open Access Journals (Sweden)

    Sorribas Albert

    2009-11-01

    Full Text Available Abstract Background Optimization methods allow designing changes in a system so that specific goals are attained. These techniques are fundamental for metabolic engineering. However, they are not directly applicable for investigating the evolution of metabolic adaptation to environmental changes. Although biological systems have evolved by natural selection and result in well-adapted systems, we can hardly expect that actual metabolic processes are at the theoretical optimum that could result from an optimization analysis. More likely, natural systems are to be found in a feasible region compatible with global physiological requirements. Results We first present a new method for globally optimizing nonlinear models of metabolic pathways that are based on the Generalized Mass Action (GMA representation. The optimization task is posed as a nonconvex nonlinear programming (NLP problem that is solved by an outer-approximation algorithm. This method relies on solving iteratively reduced NLP slave subproblems and mixed-integer linear programming (MILP master problems that provide valid upper and lower bounds, respectively, on the global solution to the original NLP. The capabilities of this method are illustrated through its application to the anaerobic fermentation pathway in Saccharomyces cerevisiae. We next introduce a method to identify the feasibility parametric regions that allow a system to meet a set of physiological constraints that can be represented in mathematical terms through algebraic equations. This technique is based on applying the outer-approximation based algorithm iteratively over a reduced search space in order to identify regions that contain feasible solutions to the problem and discard others in which no feasible solution exists. As an example, we characterize the feasible enzyme activity changes that are compatible with an appropriate adaptive response of yeast Saccharomyces cerevisiae to heat shock Conclusion Our results

  20. In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

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    Alessandro Carugo

    2016-06-01

    Full Text Available Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4 MLL (1–4 methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease.

  1. Expression microarray meta-analysis identifies genes associated with Ras/MAPK and related pathways in progression of muscle-invasive bladder transition cell carcinoma.

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    Jonathan A Ewald

    Full Text Available The effective detection and management of muscle-invasive bladder Transition Cell Carcinoma (TCC continues to be an urgent clinical challenge. While some differences of gene expression and function in papillary (Ta, superficial (T1 and muscle-invasive (≥T2 bladder cancers have been investigated, the understanding of mechanisms involved in the progression of bladder tumors remains incomplete. Statistical methods of pathway-enrichment, cluster analysis and text-mining can extract and help interpret functional information about gene expression patterns in large sets of genomic data. The public availability of patient-derived expression microarray data allows open access and analysis of large amounts of clinical data. Using these resources, we investigated gene expression differences associated with tumor progression and muscle-invasive TCC. Gene expression was calculated relative to Ta tumors to assess progression-associated differences, revealing a network of genes related to Ras/MAPK and PI3K signaling pathways with increased expression. Further, we identified genes within this network that are similarly expressed in superficial Ta and T1 stages but altered in muscle-invasive T2 tumors, finding 7 genes (COL3A1, COL5A1, COL11A1, FN1, ErbB3, MAPK10 and CDC25C whose expression patterns in muscle-invasive tumors are consistent in 5 to 7 independent outside microarray studies. Further, we found increased expression of the fibrillar collagen proteins COL3A1 and COL5A1 in muscle-invasive tumor samples and metastatic T24 cells. Our results suggest that increased expression of genes involved in mitogenic signaling may support the progression of muscle-invasive bladder tumors that generally lack activating mutations in these pathways, while expression changes of fibrillar collagens, fibronectin and specific signaling proteins are associated with muscle-invasive disease. These results identify potential biomarkers and targets for TCC treatments, and

  2. Physiological and proteomic analyses of leaves from the halophyte Tangut Nitraria reveals diverse response pathways critical for high salinity tolerance

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    Tielong eCheng

    2015-02-01

    Full Text Available Soil salinization poses a serious threat to the environment and agricultural productivity worldwide. Studies on the physiological and molecular mechanisms of salinity tolerance in halophytic plants provide valuable information to enhance their salt tolerance. Tangut Nitraria is a widely distributed halophyte in saline–alkali soil in the northern areas of China. In this study, we used a proteomic approach to investigate the molecular pathways of the high salt tolerance of T. Nitraria. We analyzed the changes in biomass, photosynthesis, and redox-related enzyme activities in T. Nitraria leaves from plant seedlings treated with high salt concentration. Comparative proteomic analysis of the leaves revealed that the expression of 71 proteins was significantly altered after salinity treatments of T. Nitraria. These salinity-responsive proteins were mainly involved in photosynthesis, redox homeostasis, stress/defense, carbohydrate and energy metabolism, protein metabolism, signal transduction, and membrane transport. Results showed that the reduction of photosynthesis under salt stress was attributed to the down-regulation of the enzymes and proteins involved in the light reaction and Calvin cycle. Protein–protein interaction analysis revealed that the proteins involved in redox homeostasis, photosynthesis, and energy metabolism constructed two types of response networks to high salt stress. T. Nitraria plants developed diverse mechanisms for scavenging reactive oxygen species in their leaves to cope with stress induced by high salinity. This study provides important information regarding the salt tolerance of the halophyte T. Nitraria.

  3. Curcumin-Induced Apoptosis in Human Hepatocellular Carcinoma J5 Cells: Critical Role of Ca+2-Dependent Pathway

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    Wei-Hsun Wang

    2012-01-01

    Full Text Available The antitumor effects of curcumin, a natural biologically active compound extracted from rhizomes of Curcuma longa, have been studied in many cancer cell types including human hepatocellular carcinoma (HCC. Here, we investigated the effects of Ca2+ on curcumin-induced apoptosis in human HCC J5 cells. The abrogation of mitochondrial membrane potential (ΔΨm, the increase of reactive oxygen species (ROS production, and calcium release were demonstrated with flow cytometry as early as 15 minutes after curcumin treatment. In addition, an increase level of cytochrome c in the cytoplasm which led to DNA fragmentation was observed. To verify the role of Ca2+ in curcumin-induced apoptosis, 1,2-bis(o-aminophenoxyethane-N,N,N′,N′-tetraacetic acid (BAPTA, an intracellular calcium chelator, was applied. Cell viability was increased, but ΔΨm, ROS production, activation of caspase 3, and cell death were decreased in J5 cells pretreated with BAPTA for 2 h followed by the treatment of 25 μM curcumin. These results suggest that the curcumin-induced apoptosis in human HCC J5 cells is via mitochondria-dependent pathway and is closely related to the level of intracellular accumulation of calcium.

  4. Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Nanoparticle Titanium Dioxide

    Science.gov (United States)

    Identification of toxicity pathways linked to chemical -exposure is critical for a better understanding of biological effects of the exposure, toxic mechanisms, and for enhancement of the prediction of chemical toxicity and adverse health outcomes. To identify toxicity pathways a...

  5. Comment: critical examination of stable isotope analysis as a means for tracing carbon pathways in stream ecosystems

    International Nuclear Information System (INIS)

    Doucett, R.R.; Barton, D.R.; Guiguer, K.R.A.; Power, G.; Drimmie, R.J.

    1996-01-01

    Stable isotope analysis (SIA) is studied as a technique for deciphering food webs and identifying impacts of alterations in land use. The 13 C values for allochthonous litter, attached algae and consumers in stream ecosystems were discussed as using stable isotope analysis. 17 refs

  6. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility.

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    Wintermantel, Tim M; Campbell, Rebecca E; Porteous, Robert; Bock, Dagmar; Gröne, Hermann-Josef; Todman, Martin G; Korach, Kenneth S; Greiner, Erich; Pérez, Cristian A; Schütz, Günther; Herbison, Allan E

    2006-10-19

    The mechanisms through which estrogen regulates gonadotropin-releasing hormone (GnRH) neurons to control mammalian ovulation are unknown. We found that estrogen positive feedback to generate the preovulatory gonadotropin surge was normal in estrogen receptor beta knockout (ERbeta) mutant mice, but absent in ERalpha mutant mice. An ERalpha-selective compound was sufficient to generate positive feedback in wild-type mice. As GnRH neurons do not express ERalpha, estrogen positive feedback upon GnRH neurons must be indirect in nature. To establish the cell type responsible, we generated a neuron-specific ERalpha mutant mouse line. These mice failed to exhibit estrogen positive feedback, demonstrating that neurons expressing ERalpha are critical. We then used a GnRH neuron-specific Pseudorabies virus (PRV) tracing approach to show that the ERalpha-expressing neurons innervating GnRH neurons are located within rostral periventricular regions of the hypothalamus. These studies demonstrate that ovulation is driven by estrogen actions upon ERalpha-expressing neuronal afferents to GnRH neurons.

  7. Several 'problem nutrients' are identified in complementary feeding of Guatemalan infants with continued breastfeeding using the concept of 'critical nutrient density'.

    Science.gov (United States)

    Vossenaar, M; Hernández, L; Campos, R; Solomons, N W

    2013-01-01

    The World Health Organization (WHO) recommends nutritionally adequate complementary feeding (CF) through the introduction of indigenous foodstuffs and local foods while breastfeeding for at least 2 years. To determine the adequacy of the contribution of CF to the diets of Guatemalan infants at the 7th-12th month of life receiving high-intensity continued breastfeeding. Critical nutrient densities for CF were modelled using age- and sex-specific energy and protein requirements assuming children to be at the 50th weight percentile of local peers and 15th weight percentiles of the 2006 WHO standards. Nutrient requirements for the total diet were determined using the recommended nutrient intakes. Breast milk was assumed to provide 75% of total energy at the 7th-9th month and 50% at the 10th-12th month. Gaps between computed critical nutrient densities and the CF consumption of 128 Guatemalan infants based on data collected by means of three nonconsecutive 24-h quantitative intake recalls were examined. Locally consumed foods with nutrient densities above the modelled critical densities were identified. Observed non-breast milk complementation would result in total diets providing inadequate nutrient density for vitamin A, niacin and vitamin C in some age groups. Major gaps for calcium, iron and zinc were ubiquitous across all groups. Few foods commonly consumed among Guatemalan infants had adequate densities of 'problem nutrients'. The critical nutrient density concept is useful to evaluate the nutrient adequacy of the infant's diet. Fortified foods are essential sources of the main 'problem nutrients', namely calcium, iron and zinc, given that natural sources are scarce.

  8. Incorporation of spatial interactions in location networks to identify critical geo-referenced routes for assessing disease control measures on a large-scale campus.

    Science.gov (United States)

    Wen, Tzai-Hung; Chin, Wei Chien Benny

    2015-04-14

    Respiratory diseases mainly spread through interpersonal contact. Class suspension is the most direct strategy to prevent the spread of disease through elementary or secondary schools by blocking the contact network. However, as university students usually attend courses in different buildings, the daily contact patterns on a university campus are complicated, and once disease clusters have occurred, suspending classes is far from an efficient strategy to control disease spread. The purpose of this study is to propose a methodological framework for generating campus location networks from a routine administration database, analyzing the community structure of the network, and identifying the critical links and nodes for blocking respiratory disease transmission. The data comes from the student enrollment records of a major comprehensive university in Taiwan. We combined the social network analysis and spatial interaction model to establish a geo-referenced community structure among the classroom buildings. We also identified the critical links among the communities that were acting as contact bridges and explored the changes in the location network after the sequential removal of the high-risk buildings. Instead of conducting a questionnaire survey, the study established a standard procedure for constructing a location network on a large-scale campus from a routine curriculum database. We also present how a location network structure at a campus could function to target the high-risk buildings as the bridges connecting communities for blocking disease transmission.

  9. Incorporation of Spatial Interactions in Location Networks to Identify Critical Geo-Referenced Routes for Assessing Disease Control Measures on a Large-Scale Campus

    Directory of Open Access Journals (Sweden)

    Tzai-Hung Wen

    2015-04-01

    Full Text Available Respiratory diseases mainly spread through interpersonal contact. Class suspension is the most direct strategy to prevent the spread of disease through elementary or secondary schools by blocking the contact network. However, as university students usually attend courses in different buildings, the daily contact patterns on a university campus are complicated, and once disease clusters have occurred, suspending classes is far from an efficient strategy to control disease spread. The purpose of this study is to propose a methodological framework for generating campus location networks from a routine administration database, analyzing the community structure of the network, and identifying the critical links and nodes for blocking respiratory disease transmission. The data comes from the student enrollment records of a major comprehensive university in Taiwan. We combined the social network analysis and spatial interaction model to establish a geo-referenced community structure among the classroom buildings. We also identified the critical links among the communities that were acting as contact bridges and explored the changes in the location network after the sequential removal of the high-risk buildings. Instead of conducting a questionnaire survey, the study established a standard procedure for constructing a location network on a large-scale campus from a routine curriculum database. We also present how a location network structure at a campus could function to target the high-risk buildings as the bridges connecting communities for blocking disease transmission.

  10. Integrating high-content imaging and chemical genetics to probe host cellular pathways critical for Yersinia pestis infection.

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    Krishna P Kota

    Full Text Available The molecular machinery that regulates the entry and survival of Yersinia pestis in host macrophages is poorly understood. Here, we report the development of automated high-content imaging assays to quantitate the internalization of virulent Y. pestis CO92 by macrophages and the subsequent activation of host NF-κB. Implementation of these assays in a focused chemical screen identified kinase inhibitors that inhibited both of these processes. Rac-2-ethoxy-3 octadecanamido-1-propylphosphocholine (a protein Kinase C inhibitor, wortmannin (a PI3K inhibitor, and parthenolide (an IκB kinase inhibitor, inhibited pathogen-induced NF-κB activation and reduced bacterial entry and survival within macrophages. Parthenolide inhibited NF-κB activation in response to stimulation with Pam3CSK4 (a TLR2 agonist, E. coli LPS (a TLR4 agonist or Y. pestis infection, while the PI3K and PKC inhibitors were selective only for Y. pestis infection. Together, our results suggest that phagocytosis is the major stimulus for NF-κB activation in response to Y. pestis infection, and that Y. pestis entry into macrophages may involve the participation of protein kinases such as PI3K and PKC. More importantly, the automated image-based screening platform described here can be applied to the study of other bacteria in general and, in combination with chemical genetic screening, can be used to identify host cell functions facilitating the identification of novel antibacterial therapeutics.

  11. Integrative systems analysis of diet-induced obesity identified a critical transition in the transcriptomes of the murine liver and epididymal white adipose tissue.

    Science.gov (United States)

    Kim, J; Kwon, E-Y; Park, S; Kim, J-R; Choi, S-W; Choi, M-S; Kim, S-J

    2016-02-01

    It is well known that high-fat diet (HFD) can cause immune system-related pathological alterations after a significant body weight gain. The mechanisms of the delayed pathological alterations during the development of diet-induced obesity (DIO) are not fully understood. To elucidate the mechanisms underlying DIO development, we analyzed time-course microarray data obtained from a previous study. First, differentially expressed genes (DEGs) were identified at each time point by comparing the hepatic transcriptome of mice fed HFD with that of mice fed normal diet. Next, we clustered the union of DEGs and identified annotations related to each cluster. Finally, we constructed an 'integrated obesity-associated gene regulatory network (GRN) in murine liver'. We analyzed the epididymal white adipose tissue (eWAT) transcriptome usig the same procedure. Based on time-course microarray data, we found that the genes associated with immune responses were upregulated with an oscillating expression pattern between weeks 2 and 8, relatively downregulated between weeks 12 and 16, and eventually upregulated after week 20 in the liver of the mice fed HFD. The genes associated with immune responses were also upregulated at late stage, in the eWAT of the mice fed HFD. These results suggested that a critical transition occurred in the immune system-related transcriptomes of the liver and eWAT around week 16 of the DIO development, and this may be associated with the delayed pathological alterations. The GRN analysis suggested that Maff may be a key transcription factor for the immune system-related critical transition thatoccurred at week 16. We found that transcription factors associated with immune responses were centrally located in the integrated obesity-associated GRN in the liver. In this study, systems analysis identified regulatory network modules underlying the delayed immune system-related pathological changes during the development of DIO and could suggest possible

  12. Daily visual stimulation in the critical period enhances multiple aspects of vision through BDNF-mediated pathways in the mouse retina.

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    Mui, Amanda M; Yang, Victoria; Aung, Moe H; Fu, Jieming; Adekunle, Adewumi N; Prall, Brian C; Sidhu, Curran S; Park, Han Na; Boatright, Jeffrey H; Iuvone, P Michael; Pardue, Machelle T

    2018-01-01

    Visual experience during the critical period modulates visual development such that deprivation causes visual impairments while stimulation induces enhancements. This study aimed to determine whether visual stimulation in the form of daily optomotor response (OMR) testing during the mouse critical period (1) improves aspects of visual function, (2) involves retinal mechanisms and (3) is mediated by brain derived neurotrophic factor (BDNF) and dopamine (DA) signaling pathways. We tested spatial frequency thresholds in C57BL/6J mice daily from postnatal days 16 to 23 (P16 to P23) using OMR testing. Daily OMR-treated mice were compared to littermate controls that were placed in the OMR chamber without moving gratings. Contrast sensitivity thresholds, electroretinograms (ERGs), visual evoked potentials, and pattern ERGs were acquired at P21. To determine the role of BDNF signaling, a TrkB receptor antagonist (ANA-12) was systemically injected 2 hours prior to OMR testing in another cohort of mice. BDNF immunohistochemistry was performed on retina and brain sections. Retinal DA levels were measured using high-performance liquid chromatography. Daily OMR testing enhanced spatial frequency thresholds and contrast sensitivity compared to controls. OMR-treated mice also had improved rod-driven ERG oscillatory potential response times, greater BDNF immunoreactivity in the retinal ganglion cell layer, and increased retinal DA content compared to controls. VEPs and pattern ERGs were unchanged. Systemic delivery of ANA-12 attenuated OMR-induced visual enhancements. Daily OMR testing during the critical period leads to general visual function improvements accompanied by increased DA and BDNF in the retina, with this process being requisitely mediated by TrkB activation. These results suggest that novel combination therapies involving visual stimulation and using both behavioral and molecular approaches may benefit degenerative retinal diseases or amblyopia.

  13. Identifying early pathways of risk and resilience: The co-development of internalizing and externalizing symptoms and the role of harsh parenting

    Science.gov (United States)

    Wiggins, Jillian Lee; Mitchell, Colter; Hyde, Luke W.; Monk, Christopher S.

    2016-01-01

    Psychological disorders co-occur often in children, but little has been done to document the types of conjoint pathways internalizing and externalizing symptoms may take from the crucial early period of toddlerhood or how harsh parenting may overlap with early symptom co-development. To examine symptom co-development trajectories, we identified latent classes of individuals based on internalizing and externalizing symptoms across ages 3–9 and found three symptom co-development classes: normative symptoms (low), severe-decreasing symptoms (initially high but rapidly declining) and severe symptoms (high) trajectories. Next, joint models examined how parenting trajectories overlapped with internalizing and externalizing symptom trajectories. These trajectory classes demonstrated that, normatively, harsh parenting increased after toddlerhood, but the severe symptoms class was characterized by a higher level and steeper increase in harsh parenting and the severe-decreasing class by high, stable harsh parenting. Additionally, a transactional model examined the bi-directional relationships among internalizing and externalizing symptoms and harsh parenting as they may cascade over time in this early period. Harsh parenting uniquely contributed to externalizing symptoms, controlling for internalizing symptoms, but not vice versa. Also, internalizing symptoms appeared to be a mechanism by which externalizing symptoms increase. Results highlight the importance accounting for both internalizing and externalizing symptoms from an early age to understand risk for developing psychopathology and the role harsh parenting plays in influencing these trajectories. PMID:26439075

  14. Dominant mutations in S. cerevisiae PMS1 identify the Mlh1-Pms1 endonuclease active site and an exonuclease 1-independent mismatch repair pathway.

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    Catherine E Smith

    2013-10-01

    Full Text Available Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2/scPMS1. To better understand the function of Mlh1-Pms1 in MMR, we used Saccharomyces cerevisiae to identify six pms1 mutations (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A that were weakly dominant in wild-type cells, which surprisingly caused a strong MMR defect when present on low copy plasmids in an exo1Δ mutant. Molecular modeling showed these mutations caused amino acid substitutions in the metal coordination pocket of the Pms1 endonuclease active site and biochemical studies showed that they inactivated the endonuclease activity. This model of Mlh1-Pms1 suggested that the Mlh1-FERC motif contributes to the endonuclease active site. Consistent with this, the mlh1-E767stp mutation caused both MMR and endonuclease defects similar to those caused by the dominant pms1 mutations whereas mutations affecting the predicted metal coordinating residue Mlh1-C769 had no effect. These studies establish that the Mlh1-Pms1 endonuclease is required for MMR in a previously uncharacterized Exo1-independent MMR pathway.

  15. Inference of Longevity-Related Genes from a Robust Coexpression Network of Seed Maturation Identifies Regulators Linking Seed Storability to Biotic Defense-Related Pathways.

    Science.gov (United States)

    Righetti, Karima; Vu, Joseph Ly; Pelletier, Sandra; Vu, Benoit Ly; Glaab, Enrico; Lalanne, David; Pasha, Asher; Patel, Rohan V; Provart, Nicholas J; Verdier, Jerome; Leprince, Olivier; Buitink, Julia

    2015-10-01

    Seed longevity, the maintenance of viability during storage, is a crucial factor for preservation of genetic resources and ensuring proper seedling establishment and high crop yield. We used a systems biology approach to identify key genes regulating the acquisition of longevity during seed maturation of Medicago truncatula. Using 104 transcriptomes from seed developmental time courses obtained in five growth environments, we generated a robust, stable coexpression network (MatNet), thereby capturing the conserved backbone of maturation. Using a trait-based gene significance measure, a coexpression module related to the acquisition of longevity was inferred from MatNet. Comparative analysis of the maturation processes in M. truncatula and Arabidopsis thaliana seeds and mining Arabidopsis interaction databases revealed conserved connectivity for 87% of longevity module nodes between both species. Arabidopsis mutant screening for longevity and maturation phenotypes demonstrated high predictive power of the longevity cross-species network. Overrepresentation analysis of the network nodes indicated biological functions related to defense, light, and auxin. Characterization of defense-related wrky3 and nf-x1-like1 (nfxl1) transcription factor mutants demonstrated that these genes regulate some of the network nodes and exhibit impaired acquisition of longevity during maturation. These data suggest that seed longevity evolved by co-opting existing genetic pathways regulating the activation of defense against pathogens. © 2015 American Society of Plant Biologists. All rights reserved.

  16. Integrated analysis of oral tongue squamous cell carcinoma identifies key variants and pathways linked to risk habits, HPV, clinical parameters and tumor recurrence [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Neeraja Krishnan

    2015-11-01

    Full Text Available Oral tongue squamous cell carcinomas (OTSCC are a homogeneous group of tumors characterized by aggressive behavior, early spread to lymph nodes and a higher rate of regional failure. Additionally, the incidence of OTSCC among younger population (<50yrs is on the rise; many of whom lack the typical associated risk factors of alcohol and/or tobacco exposure. We present data on single nucleotide variations (SNVs, indels, regions with loss of heterozygosity (LOH, and copy number variations (CNVs from fifty-paired oral tongue primary tumors and link the significant somatic variants with clinical parameters, epidemiological factors including human papilloma virus (HPV infection and tumor recurrence. Apart from the frequent somatic variants harbored in TP53, CASP8, RASA1, NOTCH and CDKN2A genes, significant amplifications and/or deletions were detected in chromosomes 6-9, and 11 in the tumors. Variants in CASP8 and CDKN2A were mutually exclusive. CDKN2A, PIK3CA, RASA1 and DMD variants were exclusively linked to smoking, chewing, HPV infection and tumor stage. We also performed a whole-genome gene expression study that identified matrix metalloproteases to be highly expressed in tumors and linked pathways involving arachidonic acid and NF-k-B to habits and distant metastasis, respectively. Functional knockdown studies in cell lines demonstrated the role of CASP8 in a HPV-negative OTSCC cell line. Finally, we identified a 38-gene minimal signature that predicts tumor recurrence using an ensemble machine-learning method. Taken together, this study links molecular signatures to various clinical and epidemiological factors in a homogeneous tumor population with a relatively high HPV prevalence.

  17. An integrated approach to identify critical transcription factors in the protection against hydrogen peroxide-induced oxidative stress by Danhong injection.

    Science.gov (United States)

    Zhang, Jingjing; Guo, Feifei; Wei, Junying; Xian, Minghua; Tang, Shihuan; Zhao, Ye; Liu, Mingwei; Song, Lei; Geng, Ya; Yang, Hongjun; Ding, Chen; Huang, Luqi

    2017-11-01

    Oxidative stress plays a vital role in many pathological processes of the cardiovascular diseases. However, the underlying mechanism remains unclear, especially on a transcription factor (TF) level. In this study, a new method, concatenated tandem array of consensus transcription factor response elements (catTFREs), and an Illumina-based RNA-seq technology were integrated to systematically investigate the role of TFs in hydrogen peroxide (H 2 O 2 )-induced oxidative stress in cardiomyocytes; the damage was then rescued by Danhong injection (DHI), a Chinese standardized product approved for cardiovascular diseases treatment. The overall gene expression revealed cell apoptosis and DNA repair were vital for cardiomyocytes in resisting oxidative stress. By comprehensively integrating the transcription activity of TFs and their downstream target genes, an important TFs-target network were constructed and 13 TFs were identified as critical TFs in DHI-mediated protection in H 2 O 2 -induced oxidative stress. By using the integrated approach, seven TFs of these 13 TFs were also identified in melatonin-mediated protection in H 2 O 2 -induced damage. Furthermore, the transcription activity of DNA-(apurinic or apyrimidinic site) lyase (Apex1), Myocyte-specific enhancer factor 2D (Mef2d) and Pre B-cell leukemia transcription factor 3 (Pbx3) was further verified in pluripotent stem cell-derived cardiomyocytes. This research offers a new understanding of cardiomyocytes in response to H 2 O 2 -induced oxidative stress and reveals additional potential therapeutic targets. The combination of two parallel omics datasets (corresponding to the transcriptome and proteome) can reduce the noise in high-throughput data and reveal the fundamental changes of the biological process, making it suitable and reliable for investigation of critical targets in many other complicated pathological processes. Copyright © 2017. Published by Elsevier Inc.

  18. Integrated RNA-Seq and sRNA-Seq Analysis Identifies Chilling and Freezing Responsive Key Molecular Players and Pathways in Tea Plant (Camellia sinensis)

    Science.gov (United States)

    Zheng, Chao; Zhao, Lei; Wang, Yu; Shen, Jiazhi; Zhang, Yinfei; Jia, Sisi; Li, Yusheng; Ding, Zhaotang

    2015-01-01

    Tea [Camellia sinensis (L) O. Kuntze, Theaceae] is one of the most popular non-alcoholic beverages worldwide. Cold stress is one of the most severe abiotic stresses that limit tea plants’ growth, survival and geographical distribution. However, the genetic regulatory network and signaling pathways involved in cold stress responses in tea plants remain unearthed. Using RNA-Seq, DGE and sRNA-Seq technologies, we performed an integrative analysis of miRNA and mRNA expression profiling and their regulatory network of tea plants under chilling (4℃) and freezing (-5℃) stress. Differentially expressed (DE) miRNA and mRNA profiles were obtained based on fold change analysis, miRNAs and target mRNAs were found to show both coherent and incoherent relationships in the regulatory network. Furthermore, we compared several key pathways (e.g., ‘Photosynthesis’), GO terms (e.g., ‘response to karrikin’) and transcriptional factors (TFs, e.g., DREB1b/CBF1) which were identified as involved in the early chilling and/or freezing response of tea plants. Intriguingly, we found that karrikins, a new group of plant growth regulators, and β-primeverosidase (BPR), a key enzyme functionally relevant with the formation of tea aroma might play an important role in both early chilling and freezing response of tea plants. Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis further confirmed the results from RNA-Seq and sRNA-Seq analysis. This is the first study to simultaneously profile the expression patterns of both miRNAs and mRNAs on a genome-wide scale to elucidate the molecular mechanisms of early responses of tea plants to cold stress. In addition to gaining a deeper insight into the cold resistant characteristics of tea plants, we provide a good case study to analyse mRNA/miRNA expression and profiling of non-model plant species using next-generation sequencing technology. PMID:25901577

  19. Prevention of alcohol-heightened aggression by CRF-R1 antagonists in mice: critical role for DRN-PFC serotonin pathway.

    Science.gov (United States)

    Quadros, Isabel M; Hwa, Lara S; Shimamoto, Akiko; Carlson, Julia; DeBold, Joseph F; Miczek, Klaus A

    2014-11-01

    Alcohol can escalate aggressive behavior in a significant subgroup of rodents, humans, and nonhuman primates. The present study investigated whether blockade of corticotropin-releasing factor receptor type 1 (CRF-R1) could prevent the emergence of alcohol-heightened aggression in mice. The serotonin (5-HT) pathway from the dorsal raphe nucleus (DRN) to the medial prefrontal cortex (mPFC) by CRF-R1 was investigated as a possible target for the prevention of alcohol-heightened aggressive behavior. Male CFW mice that reliably exhibited aggressive behaviors after consuming 1 g/kg of alcohol received systemic or intra-DRN administration of CRF-R1 antagonists, CP-154,526 or MTIP, before a confrontation with a male conspecific. Blockade of DRN CRF-R1 receptors with both antagonists significantly reduced only alcohol-heightened aggression, whereas systemic administration reduced both alcohol-heightened and species-typical aggression. Next, a 5-HT1A agonist, 8-OH-DPAT, was coadministered with CP-154,526 into the DRN to temporarily disrupt 5-HT activity. This manipulation abolished the antiaggressive effects of intra-DRN CP-154,526. In the mPFC, in vivo microdialysis revealed that extracellular 5-HT levels were increased in mice that consumed alcohol and were then injected with CP-154,526, both systemically or intra-DRN. Neither alcohol nor CP-154,526 alone affected 5-HT release in the mPFC. The present results suggest the DRN as a critical site for CRF-R1 to modulate alcohol-heightened aggression via action on the serotonergic DRN-PFC pathway.

  20. The Liverpool Care Pathway for the Dying Patient: a critical analysis of its rise, demise and legacy in England [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Jane Seymour

    2018-02-01

    Full Text Available Background: The Liverpool Care Pathway for the Dying Patient (‘the LCP’ was an integrated care pathway (ICP recommended by successive governments in England and Wales to improve end-of-life care, using insights from hospice and palliative care. It was discontinued in 2014 following mounting criticism and a national review.  The ensuing debate among clinicians polarised between ‘blaming’ of the LCP and regret at its removal. Employing the concept of ‘boundary objects’, we aimed to address three questions: 1 why and how did the LCP come to prominence as a vehicle of policy and practice 2 what factors contributed to its demise? 3 what immediate implications and lessons resulted from its withdrawal? Methods: We use primary and secondary sources in the public domain to assemble a critical and historical review. Results: The rapidity of transfer and translation of the LCP reflected uncritical enthusiasm for ICPs in the early 2000s. The subsequent LCP ‘scandal’ demonstrated the power of social media in creating knowledge, as well as conflicting perceptions about end-of-life interventions. While the LCP had some weaknesses in its formulation and implementation, it became the bearer of responsibility for all aspects of NHS end-of-life care. This was beyond its original remit. It exposed fault lines in the NHS, provided a platform for debates about the ‘evidence’ required to underpin innovations in palliative care and became a conduit of discord about ‘good’ or ‘bad’ practice in care of the dying. It also fostered a previously unseen critique of assumptions within palliative care.  Conclusions:  In contrast to most observers of the LCP story who refer to the dangers of scaling up clinical interventions without an evidence base, we call for greater assessment of the wider risks and more careful consideration of the unintended consequences that might result from the roll out of new end-of-life interventions.

  1. Critical pathway for the management of acute heart failure at the Veterans Affairs San Diego Healthcare System: transforming performance measures into cardiac care.

    Science.gov (United States)

    Gardetto, Nancy J; Greaney, Karen; Arai, Lisa; Brenner, April; Carroll, Karen C; Howerton, Nancy M; Lee, Melinda; Pada, Laureen; Tseng, Marilynne; Maisel, Alan S

    2008-09-01

    Acute decompensated heart failure (ADHF) is a major public health problem and leading cause for hospitalization in people 65 years and older. Admission rates for ADHF, accounted for more than 1 million heart failure (HF) hospitalizations in 2004, and more than 6.5 million inpatient hospital days. Despite significant advances in HF management, including pharmacotherapy and devices; and extensive collaborative efforts of the American College of Cardiology, and American Heart Association to disseminate evidence-based practice guidelines for management of chronic HF in adults; 3 patients continue to present to the emergency departments in ADHF. The hospital treatment of HF frequently does not follow published guidelines, potentially contributing to the high morbidity, mortality, and economic cost of this disorder. This highlights an ongoing need for development of quality improvement programs that focus on delivering reliable, evidence-based care for patients with ADHF. Consequently, the development of clinical pathways has the potential to reduce the current variability in care, enhance guideline adherence, and improve outcomes for patients. The Veterans Affairs San Diego Healthcare System (VASDHCS) formed a multidisciplinary HF performance improvement team. The team set forth on the task of developing standard order sets for patients with ADHF. After analyzing local care processes, reviewing evidence of best care practices, and defining appropriate goals to satisfy the multidimensional needs of HF patient; the team developed a computerized pathway in a user-friendly format that is simple, yet comprehensive; and focuses on early stages of HF evaluation and treatment for patients presenting to the emergency department. Successful strategies to improve care for HF patients need to assist health care providers with rapid recognition and early aggressive treatment, while creating a reliable process that ensures continuity of care. This critical pathway for management of

  2. Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans

    Science.gov (United States)

    Ruparelia, Neil; Godec, Jernej; Lee, Regent; Chai, Joshua T.; Dall'Armellina, Erica; McAndrew, Debra; Digby, Janet E.; Forfar, J. Colin; Prendergast, Bernard D.; Kharbanda, Rajesh K.; Banning, Adrian P.; Neubauer, Stefan; Lygate, Craig A.; Channon, Keith M.; Haining, Nicholas W.; Choudhury, Robin P.

    2015-01-01

    Aims Monocytes play critical roles in tissue injury and repair following acute myocardial infarction (AMI). Specifically targeting inflammatory monocytes in experimental models leads to reduced infarct size and improved healing. However, data from humans are sparse, and it remains unclear whether monocytes play an equally important role in humans. The aim of this study was to investigate whether the monocyte response following AMI is conserved between humans and mice and interrogate patterns of gene expression to identify regulated functions. Methods and results Thirty patients (AMI) and 24 control patients (stable coronary atherosclerosis) were enrolled. Female C57BL/6J mice (n = 6/group) underwent AMI by surgical coronary ligation. Myocardial injury was quantified by magnetic resonance imaging (human) and echocardiography (mice). Peripheral monocytes were isolated at presentation and at 48 h. RNA from separated monocytes was hybridized to Illumina beadchips. Acute myocardial infarction resulted in a significant peripheral monocytosis in both species that positively correlated with the extent of myocardial injury. Analysis of the monocyte transcriptome following AMI demonstrated significant conservation and identified inflammation and mitosis as central processes to this response. These findings were validated in both species. Conclusions Our findings show that the monocyte transcriptome is conserved between mice and humans following AMI. Patterns of gene expression associated with inflammation and proliferation appear to be switched on prior to their infiltration of injured myocardium suggesting that the specific targeting of inflammatory and proliferative processes in these immune cells in humans are possible therapeutic strategies. Importantly, they could be effective in the hours after AMI. PMID:25982896

  3. A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.

    Science.gov (United States)

    Bustamante, Mariona; Standl, Marie; Bassat, Quique; Vilor-Tejedor, Natalia; Medina-Gomez, Carolina; Bonilla, Carolina; Ahluwalia, Tarunveer S; Bacelis, Jonas; Bradfield, Jonathan P; Tiesler, Carla M T; Rivadeneira, Fernando; Ring, Susan; Vissing, Nadja H; Fink, Nadia R; Jugessur, Astanand; Mentch, Frank D; Ballester, Ferran; Kriebel, Jennifer; Kiefte-de Jong, Jessica C; Wolsk, Helene M; Llop, Sabrina; Thiering, Elisabeth; Beth, Systke A; Timpson, Nicholas J; Andersen, Josefine; Schulz, Holger; Jaddoe, Vincent W V; Evans, David M; Waage, Johannes; Hakonarson, Hakon; Grant, Struan F A; Jacobsson, Bo; Bønnelykke, Klaus; Bisgaard, Hans; Davey Smith, George; Moll, Henriette A; Heinrich, Joachim; Estivill, Xavier; Sunyer, Jordi

    2016-09-15

    More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Applying meta-pathway analyses through metagenomics to identify the functional properties of the major bacterial communities of a single spontaneous cocoa bean fermentation process sample.

    Science.gov (United States)

    Illeghems, Koen; Weckx, Stefan; De Vuyst, Luc

    2015-09-01

    A high-resolution functional metagenomic analysis of a representative single sample of a Brazilian spontaneous cocoa bean fermentation process was carried out to gain insight into its bacterial community functioning. By reconstruction of microbial meta-pathways based on metagenomic data, the current knowledge about the metabolic capabilities of bacterial members involved in the cocoa bean fermentation ecosystem was extended. Functional meta-pathway analysis revealed the distribution of the metabolic pathways between the bacterial members involved. The metabolic capabilities of the lactic acid bacteria present were most associated with the heterolactic fermentation and citrate assimilation pathways. The role of Enterobacteriaceae in the conversion of substrates was shown through the use of the mixed-acid fermentation and methylglyoxal detoxification pathways. Furthermore, several other potential functional roles for Enterobacteriaceae were indicated, such as pectinolysis and citrate assimilation. Concerning acetic acid bacteria, metabolic pathways were partially reconstructed, in particular those related to responses toward stress, explaining their metabolic activities during cocoa bean fermentation processes. Further, the in-depth metagenomic analysis unveiled functionalities involved in bacterial competitiveness, such as the occurrence of CRISPRs and potential bacteriocin production. Finally, comparative analysis of the metagenomic data with bacterial genomes of cocoa bean fermentation isolates revealed the applicability of the selected strains as functional starter cultures. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. P53 and MITF/Bcl-2 identified as key pathways in the acquired resistance of NRAS-mutant melanoma to MEK inhibition.

    Science.gov (United States)

    Najem, Ahmad; Krayem, Mohammad; Salès, François; Hussein, Nader; Badran, Bassam; Robert, Caroline; Awada, Ahmad; Journe, Fabrice; Ghanem, Ghanem E

    2017-09-01

    Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors. Indeed, drug combinations targeting both mutant BRAF and MITF or one of its important targets Bcl-2 were effective in mutant BRAF melanoma but had no effect on acquired resistance. Therefore, we aimed to further investigate the downstream MITF targets that can explain this anti-apoptotic effect and to evaluate in parallel the effect of p53 reactivation on the promotion of apoptosis under MEK inhibition in a panel of Q61 NRAS-mutant melanoma cells. First, we showed that MEK inhibition (pimasertib) led to a significant inhibition of cell proliferation but with a limited effect on apoptosis that could be explained by the systematic MITF upregulation. Mimicking the MITF effect via cyclic adenosine monophosphate activation conferred resistance to MEK inhibition and upregulated Bcl-2 expression. In addition, acquired resistance to MEK inhibition was associated with a strong activation of the anti-apoptotic signalling MITF/Bcl-2. More importantly, selective Bcl-2 inhibition by ABT-199 or Bcl-2 knockout using CRISPR/Cas9 system annihilated the acquired resistance and restored the sensitivity of NRAS-mutant melanoma cells to MEK inhibition. Strikingly and similarly, direct p53 reactivation (PRIMA-1 Met , APR-246) also broke resistance and synergised with MEK

  6. Assessment of genetic diversity in the critically endangered Australian corroboree frogs, Pseudophryne corroboree and Pseudophryne pengilleyi, identifies four evolutionarily significant units for conservation.

    Science.gov (United States)

    Morgan, Matthew J; Hunter, David; Pietsch, Rod; Osborne, William; Keogh, J Scott

    2008-08-01

    The iconic and brightly coloured Australian northern corroboree frog, Pseudophryne pengilleyi, and the southern corroboree frog, Pseudophryne corroboree are critically endangered and may be extinct in the wild within 3 years. We have assembled samples that cover the current range of both species and applied hypervariable microsatellite markers and mitochondrial DNA sequences to assess the levels and patterns of genetic variation. The four loci used in the study were highly variable, the total number of alleles observed ranged from 13 to 30 and the average number of alleles per locus was 19. Expected heterozygosity of the four microsatellite loci across all populations was high and varied between 0.830 and 0.935. Bayesian clustering analyses in STRUCTURE strongly supported four genetically distinct populations, which correspond exactly to the four main allopatric geographical regions in which the frogs are currently found. Individual analyses performed on the separate regions showed that breeding sites within these four regions could not be separated into distinct populations. Twelve mtND2 haplotypes were identified from 66 individuals from throughout the four geographical regions. A statistical parsimony network of mtDNA haplotypes shows two distinct groups, which correspond to the two species of corroboree frog, but with most of the haplotype diversity distributed in P. pengilleyi. These results demonstrate an unexpectedly high level of genetic diversity in both species. Our data have important implications for how the genetic diversity is managed in the future. The four evolutionarily significant units must be protected and maintained in captive breeding programmes for as long as it is possible to do.

  7. Developing a workbook to support the contextualisation of global health systems guidance: a case study identifying steps and critical factors for success in this process at WHO.

    Science.gov (United States)

    Alvarez, Elizabeth; Lavis, John N; Brouwers, Melissa; Schwartz, Lisa

    2018-03-02

    Global guidance can help countries strengthen their health systems to deliver effective interventions to their populations. However, to have an impact, guidance needs to be contextualised or adapted to local settings; this process includes consideration of health system arrangements and political system factors. To date, methods to support contextualisation do not exist. In response, a workbook was designed to provide specific methods and strategies to enable the contextualisation of WHO's 'Optimizing health worker roles to improve maternal and newborn health' (OptimizeMNH) guidance at the national or subnational level. The objective of this study was to describe the process of developing the workbook and identify key steps of the development process, barriers that arose and facilitators that helped overcome some of these barriers. A qualitative single case study design was carried out. Interviews, documents and a reflexive journal were used. Constant comparison and an edit-style of organisation were used during data analysis to develop concepts, themes, subthemes and relationships among them. Thirteen interviews were conducted and 52 documents were reviewed. Three main steps were identified in the process of developing the workbook for health systems guidance contextualisation, namely (1) determining the need for and gaining approval to develop the workbook, (2) developing the workbook (taking on the task, creating the structure of the workbook, operationalising its components, undergoing approval processes and editing it), and (3) implementing the workbook both at the WHO level and at the national/subnational level. Five barriers and/or facilitators emerged relevant to each step, namely (1) having well-placed and credible champions, (2) creating and capitalising on opportunities, (3) finding the right language to engage various actors and obtain buy-in, (4) obtaining and maintaining meaningful buy-in, and (5) ensuring access to resources. Understanding the key

  8. The Critical Role of Redox Homeostasis in Shikonin-Induced HL-60 Cell Differentiation via Unique Modulation of the Nrf2/ARE Pathway

    Directory of Open Access Journals (Sweden)

    Bo Zhang

    2012-01-01

    Full Text Available Among various cancer cell lines, the leukemia cell line HL-60 was most sensitive to Shikonin, with evidence showing both the prooxidative activities and proapoptotic effects of micromolar concentrations of Shikonin. However, the mechanism involved in the cytotoxicity of Shikonin in the submicromolar range has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the prodifferentiated profiles of Shikonin and evaluated the redox homeostasis during HL-60 differentiation. The data showed a strong dose-response relationship between Shikonin exposure and the characteristics of HL-60 differentiation in terms of morphology changes, nitroblue tetrazolium (NBT reductive activity, and the expression level of surface antigens CD11b/CD14. During drug exposure, intercellular redox homeostasis changes towards oxidation are necessary to support Shikonin-induced differentiation, which was proven by additional enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P<0.05 was recorded with regard to the unique expression levels of the Nrf2/ARE downstream target genes in HL-60 cells undergoing late differentiation, which were restored with further antioxidants employed with the Shikonin treatment. Our research demonstrated that Shikonin is a differentiation-inducing agent, and its mechanisms involve the Nrf2/ARE pathway to modulate the intercellular redox homeostasis, thus facilitating differentiation.

  9. Believer-Skeptic meets Actor-Critic: Rethinking the role of basal ganglia pathways during decision-making and reinforcement learning

    Directory of Open Access Journals (Sweden)

    Kyle eDunovan

    2016-03-01

    Full Text Available The flexibility of behavioral control is a testament to the brain’s capacity for dynamically resolving uncertainty during goal-directed actions. This ability to select actions and learn from immediate feedback is driven by the dynamics of basal ganglia (BG pathways. A growing body of empirical evidence conflicts with the traditional view that these pathways act as independent levers for facilitating (i.e., direct pathway or suppressing (i.e., indirect pathway motor output, suggesting instead that they engage in a dynamic competition during action decisions that computationally captures action uncertainty. Here we discuss the utility of encoding action uncertainty as a dynamic competition between opposing control pathways and provide evidence that this simple mechanism may have powerful implications for bridging neurocomputational theories of decision making and reinforcement learning.

  10. Critical Review

    DEFF Research Database (Denmark)

    Rosenbaum, Ralph K.; Olsen, Stig Irving

    2017-01-01

    Manipulation and mistakes in LCA studies are as old as the tool itself, and so is its critical review. Besides preventing misuse and unsupported claims, critical review may also help identifying mistakes and more justifiable assumptions as well as generally improve the quality of a study. It thus...

  11. LncSubpathway: a novel approach for identifying dysfunctional subpathways associated with risk lncRNAs by integrating lncRNA and mRNA expression profiles and pathway topologies.

    Science.gov (United States)

    Xu, Yanjun; Li, Feng; Wu, Tan; Xu, Yingqi; Yang, Haixiu; Dong, Qun; Zheng, Meiyu; Shang, Desi; Zhang, Chunlong; Zhang, Yunpeng; Li, Xia

    2017-02-28

    Long non-coding RNAs (lncRNAs) play important roles in various biological processes, including the development of many diseases. Pathway analysis is a valuable aid for understanding the cellular functions of these transcripts. We have developed and characterized LncSubpathway, a novel method that integrates lncRNA and protein coding gene (PCG) expression with interactome data to identify disease risk subpathways that functionally associated with risk lncRNAs. LncSubpathway identifies the most relevance regions which are related with risk lncRNA set and implicated with study conditions through simultaneously considering the dysregulation extent of lncRNAs, PCGs and their correlations. Simulation studies demonstrated that the sensitivity and false positive rates of LncSubpathway were within acceptable ranges, and that LncSubpathway could accurately identify dysregulated regions that related with disease risk lncRNAs within pathways. When LncSubpathway was applied to colorectal carcinoma and breast cancer subtype datasets, it identified cancer type- and breast cancer subtype-related meaningful subpathways. Further, analysis of its robustness and reproducibility indicated that LncSubpathway was a reliable means of identifying subpathways that functionally associated with lncRNAs. LncSubpathway is freely available at http://www.bio-bigdata.com/lncSubpathway/.

  12. Combined Transcriptomic and Proteomic Approach to Identify Toxicity Pathways in Early Life Stages of Japanese Medaka (Oryzias latipes) Exposed to 1,2,5,6-Tetrabromocyclooctane (TBCO).

    Science.gov (United States)

    Sun, Jianxian; Tang, Song; Peng, Hui; Saunders, David M V; Doering, Jon A; Hecker, Markus; Jones, Paul D; Giesy, John P; Wiseman, Steve

    2016-07-19

    Currently, the novel brominated flame retardant 1,2,5,6-tetrabromocyclooctane (TBCO) is considered a potential replacement for hexabromocyclododecane (HBCD). Therefore, use of TBCO could increase in the near future. To assess potential toxicological risks to aquatic organisms, embryos of Japanese medaka (Oryzias latipes) were exposed to 10, 100, or 1000 μg/L TBCO from 2 h postfertilization until 1 day post-hatch. TBCO accumulated in embryos in the order of 0.43-1.3 × 10(4)-fold, and the rate constant of accumulation was 1.7-1.8 per day. The number of days to hatch and the hatching success of embryos exposed to the medium and the greatest concentrations of TBCO were impaired. Responses of the transcriptome (RNA-seq) and proteome were characterized in embryos exposed to 100 μg/L TBCO because this was the least concentration of TBCO that caused an effect on hatching. Consistent with effects on hatching, proteins whose abundances were reduced by exposure to TBCO were enriched in embryo development and hatching pathways. Also, on the basis of the responses of transcriptome and proteome, it was predicted that TBCO might impair vision and contraction of cardiac muscle, respectively, and these effects were confirmed by targeted bioassays. This study provided a comprehensive understanding of effects of TBCO on medaka at early life stages and illustrated the power of "omics" to explain and predict phenotypic responses to chemicals.

  13. Gene interactions in the DNA damage-response pathway identified by genome-wide RNA-interference analysis of synthetic lethality

    NARCIS (Netherlands)

    van Haaften, Gijs; Vastenhouw, Nadine L; Nollen, Ellen A A; Plasterk, Ronald H A; Tijsterman, Marcel

    2004-01-01

    Here, we describe a systematic search for synthetic gene interactions in a multicellular organism, the nematode Caenorhabditis elegans. We established a high-throughput method to determine synthetic gene interactions by genome-wide RNA interference and identified genes that are required to protect

  14. A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways

    DEFF Research Database (Denmark)

    Bustamante, Mariona; Standl, Marie; Bassat, Quique

    2016-01-01

    questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1...

  15. DMPD: Critical role of toll-like receptors and nucleotide oligomerisation domain inthe regulation of health and disease. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available and nucleotide oligomerisation domain inthe regulation of health and disease. Pu...bmedID 17535871 Title Critical role of toll-like receptors and nucleotide oligomerisation domain inthe regulation of health...17535871 Critical role of toll-like receptors and nucleotide oligomerisation domain inthe regulation of heal...th and disease. Mitchell JA, Paul-Clark MJ, Clarke GW, McMaster SK, Cartwright N. J

  16. Emory University: MEDICI (Mining Essentiality Data to Identify Critical Interactions) for Cancer Drug Target Discovery and Development | Office of Cancer Genomics

    Science.gov (United States)

    The CTD2 Center at Emory University has developed a computational methodology to combine high-throughput knockdown data with known protein network topologies to infer the importance of protein-protein interactions (PPIs) for the survival of cancer cells.  Applying these data to the Achilles shRNA results, the CCLE cell line characterizations, and known and newly identified PPIs provides novel insights for potential new drug targets for cancer therapies and identifies important PPI hubs.

  17. Private selective sweeps identified from next-generation pool-sequencing reveal convergent pathways under selection in two inbred Schistosoma mansoni strains.

    Directory of Open Access Journals (Sweden)

    Julie A J Clément

    Full Text Available BACKGROUND: The trematode flatworms of the genus Schistosoma, the causative agents of schistosomiasis, are among the most prevalent parasites in humans, affecting more than 200 million people worldwide. In this study, we focused on two well-characterized strains of S. mansoni, to explore signatures of selection. Both strains are highly inbred and exhibit differences in life history traits, in particular in their compatibility with the intermediate host Biomphalaria glabrata. METHODOLOGY/PRINCIPAL FINDINGS: We performed high throughput sequencing of DNA from pools of individuals of each strain using Illumina technology and identified single nucleotide polymorphisms (SNP and copy number variations (CNV. In total, 708,898 SNPs were identified and roughly 2,000 CNVs. The SNPs revealed low nucleotide diversity (π = 2 × 10(-4 within each strain and a high differentiation level (Fst = 0.73 between them. Based on a recently developed in-silico approach, we further detected 12 and 19 private (i.e. specific non-overlapping selective sweeps among the 121 and 151 sweeps found in total for each strain. CONCLUSIONS/SIGNIFICANCE: Functional annotation of transcripts lying in the private selective sweeps revealed specific selection for functions related to parasitic interaction (e.g. cell-cell adhesion or redox reactions. Despite high differentiation between strains, we identified evolutionary convergence of genes related to proteolysis, known as a key virulence factor and a potential target of drug and vaccine development. Our data show that pool-sequencing can be used for the detection of selective sweeps in parasite populations and enables one to identify biological functions under selection.

  18. Tissue-specific regulation of sirtuin and nicotinamide adenine dinucleotide biosynthetic pathways identified in C57Bl/6 mice in response to high-fat feeding.

    Science.gov (United States)

    Drew, Janice E; Farquharson, Andrew J; Horgan, Graham W; Williams, Lynda M

    2016-11-01

    The sirtuin (SIRT)/nicotinamide adenine dinucleotide (NAD) system is implicated in development of type 2 diabetes (T2D) and diet-induced obesity, a major risk factor for T2D. Mechanistic links have not yet been defined. SIRT/NAD system gene expression and NAD/NADH levels were measured in liver, white adipose tissue (WAT) and skeletal muscle from mice fed either a low-fat diet or high-fat diet (HFD) for 3 days up to 16 weeks. An in-house custom-designed multiplex gene expression assay assessed all 7 mouse SIRTs (SIRT1-7) and 16 enzymes involved in conversion of tryptophan, niacin, nicotinamide riboside and metabolic precursors to NAD. Significantly altered transcription was correlated with body weight, fat mass, plasma lipids and hormones. Regulation of the SIRT/NAD system was associated with early (SIRT4, SIRT7, NAPRT1 and NMNAT2) and late phases (NMNAT3, NMRK2, ABCA1 and CD38) of glucose intolerance. TDO2 and NNMT were identified as markers of HFD consumption. Altered regulation of the SIRT/NAD system in response to HFD was prominent in liver compared with WAT or muscle. Multiple components of the SIRTs and NAD biosynthetic enzymes network respond to consumption of dietary fat. Novel molecular targets identified above could direct strategies for dietary/therapeutic interventions to limit metabolic dysfunction and development of T2D. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Meta-analysis of Arabidopsis KANADI1 direct target genes identifies basic growth-promoting module acting upstream of hormonal signaling pathways

    DEFF Research Database (Denmark)

    Xie, Yakun; Straub, Daniel; Eguen, Teinai Ebimienere

    2015-01-01

    An intricate network of antagonistically acting transcription factors mediates formation of a flat leaf lamina of Arabidopsis thaliana plants. In this context, members of the class III homeodomain leucine zipper (HD-ZIPIII) transcription factor family specify the adaxial domain (future upper side......) of the leaf, while antagonistically acting KANADI transcription factors determine the abaxial domain (future lower side). Here we used an mRNA-seq approach to identify genes regulated by KANADI1 (KAN1) and subsequently performed a meta-analysis approach combining our datasets with published genome......-wide datasets. Our analysis revealed that KAN1 acts upstream of several genes encoding auxin biosynthetic enzymes. When exposed to shade, we find three YUCCA genes, YUC2, YUC5 and YUC8 to be transcriptionally upregulated, which correlates with an increase in the levels of free auxin. When ectopically expressed...

  20. Pathway to STEM: Using Outreach Initiatives as a Method of Identifying, Educating and Recruiting the Next Generation of Scientists and Engineers

    Science.gov (United States)

    Ortiz-Arias, Deedee; Zwicker, Andrew; Dominguez, Arturo; Greco, Shannon

    2017-10-01

    The Princeton Plasma Physics Laboratory (PPPL) uses a host of outreach initiatives to inform the general population: the Young Women's Conference, Science Bowl, Science Undergraduate Laboratory Internship, My Brother's Keeper, a variety of workshops for university faculty and undergraduate students, public and scheduled lab tours, school and community interactive plasma science demonstrations. In addition to informing and educating the public about the laboratory's important work in the areas of Plasma and Fusion, these outreach initiatives, are also used as an opportunity to identify/educate/recruit the next generation of the STEM workforce. These programs provide the laboratory with the ability to: engage the next generation at different paths along their development (K-12, undergraduate, graduate, professional), at different levels of scientific content (science demonstrations, remote experiments, lectures, tours), in some instances, targeting underrepresented groups in STEM (women and minorities), and train additional STEM educators to take learned content into their own classrooms.

  1. Genomic and Transcriptomic Analyses to Identify Pathways Involved in Nanoparticle Generation in the Ubiquitous Marine Bacterium Alteromonas macleodii Under Elevated Copper Conditions

    Science.gov (United States)

    Cusick, K. D.; Dale, J.; Little, B.; Cockrell, A.; Biffinger, J.

    2016-02-01

    Alteromonas macleodii is a ubiquitous marine bacterium that clusters by molecular analyses into two ecotypes: surface and deep-water. Our group isolated a marine bacterium from copper coupons that generates nanoparticles (NPs) at elevated copper concentrations. Sequencing of the 16S rRNA gene identified it as an A. macleodii strain. In phylogenetic analyses based on the gyrB gene, it clustered with other surface isolates; however, it formed a unique cluster separate from that of other surface isolates based on rpoB gene sequences. Copper is commonly employed as an antifouling agent on the hulls of ships, and so copper tolerance and NP generation is under investigation in this strain. The overall goals of this study were: (1) to determine if copper tolerance is the result of changes at the genetic or transcriptional level and (2) to identify the genes involved in NP formation. Sub-cultures were established from the initial isolate in which copper concentrations were increased in .25 mM increments through multiple generations. These sub-cultures were assayed for NP formation in seawater medium supplemented with 3-4 mM copper. Scanning electron microscopy revealed large aggregates of NPs on the exterior surface of all sub-cultures. Additionally, a portion of the cells in all sub-cultures displayed an elongated morphology in comparison to the wild-type. No NPs were observed in wild-type controls grown without the addition of increased copper. Metagenomic sequencing of natural populations of A. macleodii revealed extreme divergence in several large genomic regions whose content includes genes coding for exopolysaccharide production and metal resistance. High-throughput sequencing is being used to determine whether copper tolerance and NP generation is the result of genetic or transcriptional changes. These results will be extended to natural communities to gain insights into the role of bacterial NPs during conditions of elevated metal concentrations in coastal systems.

  2. Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues.

    Science.gov (United States)

    He, Tianyu; Brocca-Cofano, Egidio; Gillespie, Delbert G; Xu, Cuiling; Stock, Jennifer L; Ma, Dongzhu; Policicchio, Benjamin B; Raehtz, Kevin D; Rinaldo, Charles R; Apetrei, Cristian; Jackson, Edwin K; Macatangay, Bernard J C; Pandrea, Ivona

    2015-09-01

    The role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO. Ex vivo administration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted. The mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune activation

  3. Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways

    Directory of Open Access Journals (Sweden)

    Ammara Abdullah

    2017-08-01

    the Ingenuity Pathway Analysis (IPA revealed significant enrichment of DEGs in multiple pathways, especially those responding to oxidative stress, in homozygous Cops8-CKO hearts at both 2 and 3 weeks, corroborating the occurrence of massive cardiomyocyte necrosis at 3 weeks; (2 the decreases in multiple CRL SR proteins were associated with decreased transcript levels; and (3 enrichment of DEGs in the chromatin remodeling pathway and the microtubule motility and vesicle trafficking pathways.Conclusions: Our data are consistent with the notion that Cops8/CSN plays a role in the transcriptional regulation of CRL SRs and in the redox and vesicle trafficking pathways.

  4. Label-Free Protein-RNA Interactome Analysis Identifies Khsrp Signaling Downstream of the p38/Mk2 Kinase Complex as a Critical Modulator of Cell Cycle Progression.

    Directory of Open Access Journals (Sweden)

    Jorge Boucas

    Full Text Available Growing evidence suggests a key role for RNA binding proteins (RBPs in genome stability programs. Additionally, recent developments in RNA sequencing technologies, as well as mass-spectrometry techniques, have greatly expanded our knowledge on protein-RNA interactions. We here use full transcriptome sequencing and label-free LC/MS/MS to identify global changes in protein-RNA interactions in response to etoposide-induced genotoxic stress. We show that RBPs have distinct binding patterns in response to genotoxic stress and that inactivation of the RBP regulator module, p38/MK2, can affect the entire spectrum of protein-RNA interactions that take place in response to stress. In addition to validating the role of known RBPs like Srsf1, Srsf2, Elavl1 in the genotoxic stress response, we add a new collection of RBPs to the DNA damage response. We identify Khsrp as a highly regulated RBP in response to genotoxic stress and further validate its role as a driver of the G(1/S transition through the suppression of Cdkn1a(P21 transcripts. Finally, we identify KHSRP as an indicator of overall survival, as well as disease free survival in glioblastoma multiforme.

  5. Combined Use of Gene Expression Modeling and siRNA Screening Identifies Genes and Pathways Which Enhance the Activity of Cisplatin When Added at No Effect Levels to Non-Small Cell Lung Cancer Cells In Vitro

    Science.gov (United States)

    Leung, Ada W. Y.; Hung, Stacy S.; Backstrom, Ian; Ricaurte, Daniel; Kwok, Brian; Poon, Steven; McKinney, Steven; Segovia, Romulo; Rawji, Jenna; Qadir, Mohammed A.; Aparicio, Samuel; Stirling, Peter C.; Steidl, Christian; Bally, Marcel B.

    2016-01-01

    Platinum-based combination chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). While cisplatin is effective, its use is not curative and resistance often emerges. As a consequence of microenvironmental heterogeneity, many tumour cells are exposed to sub-lethal doses of cisplatin. Further, genomic heterogeneity and unique tumor cell sub-populations with reduced sensitivities to cisplatin play a role in its effectiveness within a site of tumor growth. Being exposed to sub-lethal doses will induce changes in gene expression that contribute to the tumour cell’s ability to survive and eventually contribute to the selective pressures leading to cisplatin resistance. Such changes in gene expression, therefore, may contribute to cytoprotective mechanisms. Here, we report on studies designed to uncover how tumour cells respond to sub-lethal doses of cisplatin. A microarray study revealed changes in gene expressions that occurred when A549 cells were exposed to a no-observed-effect level (NOEL) of cisplatin (e.g. the IC10). These data were integrated with results from a genome-wide siRNA screen looking for novel therapeutic targets that when inhibited transformed a NOEL of cisplatin into one that induced significant increases in lethality. Pathway analyses were performed to identify pathways that could be targeted to enhance cisplatin activity. We found that over 100 genes were differentially expressed when A549 cells were exposed to a NOEL of cisplatin. Pathways associated with apoptosis and DNA repair were activated. The siRNA screen revealed the importance of the hedgehog, cell cycle regulation, and insulin action pathways in A549 cell survival and response to cisplatin treatment. Results from both datasets suggest that RRM2B, CABYR, ALDH3A1, and FHL2 could be further explored as cisplatin-enhancing gene targets. Finally, pathways involved in repairing double-strand DNA breaks and INO80 chromatin remodeling were enriched in both

  6. Gene Expression Analysis of an EGFR Indirectly Related Pathway Identified PTEN and MMP9 as Reliable Diagnostic Markers for Human Glial Tumor Specimens

    Directory of Open Access Journals (Sweden)

    Sergio Comincini

    2009-01-01

    Full Text Available In this study the mRNA levels of five EGFR indirectly related genes, EGFR, HB-EGF, ADAM17, PTEN, and MMP9, have been assessed by Real-time PCR in a panel of 37 glioblastoma multiforme specimens and in 5 normal brain samples; as a result, in glioblastoma, ADAM17 and PTEN expression was significantly lower than in normal brain samples, and, in particular, a statistically significant inverse correlation was found between PTEN and MMP9 mRNA levels. To verify if this correlation was conserved in gliomas, PTEN and MMP9 expression was further investigated in an additional panel of 16 anaplastic astrocytoma specimens and, in parallel, in different human normal and astrocytic tumor cell lines. In anaplastic astrocytomas PTEN expression was significantly higher than in glioblastoma multiforme, but no significant correlation was found between PTEN and MMP9 expression. PTEN and MMP9 mRNA levels were also employed to identify subgroups of specimens within the different glioma malignancy grades and to define a gene expression-based diagnostic classification scheme. In conclusion, this gene expression survey highlighted that the combined measurement of PTEN and MMP9 transcripts might represent a novel reliable tool for the differential diagnosis of high-grade gliomas, and it also suggested a functional link involving these genes in glial tumors.

  7. Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development.

    Science.gov (United States)

    Speirs, H J L; Seckl, J R; Brown, R W

    2004-04-01

    Glucocorticoids play important roles in organ development and 'fetal programming'. Fetal exposure to excess glucocorticoids reduces birth weight and causes later hypertension. To investigate these processes further we have determined the detailed ontogeny in the mouse of the glucocorticoid receptor (GR) and 11beta-hydroxysteroid dehydrogenase type-1 (11beta-HSD1), which amplifies glucocorticoid levels locally; the ontogeny was determined using in situ hybridisation from embryonic day 9.5 (E9.5, term=E19) until after birth. At E9.5 fetal GR mRNA levels are very low, except in fetal placenta. GR gene expression rises during gestation with striking tissue-specific differences in timing and extent. Before E13.5, an increase is clear in gastrointestinal (GI) and upper respiratory tracts, discrete central nervous system (CNS) regions, precartilage and especially in the liver (E10.5-E12). Later, further increases occur in lung, GI and upper respiratory tracts, muscle, pituitary and thymus. In a few tissues such increases are temporary, e.g. ureteric ducts (E13.5-E16.5) and pancreas (E14.5-E16.5, expression later falling sharply). Fetal 11beta-HSD1 mRNA expression is first clearly observed at E14.5-E15, initially in the fetal placenta then in the umbilical cord. Later, 11beta-HSD1 expression is seen as follows: (i) from E15 in lung and liver, rising strongly; (ii) thymus, from E15 (lower level); (iii) at low levels in a few brain regions, including the hippocampus (E16.5+); and (iv) in muscle group fascial planes and tendon insertions. This is the first detailed study of the ontogeny of these two genes and, in combination with previous work on the ontogeny of 11beta-HSD2 and the mineralocorticoid receptor, suggests potential critical periods of glucocorticoid sensitivity during development for several organ systems.

  8. An Eye Organoid Approach Identifies Six3 Suppression of R-spondin 2 as a Critical Step in Mouse Neuroretina Differentiation

    Directory of Open Access Journals (Sweden)

    Nozomu Takata

    2017-11-01

    Full Text Available Recent advances in self-organizing, 3-dimensional tissue cultures of embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs provided an in vitro model that recapitulates many aspects of the in vivo developmental steps. Using Rax-GFP-expressing ESCs, newly generated Six3−/− iPSCs, and conditional null Six3delta/f;Rax-Cre ESCs, we identified Six3 repression of R-spondin 2 (Rspo2 as a required step during optic vesicle morphogenesis and neuroretina differentiation. We validated these results in vivo by showing that transient ectopic expression of Rspo2 in the anterior neural plate of transgenic mouse embryos was sufficient to inhibit neuroretina differentiation. Additionally, using a chimeric eye organoid assay, we determined that Six3 null cells exert a non-cell-autonomous repressive effect during optic vesicle formation and neuroretina differentiation. Our results further validate the organoid culture system as a reliable and fast alternative to identify and evaluate genes involved in eye morphogenesis and neuroretina differentiation in vivo.

  9. Some potential material supply constraints in solar systems for heating and cooling of buildings and process heat. (A preliminary screening to identify critical materials)

    Energy Technology Data Exchange (ETDEWEB)

    Watts, R.L.; Gurwell, W.E.; Nelson, T.A.; Smith, S.A.

    1979-06-01

    Nine Solar Heating and Cooling of Buildings (SHACOB) designs and three Agricultural and Industrial Process Heat (AIPH) designs have been studied to identify potential future material constraints to their large scale installation and use. The nine SHACOB and three AIPH systems were screened and found to be free of serious future material constraints. The screening was carried out for each individual system design assuming 500 million m/sup 2/ of collector area installed by the year 2000. Also, two mixed design scenarios, containing equal portions of each system design, were screened. To keep these scenarios in perspective, note that a billion m/sup 2/ containing a mixture of the nine SHACOB designs will yield an annual solar contribution of about 1.3 Quads or will displace about 4.2 Quads of fossil fuel used to generate electricity. For AIPH a billion square meters of the mixed designs will yield about 2.8 Quads/year. Three materials were identified that could possibly restrain the deployment of solar systems in the specific scenarios investigated. They are iron and steel, soda lime glass and polyvinyl fluoride. All three of these materials are bulk materials. No raw material supply constraints were found.

  10. Proteomic identification of putative microRNA394 target genes in Arabidopsis thaliana identifies major latex protein family members critical for normal development

    DEFF Research Database (Denmark)

    Litholdo, Celso G; Parker, Benjamin; Eamens, Andrew L

    2016-01-01

    , the identification of proteins targeted by LCR F-box itself has proven problematic. Here, a proteomic analysis of shoot apices from plants with altered LCR levels identified a member of the Latex Protein (MLP) family gene as a potential LCR F-box target. Bioinformatic and molecular analyses also suggested that other...... MLP family members are likely to be targets for this post-translational regulation. Direct interaction between LCR F-Box and MLP423 was validated. Additional MLP members had reduction in protein accumulation, in varying degrees, mediated by LCR F-Box. Transgenic Arabidopsis lines, in which MLP28...... Taken together, the results demonstrate that MLPs are driven to degradation by LCR, and indicate that MLP gene family is target of miR394-LCR regulatory node, representing potential targets for directly post-translational regulation mediated by LCR F-Box. In addition, MLP28 family member is associated...

  11. A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region

    Directory of Open Access Journals (Sweden)

    McInnes L

    2010-03-01

    Full Text Available Abstract Background The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs, have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs. In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval. Methods We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR. Results Among the patients from Costa Rica, an atypical de novo deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears, single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb. Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed. Conclusions From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a

  12. Structure-function relationship of a plant NCS1 member--homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Sandra Witz

    Full Text Available Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members.

  13. Structure-function relationship of a plant NCS1 member--homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from Arabidopsis.

    Science.gov (United States)

    Witz, Sandra; Panwar, Pankaj; Schober, Markus; Deppe, Johannes; Pasha, Farhan Ahmad; Lemieux, M Joanne; Möhlmann, Torsten

    2014-01-01

    Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members.

  14. Structure-Function Relationship of a Plant NCS1 Member – Homology Modeling and Mutagenesis Identified Residues Critical for Substrate Specificity of PLUTO, a Nucleobase Transporter from Arabidopsis

    Science.gov (United States)

    Witz, Sandra; Panwar, Pankaj; Schober, Markus; Deppe, Johannes; Pasha, Farhan Ahmad; Lemieux, M. Joanne; Möhlmann, Torsten

    2014-01-01

    Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members. PMID:24621654

  15. Structure-function relationship of a plant NCS1 member - Homology modeling and mutagenesis identified residues critical for substrate specificity of PLUTO, a nucleobase transporter from arabidopsis

    KAUST Repository

    Witz, Sandra

    2014-03-12

    Plastidic uracil salvage is essential for plant growth and development. So far, PLUTO, the plastidic nucleobase transporter from Arabidopsis thaliana is the only known uracil importer at the inner plastidic membrane which represents the permeability barrier of this organelle. We present the first homology model of PLUTO, the sole plant NCS1 member from Arabidopsis based on the crystal structure of the benzyl hydantoin transporter MHP1 from Microbacterium liquefaciens and validated by molecular dynamics simulations. Polar side chains of residues Glu-227 and backbones of Val-145, Gly-147 and Thr-425 are proposed to form the binding site for the three PLUTO substrates uracil, adenine and guanine. Mutational analysis and competition studies identified Glu-227 as an important residue for uracil and to a lesser extent for guanine transport. A differential response in substrate transport was apparent with PLUTO double mutants E227Q G147Q and E227Q T425A, both of which most strongly affected adenine transport, and in V145A G147Q, which markedly affected guanine transport. These differences could be explained by docking studies, showing that uracil and guanine exhibit a similar binding mode whereas adenine binds deep into the catalytic pocket of PLUTO. Furthermore, competition studies confirmed these results. The present study defines the molecular determinants for PLUTO substrate binding and demonstrates key differences in structure-function relations between PLUTO and other NCS1 family members. 2014 Witz et al.

  16. A critical assessment of marine aquarist biodiversity data and commercial aquaculture: identifying gaps in culture initiatives to inform local fisheries managers.

    Science.gov (United States)

    Murray, Joanna M; Watson, Gordon J

    2014-01-01

    It is widely accepted that if well managed, the marine aquarium trade could provide socio-economic stability to local communities while incentivising the maintenance of coral reefs. However, the trade has also been implicated as having potentially widespread environmental impacts that has in part driven developments in aquaculture to relieve wild collection pressures. This study investigates the biodiversity in hobbyist aquaria (using an online survey) and those species currently available from an aquaculture source (commercial data and hobbyist initiatives) in the context of a traffic light system to highlight gaps in aquaculture effort and identify groups that require fisheries assessments. Two hundred and sixty nine species including clown fish, damsels, dotty backs, angelfish, gobies, sea horses and blennies, have reported breeding successes by hobbyists, a pattern mirrored by the European and US commercial organisations. However, there is a mismatch (high demand and low/non-existent aquaculture) for a number of groups including tangs, starfish, anemones and hermit crabs, which we recommend are priority candidates for local stock assessments. Hobbyist perception towards the concept of a sustainable aquarium trade is also explored with results demonstrating that only 40% of respondents were in agreement with industry and scientists who believe the trade could be an exemplar of a sustainable use of coral reefs. We believe that a more transparent evidence base, including the publication of the species collected and cultured, will go some way to align the concept of a sustainable trade across industry stakeholders and better inform the hobbyist when purchasing their aquaria stock. We conclude by proposing that a certification scheme established with government support is the most effective way to move towards a self-regulating industry. It would prevent industry "greenwashing" from multiple certification schemes, alleviate conservation concerns, and, ultimately

  17. A critical assessment of marine aquarist biodiversity data and commercial aquaculture: identifying gaps in culture initiatives to inform local fisheries managers.

    Directory of Open Access Journals (Sweden)

    Joanna M Murray

    Full Text Available It is widely accepted that if well managed, the marine aquarium trade could provide socio-economic stability to local communities while incentivising the maintenance of coral reefs. However, the trade has also been implicated as having potentially widespread environmental impacts that has in part driven developments in aquaculture to relieve wild collection pressures. This study investigates the biodiversity in hobbyist aquaria (using an online survey and those species currently available from an aquaculture source (commercial data and hobbyist initiatives in the context of a traffic light system to highlight gaps in aquaculture effort and identify groups that require fisheries assessments. Two hundred and sixty nine species including clown fish, damsels, dotty backs, angelfish, gobies, sea horses and blennies, have reported breeding successes by hobbyists, a pattern mirrored by the European and US commercial organisations. However, there is a mismatch (high demand and low/non-existent aquaculture for a number of groups including tangs, starfish, anemones and hermit crabs, which we recommend are priority candidates for local stock assessments. Hobbyist perception towards the concept of a sustainable aquarium trade is also explored with results demonstrating that only 40% of respondents were in agreement with industry and scientists who believe the trade could be an exemplar of a sustainable use of coral reefs. We believe that a more transparent evidence base, including the publication of the species collected and cultured, will go some way to align the concept of a sustainable trade across industry stakeholders and better inform the hobbyist when purchasing their aquaria stock. We conclude by proposing that a certification scheme established with government support is the most effective way to move towards a self-regulating industry. It would prevent industry "greenwashing" from multiple certification schemes, alleviate conservation concerns

  18. Formal consensus to identify clinically important changes in management resulting from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway.

    Science.gov (United States)

    Pufulete, Maria; Brierley, Rachel C; Bucciarelli-Ducci, Chiara; Greenwood, John P; Dorman, Stephen; Anderson, Richard A; Harris, Jessica; McAlindon, Elisa; Rogers, Chris A; Reeves, Barnaby C

    2017-06-22

    To define important changes in management arising from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway. Formal consensus study using literature review and cardiologist expert opinion to formulate consensus statements and setting up a consensus panel to review the statements (by completing a web-based survey, attending a face-to-face meeting to discuss survey results and modify the survey to reflect group discussion and completing the modified survey to determine which statements were in consensus). Formulation of consensus statements: four cardiologists (two CMR and two interventional) and six non-clinical researchers. Formal consensus: seven cardiologists (two CMR and three interventional, one echocardiography and one heart failure). Forty-nine additional cardiologists completed the modified survey. Thirty-seven draft statements describing changes in management following CMR were generated; these were condensed into 12 statements and reviewed through the formal consensus process. Three of 12 statements were classified in consensus in the first survey; these related to the role of CMR in identifying the cause of out-of-hospital cardiac arrest, providing a definitive diagnosis in patients found to have unobstructed arteries on angiography and identifying patients with left ventricular thrombus. Two additional statements were in consensus in the modified survey, relating to the ability of CMR to identify patients who have a poor prognosis after PPCI and assess ischaemia and viability in patients with multivessel disease. There was consensus that CMR leads to clinically important changes in management in five subgroups of patients who activate the PPCI pathway. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Identifying Reaction Pathways and their Environments

    DEFF Research Database (Denmark)

    Maronsson, Jon Bergmann

    along a path connecting the saddle points to iteratively converge to the ridge. At each iteration during the optimisation, the gradient is inverted along an unstable eigenmode perpendicular to the path, locally mapping the ridge to a minimum energy path which can be located using various techniques...... rotations occur at lower temperature than C3-type rotations and approximately 15% of the BH4 units activate at a lower temperature than the rest. For the Ca(BH4)2, in addition to the rotational dynamics, an unidentified event was detected which, according to the calculations was most likely due to H2....... Information about the ridge can be used to test the validity of the harmonic approximation to transition state theory for reaction rates, in particular to verify that second order saddle points - maxima along the ridge - are high enough compared to the first order saddle points. Furthermore, corrections...

  20. Integrated tumor and germline whole-exome sequencing identifies mutations in MAPK and PI3K pathway genes in an adolescent with rosette-forming glioneuronal tumor of the fourth ventricle

    Science.gov (United States)

    Lin, Frank Y.; Bergstrom, Katie; Person, Richard; Bavle, Abhishek; Ballester, Leomar Y.; Scollon, Sarah; Raesz-Martinez, Robin; Jea, Andrew; Birchansky, Sherri; Wheeler, David A.; Berg, Stacey L.; Chintagumpala, Murali M.; Adesina, Adekunle M.; Eng, Christine; Roy, Angshumoy; Plon, Sharon E.; Parsons, D. Williams

    2016-01-01

    The integration of genome-scale studies such as whole-exome sequencing (WES) into the clinical care of children with cancer has the potential to provide insight into the genetic basis of an individual's cancer with implications for clinical management. This report describes the results of clinical tumor and germline WES for a patient with a rare tumor diagnosis, rosette-forming glioneuronal tumor of the fourth ventricle (RGNT). Three pathogenic gene alterations with implications for clinical care were identified: somatic activating hotspot mutations in FGFR1 (p.N546K) and PIK3CA (p.H1047R) and a germline pathogenic variant in PTPN11 (p.N308S) diagnostic for Noonan syndrome. The molecular landscape of RGNT is not well-described, but these data are consistent with prior observations regarding the importance of the interconnected MAPK and PI3K/AKT/mTOR signaling pathways in this rare tumor. The co-occurrence of FGFR1, PIK3CA, and PTPN11 alterations provides further evidence for consideration of RGNT as a distinct molecular entity from pediatric low-grade gliomas and suggests potential therapeutic strategies for this patient in the event of tumor recurrence as novel agents targeting these pathways enter pediatric clinical trials. Although RGNT has not been definitively linked with cancer predisposition syndromes, two prior cases have been reported in patients with RASopathies (Noonan syndrome and neurofibromatosis type 1 [NF1]), providing an additional link between these tumors and the mitogen-activated protein kinase (MAPK) signaling pathway. In summary, this case provides an example of the potential for genome-scale sequencing technologies to provide insight into the biology of rare tumors and yield both tumor and germline results of potential relevance to patient care. PMID:27626068

  1. Exposure of Tg.AC transgenic mice to benzene suppresses hematopoietic progenitor cells and alters gene expression in critical signaling pathways

    International Nuclear Information System (INIS)

    Nwosu, Veronica C.; Kissling, Grace E.; Trempus, Carol S.; Honeycutt, Hayden; French, John E.

    2004-01-01

    The effects of acute benzene (BZ) exposure on hematopoietic progenitor cells (HPCs) derived from bone marrow cells were studied using homozygous male v-Ha-ras Tg.AC mice at 8-10 weeks of age. The mice were given 0.02% BZ in their drinking water for 28 days with the dose rate estimated to be 34 mg benzene/kg BW/day. Analysis of cultured HPCs indicated that BZ suppressed the proliferation of the multilineage colony forming unit-granulocyte, erythrocyte, macrophage, megakaryocyte (CFU-GEMM); colony forming unit-granulocyte, macrophage (CFU-GM); and blast forming unit erythrocyte/colony forming unit erythrocyte (BFUE/CFUE). A gene expression profile was generated using nylon arrays spotted with 23 cDNAs involved in selected signal pathways involved in cell distress, inflammation, DNA damage, cell cycle arrest, and apoptosis. Of the 23 marker genes, 6 (bax, c-fos, E124, hsf1, ikBa, and p57) were significantly (Mann-Whitney U tests, P < 0.05) overexpressed in BZ-exposed mice. Two genes (c-myc and IL-2) approached significance (at P = 0.053). The pattern of gene expression was consistent with BZ toxicity and the suppression of HPCs

  2. PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion.

    Science.gov (United States)

    Gari, Hamid H; DeGala, Gregory D; Ray, Rahul; Lucia, M Scott; Lambert, James R

    2016-10-01

    Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.

  3. Reprogramming of a defense signaling pathway in rough lemon and sweet orange is a critical element of the early response to ‘Candidatus Liberibacter asiaticus’

    Science.gov (United States)

    Huanglongbing (HLB) in citrus infected by Candidatus Liberibacter asiaticus (CLas) has caused tremendous losses to the citrus industry. No resistant genotypes have been identified in citrus species or close relatives. Among citrus varieties, rough lemon (Citrus jambhiri) has been considered tolerant...

  4. The cost-effectiveness of changes to the care pathway used to identify depression and provide treatment amongst people with diabetes in England: a model-based economic evaluation.

    Science.gov (United States)

    Kearns, Ben; Rafia, R; Leaviss, J; Preston, L; Brazier, J E; Palmer, S; Ara, R

    2017-01-24

    Diabetes is associated with premature death and a number of serious complications. The presence of comorbid depression makes these outcomes more likely and results in increased healthcare costs. The aim of this work was to assess the health economic outcomes associated with having both diabetes and depression, and assess the cost-effectiveness of potential policy changes to improve the care pathway: improved opportunistic screening for depression, collaborative care for depression treatment, and the combination of both. A mathematical model of the care pathways experienced by people diagnosed with type-2 diabetes in England was developed. Both an NHS perspective and wider social benefits were considered. Evidence was taken from the published literature, identified via scoping and targeted searches. Compared with current practice, all three policies reduced both the time spent with depression and the number of diabetes-related complications experienced. The policies were associated with an improvement in quality of life, but with an increase in health care costs. In an incremental analysis, collaborative care dominated improved opportunistic screening. The incremental cost-effectiveness ratio (ICER) for collaborative care compared with current practice was £10,798 per QALY. Compared to collaborative care, the combined policy had an ICER of £68,017 per QALY. Policies targeted at identifying and treating depression early in patients with diabetes may lead to reductions in diabetes related complications and depression, which in turn increase life expectancy and improve health-related quality of life. Implementing collaborative care was cost-effective based on current national guidance in England.

  5. A Systematic Approach of Employing Quality by Design Principles: Risk Assessment and Design of Experiments to Demonstrate Process Understanding and Identify the Critical Process Parameters for Coating of the Ethylcellulose Pseudolatex Dispersion Using Non-Conventional Fluid Bed Process.

    Science.gov (United States)

    Kothari, Bhaveshkumar H; Fahmy, Raafat; Claycamp, H Gregg; Moore, Christine M V; Chatterjee, Sharmista; Hoag, Stephen W

    2017-05-01

    The goal of this study was to utilize risk assessment techniques and statistical design of experiments (DoE) to gain process understanding and to identify critical process parameters for the manufacture of controlled release multiparticulate beads using a novel disk-jet fluid bed technology. The material attributes and process parameters were systematically assessed using the Ishikawa fish bone diagram and failure mode and effect analysis (FMEA) risk assessment methods. The high risk attributes identified by the FMEA analysis were further explored using resolution V fractional factorial design. To gain an understanding of the processing parameters, a resolution V fractional factorial study was conducted. Using knowledge gained from the resolution V study, a resolution IV fractional factorial study was conducted; the purpose of this IV study was to identify the critical process parameters (CPP) that impact the critical quality attributes and understand the influence of these parameters on film formation. For both studies, the microclimate, atomization pressure, inlet air volume, product temperature (during spraying and curing), curing time, and percent solids in the coating solutions were studied. The responses evaluated were percent agglomeration, percent fines, percent yield, bead aspect ratio, median particle size diameter (d50), assay, and drug release rate. Pyrobuttons® were used to record real-time temperature and humidity changes in the fluid bed. The risk assessment methods and process analytical tools helped to understand the novel disk-jet technology and to systematically develop models of the coating process parameters like process efficiency and the extent of curing during the coating process.

  6. IDENTIFYING THE CRITICAL CAUSES OF CONFLICT IN ...

    African Journals Online (AJOL)

    Completing construction projects entails inputs from various professional disciplines; this makes projects prone to conflicts. It has been acknowledged that management of conflict is crucial to improving project performance. Thus, understanding the causes of conflicts in construction project will ease the process of conflict ...

  7. Activation of the Pro-Oxidant PKCβII-p66Shc Signaling Pathway Contributes to Pericyte Dysfunction in Skeletal Muscles of Patients With Diabetes With Critical Limb Ischemia.

    Science.gov (United States)

    Vono, Rosa; Fuoco, Claudia; Testa, Stefano; Pirrò, Stefano; Maselli, Davide; Ferland McCollough, David; Sangalli, Elena; Pintus, Gianfranco; Giordo, Roberta; Finzi, Giovanna; Sessa, Fausto; Cardani, Rosanna; Gotti, Ambra; Losa, Sergio; Cesareni, Gianni; Rizzi, Roberto; Bearzi, Claudia; Cannata, Stefano; Spinetti, Gaia; Gargioli, Cesare; Madeddu, Paolo

    2016-12-01

    Critical limb ischemia (CLI), foot ulcers, former amputation, and impaired regeneration are independent risk factors for limb amputation in subjects with diabetes. The present work investigates whether and by which mechanism diabetes negatively impacts on functional properties of muscular pericytes (MPs), which are resident stem cells committed to reparative angiomyogenesis. We obtained muscle biopsy samples from patients with diabetes who were undergoing major limb amputation and control subjects. Diabetic muscles collected at the rim of normal tissue surrounding the plane of dissection showed myofiber degeneration, fat deposition, and reduction of MP vascular coverage. Diabetic MPs (D-MPs) display ultrastructural alterations, a differentiation bias toward adipogenesis at the detriment of myogenesis and an inhibitory activity on angiogenesis. Furthermore, they have an imbalanced redox state, with downregulation of the antioxidant enzymes superoxide dismutase 1 and catalase, and activation of the pro-oxidant protein kinase C isoform β-II (PKCβII)-dependent p66 Shc signaling pathway. A reactive oxygen species scavenger or, even more effectively, clinically approved PKCβII inhibitors restore D-MP angiomyogenic activity. Inhibition of the PKCβII-dependent p66 Shc signaling pathway could represent a novel therapeutic approach for the promotion of muscle repair in individuals with diabetes. © 2016 by the American Diabetes Association.

  8. Critical role of the STAT3 pathway in the cardioprotective efficacy of zoniporide in a model of myocardial preservation - the rat isolated working heart.

    Science.gov (United States)

    Gao, L; Tsun, J; Sun, L; Kwan, J; Watson, A; Macdonald, P S; Hicks, M

    2011-02-01

    Ischemia-reperfusion injury plays an important role in the development of primary allograft failure after heart transplantation. Inhibition of the Na+/H+ exchanger is one of the most promising therapeutic strategies for treating ischemia-reperfusion injury. Here we have characterized the cardioprotective efficacy of zoniporide and the underlying mechanisms in a model of myocardial preservation using rat isolated working hearts. Rat isolated hearts subjected to 6 h hypothermic (1-4°C) storage followed by 45 min reperfusion at 37°C were treated with zoniporide at different concentrations and timing. Recovery of cardiac function, levels of total and phosphorylated protein kinase B, extracellular signal-regulated kinase 1/2, glycogen synthase kinase-3β and STAT3 as well as cleaved caspase 3 were measured at the end of reperfusion. Lactate dehydrogenase release into coronary effluent before and post-storage was also measured. Zoniporide concentration-dependently improved recovery of cardiac function after reperfusion. The functional recovery induced by zoniporide was accompanied by up-regulation of p-extracellular signal-regulated kinase 1/2 and p-STAT3, and by reduction in lactate dehydrogenase release and cleaved caspase 3. There were no significant differences in any of the above indices when zoniporide was administered before, during or after ischemia. The STAT3 inhibitor, stattic, abolished zoniporide-induced improvements in functional recovery and up-regulation of p-STAT3 after reperfusion. Zoniporide is a potent cardioprotective agent and activation of STAT3 plays a critical role in the cardioprotective action of zoniporide. This agent shows promise as a supplement to storage solutions to improve preservation of donor hearts. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  9. Critical role of the STAT3 pathway in the cardioprotective efficacy of zoniporide in a model of myocardial preservation – the rat isolated working heart

    Science.gov (United States)

    Gao, L; Tsun, J; Sun, L; Kwan, J; Watson, A; Macdonald, PS; Hicks, M

    2011-01-01

    BACKGROUND AND PURPOSE Ischemia-reperfusion injury plays an important role in the development of primary allograft failure after heart transplantation. Inhibition of the Na+/H+ exchanger is one of the most promising therapeutic strategies for treating ischemia-reperfusion injury. Here we have characterized the cardioprotective efficacy of zoniporide and the underlying mechanisms in a model of myocardial preservation using rat isolated working hearts. EXPERIMENTAL APPROACH Rat isolated hearts subjected to 6 h hypothermic (1–4°C) storage followed by 45 min reperfusion at 37°C were treated with zoniporide at different concentrations and timing. Recovery of cardiac function, levels of total and phosphorylated protein kinase B, extracellular signal-regulated kinase 1/2, glycogen synthase kinase-3β and STAT3 as well as cleaved caspase 3 were measured at the end of reperfusion. Lactate dehydrogenase release into coronary effluent before and post-storage was also measured. KEY RESULTS Zoniporide concentration-dependently improved recovery of cardiac function after reperfusion. The functional recovery induced by zoniporide was accompanied by up-regulation of p-extracellular signal-regulated kinase 1/2 and p-STAT3, and by reduction in lactate dehydrogenase release and cleaved caspase 3. There were no significant differences in any of the above indices when zoniporide was administered before, during or after ischemia. The STAT3 inhibitor, stattic, abolished zoniporide-induced improvements in functional recovery and up-regulation of p-STAT3 after reperfusion. CONCLUSIONS AND IMPLICATIONS Zoniporide is a potent cardioprotective agent and activation of STAT3 plays a critical role in the cardioprotective action of zoniporide. This agent shows promise as a supplement to storage solutions to improve preservation of donor hearts. PMID:20942815

  10. Molecular dynamics simulations of Hsp40 J-domain mutants identifies disruption of the critical HPD-motif as the key factor for impaired curing in vivo of the yeast prion [URE3].

    Science.gov (United States)

    Xue, You-Lin; Wang, Hao; Riedy, Michael; Roberts, Brittany-Lee; Sun, Yuna; Song, Yong-Bo; Jones, Gary W; Masison, Daniel C; Song, Youtao

    2018-05-01

    Genetic screens using Saccharomyces cerevisiae have identified an array of Hsp40 (Ydj1p) J-domain mutants that are impaired in the ability to cure the yeast [URE3] prion through disrupting functional interactions with Hsp70. However, biochemical analysis of some of these Hsp40 J-domain mutants has so far failed to provide major insight into the specific functional changes in Hsp40-Hsp70 interactions. To explore the detailed structural and dynamic properties of the Hsp40 J-domain, 20 ns molecular dynamic simulations of 4 mutants (D9A, D36A, A30T, and F45S) and wild-type J-domain were performed, followed by Hsp70 docking simulations. Results demonstrated that although the Hsp70 interaction mechanism of the mutants may vary, the major structural change was targeted to the critical HPD motif of the J-domain. Our computational analysis fits well with previous yeast genetics studies regarding highlighting the importance of J-domain function in prion propagation. During the molecular dynamics simulations several important residues were identified and predicted to play an essential role in J-domain structure. Among these residues, Y26 and F45 were confirmed, using both in silico and in vivo methods, as being critical for Ydj1p function.

  11. Bioassay-Guided Isolation of Anti-Inflammatory Components from the Bulbs of Lilium brownii var. viridulum and Identifying the Underlying Mechanism through Acting on the NF-κB/MAPKs Pathway.

    Science.gov (United States)

    Ma, Ting; Wang, Zhen; Zhang, Yang-Mei; Luo, Jian-Guang; Kong, Ling-Yi

    2017-03-23

    The bulbs of Lilium brownii var. viridulum (LB) are commonly used as both traditional Chinese medicines and popular functional food for many centuries in China. Previous studies reported that the extract of lily bulbs exhibited anti-inflammatory activity both in vivo and in vitro, but its active components and associated molecular mechanisms remain elusive. In the present study, using bioassay-guided isolation method, two phenylpropenoid acylglycerols, 1- O -feruloyl-2- O - p -coumaroylglycerol ( 1 ) and 1,3- O -diferuloylglycerol ( 2 ), were obtained and identified from the chloroform fraction of LB. Both compounds 1 and 2 significantly decreased the production of nitrite oxide (NO) in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW264.7 cells in a dose-dependent manner with half maximal inhibitory concentration (IC 50 ) values of 9.12 ± 0.72 μM and 12.01 ± 1.07 μM, respectively. They also inhibited the production of prostaglandin E2 (PGE2) and several other pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Furthermore, compounds 1 and 2 downregulated the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). They also inhibited the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit and suppressed mitogen-activated protein kinases (MAPKs) pathway. Taken these data together, compounds 1 and 2 exhibited anti-inflammatory activities through acting on the NF-κB and MAPKs pathway. This research provides the first evidence on the major bioactive constituents and related molecular mechanisms of LB as an anti-inflammatory agent. Our findings also advanced the understanding of LB as a traditional herbal medicine for the prevention and treatment of inflammation.

  12. California Condor Critical Habitat

    Data.gov (United States)

    California Natural Resource Agency — These Data identify (in general) the areas where critical habitat for the California Condor occur. Critical habitat for the species consists of the following 10...

  13. The gene expression landscape of thermogenic skunk cabbage suggests critical roles for mitochondrial and vacuolar metabolic pathways in the regulation of thermogenesis.

    Science.gov (United States)

    Ito-Inaba, Yasuko; Hida, Yamato; Matsumura, Hideo; Masuko, Hiromi; Yazu, Fumiko; Terauchi, Ryohei; Watanabe, Masao; Inaba, Takehito

    2012-03-01

    Floral thermogenesis has been described in several plant species. Because of the lack of comprehensive gene expression profiles in thermogenic plants, the molecular mechanisms by which floral thermogenesis is regulated remain to be established. We examined the gene expression landscape of skunk cabbage (Symplocarpus renifolius) during thermogenic and post-thermogenic stages and identified expressed sequence tags from different developmental stages of the inflorescences using super serial analysis of gene expression (SuperSAGE). In-depth analysis suggested that cellular respiration and mitochondrial functions are significantly enhanced during the thermogenic stage. In contrast, genes involved in stress responses and protein degradation were significantly up-regulated during post-thermogenic stages. Quantitative comparisons indicated that the expression levels of genes involved in cellular respiration were higher in thermogenic spadices than in Arabidopsis inflorescences. Thermogenesis-associated genes seemed to be expressed abundantly in the peripheral tissues of the spadix. Our results suggest that cellular respiration and mitochondrial metabolism play key roles in heat production during floral thermogenesis. On the other hand, vacuolar cysteine protease and other degradative enzymes seem to accelerate senescence and terminate thermogenesis in the post-thermogenic stage. © 2011 Blackwell Publishing Ltd.

  14. CriticalEd

    DEFF Research Database (Denmark)

    Kjellberg, Caspar Mølholt; Meredith, David

    2014-01-01

    such as Sibelius or Finale. It was hypothesized that it would be possible to develop a Sibelius plug-in, written in Manuscript 6, that would improve the critical editing work flow, but it was found that the capabilities of this scripting language were insufficient. Instead, a 3-part system was designed and built......, consisting of a Sibelius plug-in, a cross-platform application, called CriticalEd, and a REST-based solution, which handles data storage/retrieval. A prototype has been tested at the Danish Centre for Music Publication, and the results suggest that the system could greatly improve the efficiency......The best text method is commonly applied among music scholars engaged in producing critical editions. In this method, a comment list is compiled, consisting of variant readings and editorial emendations. This list is maintained by inserting the comments into a document as the changes are made...

  15. Genome-Wide siRNA Screen Identifies Complementary Signaling Pathways Involved in Listeria Infection and Reveals Different Actin Nucleation Mechanisms during Listeria Cell Invasion and Actin Comet Tail Formation

    Science.gov (United States)

    Kühbacher, Andreas; Emmenlauer, Mario; Rämo, Pauli; Kafai, Natasha; Dehio, Christoph

    2015-01-01

    ABSTRACT Listeria monocytogenes enters nonphagocytic cells by a receptor-mediated mechanism that is dependent on a clathrin-based molecular machinery and actin rearrangements. Bacterial intra- and intercellular movements are also actin dependent and rely on the actin nucleating Arp2/3 complex, which is activated by host-derived nucleation-promoting factors downstream of the cell receptor Met during entry and by the bacterial nucleation-promoting factor ActA during comet tail formation. By genome-wide small interfering RNA (siRNA) screening for host factors involved in bacterial infection, we identified diverse cellular signaling networks and protein complexes that support or limit these processes. In addition, we could precise previously described molecular pathways involved in Listeria invasion. In particular our results show that the requirements for actin nucleators during Listeria entry and actin comet tail formation are different. Knockdown of several actin nucleators, including SPIRE2, reduced bacterial invasion while not affecting the generation of comet tails. Most interestingly, we observed that in contrast to our expectations, not all of the seven subunits of the Arp2/3 complex are required for Listeria entry into cells or actin tail formation and that the subunit requirements for each of these processes differ, highlighting a previously unsuspected versatility in Arp2/3 complex composition and function. PMID:25991686

  16. Pathways to Shape the Bioeconomy

    Directory of Open Access Journals (Sweden)

    Carmen Priefer

    2017-02-01

    Full Text Available In view of the increasing depletion of fossil fuel resources, the concept “bioeconomy” aims at the gradual replacement of fossil fuels by renewable feedstock. Seen as a comprehensive societal transition, the bioeconomy is a complex field that includes a variety of sectors, actors, and interests and is related to far-reaching changes in today’s production systems. While the objectives pursued—such as reducing dependence on fossil fuels, mitigating climate change, ensuring global food security, and increasing the industrial use of biogenic resources—are not generally contentious, there is fierce controversy over the possible pathways for achieving these objectives. Based on a thorough literature review, the article identifies major lines of conflict in the current discourse. Criticism of the prevalent concept refers mainly to the strong focus on technology, the lack of consideration given to alternative implementation pathways, the insufficient differentiation of underlying sustainability requirements, and the inadequate participation of societal stakeholders. Since today it cannot be predicted which pathway will be the most expedient—the one already being taken or one of the others proposed—this paper suggests pursuing a strategy of diversity concerning the approaches to shape the bioeconomy, the funding of research topics, and the involvement of stakeholders.

  17. Soil - the critical switch of water pathways

    Science.gov (United States)

    Vogel, Hans-Joerg; Weller, Ulrich; Wollschläger, Ute

    2017-04-01

    Generally, the port of entry for water into terrestrial systems is the soil surface. The subsequent flow path of any water molecule towards productive transpiration, nonproductive evaporation, seepage to groundwater or surface runoff is decided within the upper decimeters of soil. Moreover, a substantial fraction of 70% of the Earth's freshwater resources is used by agriculture. Thus, let's say soil is relevant. The dynamics of water within the unsaturated soil is mostly vertical, since the gradients in the gravitational field of the Earth are typically pointing either upwards or downwards. Thus a relevant scale for modeling soil water dynamics is the vertical profile across different soil layers having different hydraulic properties. Based on these considerations and having in mind the management of water resources some crucial questions pop up: i) To what detail do we need to know the basic soil hydraulic properties (i.e. water retention characteristic and unsaturated hydraulic conductivity function)? ii) How useful are sophisticated lab measurement to predict what is happening in the field? How to handle the highly non-linear change in flow paths as a function of the hydraulic state and its history? These questions are addressed based on the evidence of field measurements. Then, another crucial question is how to connect soil hydrology to the larger scales which, depending on the context, might be relevant as well.

  18. Affective and neural reactivity to criticism in individuals high and low on perceived criticism.

    Directory of Open Access Journals (Sweden)

    Jill M Hooley

    Full Text Available People who have remitted from depression are at increased risk for relapse if they rate their relatives as being critical of them on a simple self-report measure of Perceived Criticism (PC. To explore neural mechanisms associated with this we used functional magnetic resonance imaging (fMRI to examine how people with different levels of PC responded to hearing criticism from their own mothers. To maximize variability in affective reactivity, depressed, recovered depressed, and healthy control participants (n = 33 were classified as high or low in PC based on a median split. They were then exposed to personally-relevant critical and praising comments from their mothers. Perceived Criticism levels were unrelated to depression status and to negative mood change after hearing criticism. However, compared to low PC participants, those who scored high on PC showed differential activation in a network of regions associated with emotion reactivity and regulation, including increased amygdala activity and decreased reactions in prefrontal regulatory regions when they heard criticism. This was not the case for praise. Criticism may be a risk factor for relapse because it helps to "train" pathways characteristic of depressive information processing. The Perceived Criticism measure may help identify people who are more susceptible to this vulnerability.

  19. Integrative data mining of high-throughput in vitro screens, in vivo data, and disease information to identify Adverse Outcome Pathway (AOP) signatures:ToxCast high-throughput screening data and Comparative Toxicogenomics Database (CTD) as a case study.

    Science.gov (United States)

    The Adverse Outcome Pathway (AOP) framework provides a systematic way to describe linkages between molecular and cellular processes and organism or population level effects. The current AOP assembly methods however, are inefficient. Our goal is to generate computationally-pr...

  20. Investigating multiple dysregulated pathways in rheumatoid arthritis based on pathway interaction network.

    Science.gov (United States)

    Song, Xian-Dong; Song, Xian-Xu; Liu, Gui-Bo; Ren, Chun-Hui; Sun, Yuan-Bo; Liu, Ke-Xin; Liu, Bo; Liang, Shuang; Zhu, Zhu

    2018-03-01

    The traditional methods of identifying biomarkers in rheumatoid arthritis (RA) have focussed on the differentially expressed pathways or individual pathways, which however, neglect the interactions between pathways. To better understand the pathogenesis of RA, we aimed to identify dysregulated pathway sets using a pathway interaction network (PIN), which considered interactions among pathways. Firstly, RA-related gene expression profile data, protein-protein interactions (PPI) data and pathway data were taken up from the corresponding databases. Secondly, principal component analysis method was used to calculate the pathway activity of each of the pathway, and then a seed pathway was identified using data gleaned from the pathway activity. A PIN was then constructed based on the gene expression profile, pathway data, and PPI information. Finally, the dysregulated pathways were extracted from the PIN based on the seed pathway using the method of support vector machines and an area under the curve (AUC) index. The PIN comprised of a total of 854 pathways and 1064 pathway interactions. The greatest change in the activity score between RA and control samples was observed in the pathway of epigenetic regulation of gene expression, which was extracted and regarded as the seed pathway. Starting with this seed pathway, one maximum pathway set containing 10 dysregulated pathways was extracted from the PIN, having an AUC of 0.8249, and the result indicated that this pathway set could distinguish RA from the controls. These 10 dysregulated pathways might be potential biomarkers for RA diagnosis and treatment in the future.

  1. Synthetic lethality between gene defects affecting a single non-essential molecular pathway with reversible steps.

    Directory of Open Access Journals (Sweden)

    Andrei Zinovyev

    2013-04-01

    Full Text Available Systematic analysis of synthetic lethality (SL constitutes a critical tool for systems biology to decipher molecular pathways. The most accepted mechanistic explanation of SL is that the two genes function in parallel, mutually compensatory pathways, known as between-pathway SL. However, recent genome-wide analyses in yeast identified a significant number of within-pathway negative genetic interactions. The molecular mechanisms leading to within-pathway SL are not fully understood. Here, we propose a novel mechanism leading to within-pathway SL involving two genes functioning in a single non-essential pathway. This type of SL termed within-reversible-pathway SL involves reversible pathway steps, catalyzed by different enzymes in the forward and backward directions, and kinetic trapping of a potentially toxic intermediate. Experimental data with recombinational DNA repair genes validate the concept. Mathematical modeling recapitulates the possibility of kinetic trapping and revealed the potential contributions of synthetic, dosage-lethal interactions in such a genetic system as well as the possibility of within-pathway positive masking interactions. Analysis of yeast gene interaction and pathway data suggests broad applicability of this novel concept. These observations extend the canonical interpretation of synthetic-lethal or synthetic-sick interactions with direct implications to reconstruct molecular pathways and improve therapeutic approaches to diseases such as cancer.

  2. Patient pathway: the ideal approach.

    Science.gov (United States)

    Corless, Lynsey; Brew, Iain

    2018-02-07

    Hepatic encephalopathy (HE) can be a devastating complication of cirrhosis, affecting patients and their families. Multidisciplinary community and specialist teams must work together with patients and their families to recognise HE, identify and treat problems early, and minimise time spent unwell or in hospital. Primary care provides an ideal setting for patient education and reinforcement of the salient points on self-care. In the acute setting, the use of care pathways can ensure that the critical aspects of pharmacological, dietetic and supportive care are offered in a timely fashion to reduce morbidity and mortality. This article discusses strategies that can be used in primary and secondary care to help teams deliver excellent practice in HE management.

  3. Designing a Care Pathway Model – A Case Study of the Outpatient Total Hip Arthroplasty Care Pathway

    Directory of Open Access Journals (Sweden)

    Robin I. Oosterholt

    2017-03-01

    Full Text Available Introduction: Although the clinical attributes of total hip arthroplasty (THA care pathways have been thoroughly researched, a detailed understanding of the equally important organisational attributes is still lacking. The aim of this article is to contribute with a model of the outpatient THA care pathway that depicts how the care team should be organised to enable patient discharge on the day of surgery. Theory: The outpatient THA care pathway enables patients to be discharged on the day of surgery, short- ening the length of stay and intensifying the provision and organisation of care. We utilise visual care modelling to construct a visual design of the organisation of the care pathway. Methods: An embedded case study was conducted of the outpatient THA care pathway at a teaching hospital in the Netherlands. The data were collected using a visual care modelling toolkit in 16 semi- structured interviews. Problems and inefficiencies in the care pathway were identified and addressed in the iterative design process. Results: The results are two visual models of the most critical phases of the outpatient THA care pathway: diagnosis & preparation (1 and mobilisation & discharge (4. The results show the care team composition, critical value exchanges, and sequence that enable patient discharge on the day of surgery. Conclusion: The design addressed existing problems and is an optimisation of the case hospital’s pathway. The network of actors consists of the patient (1, radiologist (1, anaesthetist (1, nurse specialist (1, pharmacist (1, orthopaedic surgeon (1,4, physiotherapist (1,4, nurse (4, doctor (4 and patient applica- tion (1,4. The critical value exchanges include patient preparation (mental and practical, patient education, aligned care team, efficient sequence of value exchanges, early patient mobilisation, flexible availability of the physiotherapist, functional discharge criteria, joint decision making and availability of the care team.

  4. A systems biology approach reveals common metastatic pathways in osteosarcoma

    Directory of Open Access Journals (Sweden)

    Flores Ricardo J

    2012-05-01

    OS-2/LM7 and HOS/143B models was further validated using an orthogonal Reverse Phase Protein Array platform. Conclusions In this study, we used a systems biology approach by integrating genomic and proteomic data to identify key and common metastatic mechanisms in OS. The use of the topological analysis revealed hidden biological pathways that are known to play critical roles in metastasis. Wnt signaling has been previously implicated in OS and other tumors, and inhibitors of Wnt signaling pathways are available for clinical testing. Further characterization of this common pathway and other topological pathways identified from this study may lead to a novel therapeutic strategy for the treatment of metastatic OS.

  5. Analysis of common bean expressed sequence tags identifies sulfur metabolic pathways active in seed and sulfur-rich proteins highly expressed in the absence of phaseolin and major lectins

    Directory of Open Access Journals (Sweden)

    Sharpe Andrew

    2011-05-01

    Full Text Available Abstract Background A deficiency in phaseolin and phytohemagglutinin is associated with a near doubling of sulfur amino acid content in genetically related lines of common bean (Phaseolus vulgaris, particularly cysteine, elevated by 70%, and methionine, elevated by 10%. This mostly takes place at the expense of an abundant non-protein amino acid, S-methyl-cysteine. The deficiency in phaseolin and phytohemagglutinin is mainly compensated by increased levels of the 11S globulin legumin and residual lectins. Legumin, albumin-2, defensin and albumin-1 were previously identified as contributing to the increased sulfur amino acid content in the mutant line, on the basis of similarity to proteins from other legumes. Results Profiling of free amino acid in developing seeds of the BAT93 reference genotype revealed a biphasic accumulation of gamma-glutamyl-S-methyl-cysteine, the main soluble form of S-methyl-cysteine, with a lag phase occurring during storage protein accumulation. A collection of 30,147 expressed sequence tags (ESTs was generated from four developmental stages, corresponding to distinct phases of gamma-glutamyl-S-methyl-cysteine accumulation, and covering the transitions to reserve accumulation and dessication. Analysis of gene ontology categories indicated the occurrence of multiple sulfur metabolic pathways, including all enzymatic activities responsible for sulfate assimilation, de novo cysteine and methionine biosynthesis. Integration of genomic and proteomic data enabled the identification and isolation of cDNAs coding for legumin, albumin-2, defensin D1 and albumin-1A and -B induced in the absence of phaseolin and phytohemagglutinin. Their deduced amino acid sequences have a higher content of cysteine than methionine, providing an explanation for the preferential increase of cysteine in the mutant line. Conclusion The EST collection provides a foundation to further investigate sulfur metabolism and the differential accumulation of

  6. Delirium risk stratification in consecutive unselected admissions to acute medicine: validation of a susceptibility score based on factors identified externally in pooled data for use at entry to the acute care pathway.

    Science.gov (United States)

    Pendlebury, Sarah T; Lovett, Nicola G; Smith, Sarah C; Wharton, Rose; Rothwell, Peter M

    2017-03-01

    recognition of prevalent delirium and prediction of incident delirium may be difficult at first assessment. We therefore aimed to validate a pragmatic delirium susceptibility (for any, prevalent and incident delirium) score for use in front-line clinical practice in a consecutive cohort of older acute medicine patients. consecutive patients aged ≥65 years over two 8-week periods (2010-12) were screened prospectively for delirium using the Confusion Assessment Method (CAM), and delirium was diagnosed using the DSM IV criteria. The delirium susceptibility score was the sum of weighted risk factors derived using pooled data from UK-NICE guidelines: age >80 = 2, cognitive impairment (cognitive score below cut-off/dementia) = 2, severe illness (systemic inflammatory response syndrome) = 1, infection = 1, visual impairment = 1. Score reliability was determined by the area under the receiver operating curve (AUC). among 308 consecutive patients aged ≥65 years (mean age/SD = 81/8 years, 164 (54%) female), AUC was 0.78 (95% CI 0.71-0.84) for any delirium; 0.71 (0.64-0.79), for prevalent delirium; 0.81 (0.70-0.92), for incident delirium; odds ratios (ORs) for risk score 5-7 versus delirium, 8.1 (2.2-29.7), P = 0.002 for prevalent delirium, and 25.0 (3.0-208.9) P = 0.003 for incident delirium, with corresponding relative risks of 5.4, 4.7 and 13. Higher risk scores were associated with frailty markers, increased care needs and poor outcomes. the externally derived delirium susceptibility score reliably identified prevalent and incident delirium using clinical data routinely available at initial patient assessment and might therefore aid recognition of vulnerability in acute medical admissions early in the acute care pathway. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society.

  7. Academic provenance: Investigation of pathways that lead students into the geosciences

    Science.gov (United States)

    Houlton, Heather R.

    Pathways that lead students into the geosciences as a college major have not been fully explored in the current literature, despite the recent studies on the "geoscience pipeline model." Anecdotal evidence suggests low quality geoscience curriculum in K-12 education, lack of visibility of the discipline and lack of knowledge about geoscience careers contribute to low geoscience enrollments at universities. This study investigated the reasons why college students decided to major in the geosciences. Students' interests, experiences, motivations and desired future careers were examined to develop a pathway model. In addition, self-efficacy was used to inform pathway analyses, as it is an influential factor in academic major and career choice. These results and interpretations have strong implications for recruitment and retention in academia and industry. A semi-structured interview protocol was developed, which was informed by John Flanagan's critical incident theory. The responses to this interview were used to identify common experiences that diverse students shared for reasons they became geoscience majors. Researchers used self-efficacy theory by Alfred Bandura to assess students' pathways. Seventeen undergraduate geoscience majors from two U.S. Midwest research universities were sampled for cross-comparison and analysis. Qualitative analyses led to the development of six categorical steps for the geoscience pathway. The six pathway steps are: innate attributes/interest sources, pre-college critical incidents, college critical incidents, current/near future goals, expected career attributes and desired future careers. Although, how students traversed through each step was unique for individuals, similar patterns were identified between different populations in our participants: Natives, Immigrants and Refugees. In addition, critical incidents were found to act on behavior in two different ways: to support and confirm decision-making behavior (supportive critical

  8. Empresas de Base Cultural y Creativa: Identificación y Clasificación de sus Factores Críticos de Desempeño (Culture and creative based companies: identifying and classifying their critical performance factors

    Directory of Open Access Journals (Sweden)

    Paola Podestá

    2012-11-01

    Full Text Available El sector de las industrias culturales y creativas ha venido generando un interés creciente en la economía productiva; es por esto que la relación entre economía y cultura ocupa hoy un lugar predominante, especialmente por las altas inversiones que esta industria requiere, aunadas a las significativas ganancias que reporta. Este artículo es el resultado de un estudio realizado por la Universidad EAFIT sobre el mencionado sector, y responde a la necesidad de conocer mejor el emprendimiento en industrias que se caracterizan por conjugar la creatividad y la cultura. El estudio permitió identificar los factores críticos de desempeño que hacen que estas industrias sean viables y cumplan sus objetivos. Los resultados sirven como referente para desarrollar un marco conceptual y pedagógico dirigido, en principio, a la formación de profesionales en el campo de las empresas culturales y creativas, y se suma a los estudios que se han conducido y continúan haciéndose alrededor de este particular sector del emprendimiento empresarial.   ABSTRACT The culture and creative industry sector has generated a growing interest into productive economies; thus the relationship between economy and culture is highly regarded today due to the high investment required and the high yields resulting from this sector. This paper resulted from a research by the EAFIT university about this sector and answers the need to better known entrepreneurship in industries based in both creativity and culture. We were able to identify critical performance factors that made these industries viable and reach their goals. Results can be used to develop a conceptual and pedagogical frame to form professionals able to work in them, and also adds to previous and ongoing knowledge developed for this particular entrepreneurial sector.

  9. The Kynurenine Pathway in Stem Cell Biology

    Directory of Open Access Journals (Sweden)

    Simon P. Jones

    2013-01-01

    Full Text Available The kynurenine pathway (KP is the main catabolic pathway of the essential amino acid tryptophan. The KP has been identified to play a critical role in regulating immune responses in a variety of experimental settings. It is also known to be involved in several neuroinflammatory diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. This review considers the current understanding of the role of the KP in stem cell biology. Both of these fundamental areas of cell biology have independently been the focus of a burgeoning research interest in recent years. A systematic review of how the two interact has not yet been conducted. Several inflammatory and infectious diseases in which the KP has been implicated include those for which stem cell therapies are being actively explored at a clinical level. Therefore, it is highly relevant to consider the evidence showing that the KP influences stem cell biology and impacts the functional behavior of progenitor cells.

  10. The kynurenine pathway in stem cell biology.

    Science.gov (United States)

    Jones, Simon P; Guillemin, Gilles J; Brew, Bruce J

    2013-09-15

    The kynurenine pathway (KP) is the main catabolic pathway of the essential amino acid tryptophan. The KP has been identified to play a critical role in regulating immune responses in a variety of experimental settings. It is also known to be involved in several neuroinflammatory diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. This review considers the current understanding of the role of the KP in stem cell biology. Both of these fundamental areas of cell biology have independently been the focus of a burgeoning research interest in recent years. A systematic review of how the two interact has not yet been conducted. Several inflammatory and infectious diseases in which the KP has been implicated include those for which stem cell therapies are being actively explored at a clinical level. Therefore, it is highly relevant to consider the evidence showing that the KP influences stem cell biology and impacts the functional behavior of progenitor cells.

  11. Thinking Critically about Critical Thinking

    Science.gov (United States)

    Mulnix, Jennifer Wilson

    2012-01-01

    As a philosophy professor, one of my central goals is to teach students to think critically. However, one difficulty with determining whether critical thinking can be taught, or even measured, is that there is widespread disagreement over what critical thinking actually is. Here, I reflect on several conceptions of critical thinking, subjecting…

  12. Biological Pathways

    Science.gov (United States)

    Skip to main content Biological Pathways Fact Sheet Enter Search Term(s): Español Research Funding An Overview Bioinformatics Current Grants Education and Training Funding Extramural Research News Features ...

  13. Critical Hospitality Management Research

    OpenAIRE

    Morrison, A; Lynch, P; Lugosi, P

    2009-01-01

    This paper discusses the development of critical hospitality management research (CHMR) and explores key issues that such approaches raise. The paper is split into two parts. The first reviews contemporary writings that reflect the changing nature of hospitality management research and accounts for the emergence of a critical tradition. The second part identifies eight areas which are central concerns for the future development of CHMR: criticality, ethics and advocacy, scale, claims of legit...

  14. Defining critical thoughts.

    Science.gov (United States)

    Lovatt, Abbie

    2014-05-01

    Nursing education has long struggled to define critical thinking and explain how the process of critical thinking fits into the context of nursing. Despite this long time struggle, nurses and nurse educators continue to strive to foster critical thinking skills in nursing students as intuitively most nurses believe that critical thinking is necessary to function competently in the workplace. This article explores the most recent work of Dr. Stephen Brookfield and ties the concepts which are explored in Brookfield's work to nursing practice. Brookfield identifies that learners understand the meaning of critical thinking the best when the process is first demonstrated. Role modeling is a method educators can use to demonstrate critical thinking and is a strategy which nurses often use in the clinical area to train and mentor new nursing staff. Although it is not a new strategy in nursing education, it is a valuable strategy to engage learners in critical thinking activities. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Fuel Dependence of Benzene Pathways

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, H; Eddings, E; Sarofim, A; Westbrook, C

    2008-07-14

    The relative importance of formation pathways for benzene, an important precursor to soot formation, was determined from the simulation of 22 premixed flames for a wide range of equivalence ratios (1.0 to 3.06), fuels (C{sub 1}-C{sub 12}), and pressures (20 to 760 torr). The maximum benzene concentrations in 15 out of these flames were well reproduced within 30% of the experimental data. Fuel structural properties were found to be critical for benzene production. Cyclohexanes and C{sub 3} and C{sub 4} fuels were found to be among the most productive in benzene formation; and long-chain normal paraffins produce the least amount of benzene. Other properties, such as equivalence ratio and combustion temperatures, were also found to be important in determining the amount of benzene produced in flames. Reaction pathways for benzene formation were examined critically in four premixed flames of structurally different fuels of acetylene, n-decane, butadiene, and cyclohexane. Reactions involving precursors, such as C{sub 3} and C{sub 4} species, were examined. Combination reactions of C{sub 3} species were identified to be the major benzene formation routes with the exception of the cyclohexane flame, in which benzene is formed exclusively from cascading fuel dehydrogenation via cyclohexene and cyclohexadiene intermediates. Acetylene addition makes a minor contribution to benzene formation, except in the butadiene flame where C{sub 4}H{sub 5} radicals are produced directly from the fuel, and in the n-decane flame where C{sub 4}H{sub 5} radicals are produced from large alkyl radical decomposition and H atom abstraction from the resulting large olefins.

  16. Critical Care

    Science.gov (United States)

    Critical care helps people with life-threatening injuries and illnesses. It might treat problems such as complications from surgery, ... attention by a team of specially-trained health care providers. Critical care usually takes place in an ...

  17. Genome-wide expression studies of atherosclerosis: critical issues in methodology, analysis, interpretation of transcriptomics data

    NARCIS (Netherlands)

    Bijnens, A. P. J. J.; Lutgens, E.; Ayoubi, T.; Kuiper, J.; Horrevoets, A. J.; Daemen, M. J. A. P.

    2006-01-01

    During the past 6 years, gene expression profiling of atherosclerosis has been used to identify genes and pathways relevant in vascular (patho)physiology. This review discusses some critical issues in the methodology, analysis, and interpretation of the data of gene expression studies that have made

  18. Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility.

    LENUS (Irish Health Repository)

    O'Dushlaine, C

    2011-03-01

    Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P<0.05) to nonsignificant SNPs in a given pathway to identify the \\'enrichment\\' for association signals. We applied this approach to the discovery (the International Schizophrenia Consortium (n=6909)) and validation (Genetic Association Information Network (n=2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery sample. Nominally significant pathways were tested in the validation sample, and five pathways were found to be significant (P=0.03-0.001); only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (n=4847)) (P=0.01). At a gene level, CAM genes associated in all three samples (NRXN1 and CNTNAP2), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes.

  19. Understanding pathways of exposure using site-specific habits surveys, particularly new pathways and methodologies

    International Nuclear Information System (INIS)

    Grzechnik, M.; McTaggart, K.; Clyne, F.

    2006-01-01

    Full text of publication follows: UK policy on the control of radiation exposure via routine discharges from nuclear licensed sites has long been based on ICRP recommendations that embody the principles of justification of practices, optimisation of protection, and dose limitation. Radiological protection of the public is based on the concept of a critical group of individuals. This group is defined as those people who, as a result of the area they reside and their habits, receive the highest radiation dose due to the operations of a site. Therefore, if the dose to this critical group is acceptable in relation to relevant dose limits and constraints, then other members of the public will receive lower doses. Thus, the principle of critical groups provides overall protection for the public. Surveys to determine local habits involve an integrated methodology, whereby the potential radioactive exposure pathways from liquid and gaseous discharges and direct radiation from the site are investigated. Surveys to identify these habits must be undertaken rigorously for consistency, and have been known to reveal unexpected pathways of radiation exposure. Pathways typically include consumption of local foodstuffs and external exposure. Furthermore, a number of critical groups ma y be identified within a single survey area if the habits of one group do not adequately describe those of the other inhabitants of the area. Survey preparation involves the initial identification of high producers and consumers of local foods in a geographically defined area surrounding the nuclear facility. Pathways can be broken down into three general groups, which include exposure arising from; 1) Terrestrial (gaseous) discharges surveyed within 5 km of the site 2) Direct radiation surveyed within 1 km of the site 3) Aquatic (liquid) discharges surveyed within local areas affected by the discharges, including seas, rivers and sewage works. The survey fieldwork involves interviewing members of the

  20. Molecular pathways

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine Terra

    2014-01-01

    that 45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked; however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection...... of fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. Clin Cancer Res; 20(14); 3637-43. ©2014 AACR....